IMMUNOREGULATORY PEPTIDES

Abstract: Peptides and peptide derivatives, and method of using the same in mammalian immune systems to suppress autoimmune responses, organ transplantation rejection responses, or neoplastic cell growth. The peptides are characterized by the formula A-X-(B-Y)n-C wherein X and Y are residues of amino acids or amino acid derivatives with positively charged side chains, e.g., Lys, Orn, Arg, His, D-Lys, D-Orn, D-Arg, or D-His, or D-enantiomers of any of these residues, A and C are any substituents that preserve or augment the immunoregulatory activity of the peptides, B is a residue of an amino acid or amino acid derivative that preserves or augments the immunoregulatory activity of the peptide, and n is 0 or 1. The activity of the subject peptides includes suppression of the proliferation of T-lymphocytes in in vitro systems that are analogous to mammalian in vivo disease conditions, regulation of tumor cell proliferation in vitro and in vivo, and reduction of autoimmune disease-associated lesions in vivo. The peptides have potential human therapeutic benefits related to the treatment of autoimmune, organ or graft rejection, neoplastic and other diseases.

Description: IMMUNOREGULATORY PEPTIDES BACKGROUND OF THE INVENTION The mammalian immune system consists of a collection of cells and molecules which contribute to the defense of the host against foreign and other undesirable agents including infectious agents and cancer. The molecular portion of the immune system includes immunoglobulins, complement, histocompatibility anti¬ gens, and a variety of chemicals and peptide hormones which may either stimulate or inhibit the growth, development and activa- tion of portions of .the cellular immune system. The cellular immune system consists of white blood cells (leukocytes) and includes lymphocytes, monocytes, macrophages, neutrophils, eosinophils, basophils and mast cells, among others. Depending on the cell type, leukocytes may circulate in blood or other body fluids, or may be fixed in various lytnphoid organs including the thy us, bone marrow, lymph nodes and other organs. In order to provide an effective immune defense, the cellular and molecular immune systems must interact in a highly intricate and complex manner. Optimally, the immune defense re- sponse should be precisely balanced to provide sufficent destruc¬ tive force to eliminate infectious or foreign agents or cancer cells without unnecessarily destroying healthy cells. A subop- timal immune response may result in uncontrolled growth of an infectious agent or cancer which may lead to the death of the host. A excessive immune response, by contrast, may destroy not only the intended target, but substantial quantities of surround¬ ing healthy tissue as well. The many molecules of the molecular immune system play a major role in regulating and "fine tuning" the cellular immune response to maximize destruction of infecti¬ ous agents and cancer cells while minimizing destruction of surrounding healthy cells. There are many diseases which are believed to occur be¬ cause of a regulatory imbalance in the immune system. Autoimmune diseases are an example of conditions in which a substantial por¬ tion of an immune response is directed toward healthy host cells. The causes for- such misdirection of immune responsive¬ ness are unknown for many diseases. " Under normal conditions, the immune system exhibits tolerance toward cells of the host which prevents the immune system from attacking normal, healthy cells. It is this critical ability of the immune system to distinguish "self" from foreign cells and molecules that provides selectivity of an immune system attack. In autoimmune diseases, tolerance for host cells and molecules is reduced or eliminated resulting in significant destruction of otherwise healthy cells and organs. The tendency of a host's immune system to display reduced tolerance to normal cells is strongly influenced by cell surface molecules whose genes are associated with the host's major histocompatibility complex (MHC) . A particular MHC haplo- type may substantially increase the risk of self-tolerance loss and subsequent autoimmunity. In certain autoimmune diseases, infection by certain viruses or bacteria is believed to trigger the loss of self-tolerance which, in the setting of an appropri¬ ate MHC haplotype, results in an autoimmune disease. In other autoimmune diseases the triggering events which lead to a loss of self-tolerance remain unknown. Autoimmune diseases may affect every organ of the body. Examples of diseases thought to have an autoimmune pathogenesis include, but are not limited to, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, ankylosing spondylitis, Reiter's syndrome, Sjogren's syndrome, polymyositis-dermatomyosi tis, thrombocytopenic purpura, autoimmune hemolytic anemia, ulcerative colitis, regional enteritis (Crohn's disease), chroni active hepatitis, primary biliary cirrhosis, idiopathic intersti tial pulmonary fibrosis, Goodpasture's syndrome, postviral encephalomyelitis, Guillain-Barre syndrome, myasthenia gravis, Grave's disease, Hashimoto's thyroiditis, juvenile onset insulin dependent diabetes, Addison's disease, pernicious anemia, pemphigus, bullous pemphigoid and other diseases and conditions. The immune response responsible for the rejection of transplanted organs among genetically non-identical animals or humans in many ways resembles an autoimmune disease in that an otherwise healthy transplanted organ may be destroyed by the recipient's immune system. Such destruction occurs because the recipient's immune system recognizes the "foreign" histocom- patibility antigens present on cells of the transplanted organ and trigger a destructive immune response. The complex regulation of immune responsiveness results from interactions between all classes of leukocytes, molecules secreted by leukocytes and cells and molecules from other organ systems. One class of leukocytes in particular, termed thymus- derived lymphocytes or T-lymphocytes (T cells) is considered to be critically important to the coordination and regulation of most immune responses. T cells may be divided into various sub¬ sets which have distinct immune functions. Helper T cells, for example, are critical for the growth and development of B cells into antibody-secreting plasma cells. Helper T cells are also critical for the growth and development of other T cell subsets such as Killer T cells which can directly destroy infectious agents, cancer cells, transplanted organs and, in autoimmune disease, healthy cells. By contrast, other T cell subsets terme suppressor T cells actively suppress the growth and development of B cells. Killer T cells and other lymphoid cells. Suppressor T cells are also critical for the development and maintenance of immune tolerance that prevents the development of autoimmune disease and organ transplantation rejection. Because T cells have a powerful influence on the induc- tion or suppression of the immune responses that lead to auto- immunity and organ transplantation rejection, pharmacologic agents which regulate T cell functions may provide significant therapeutic benefit in the treatment of human or animal disease. Thymulin and Thymic Hormone-Related Peptides Researchers have reported peptides that exhibit effects on the immune system, including effects relating to T-lymphocyte differentiation. In 1976, Bach et al. isolated and identified from porcine thy us the nonapeptide Serum Thymic Factor (FTS), now known as thymulin, having the sequence Glx-Ala-Lys-Ser-Gln- Gly-Gly-Ser-Asn (where "Glx" is either glutamine or pyroglutamic acid). (Bach, C. R. Acad. Sc. Paris, t. 283 (Nov. 29, 1976), Series D-1605; Nature 266:55 (March 3, 1977).) Thymulin has been shown to have hormonal properties related to the promotion, of T- lymphocyte differentiation which include the induction of various antigenic markers on murine and human T-lymphocyte precursors, the delaying of allogeneic skin graft rejection in mice, enhance¬ ment of the generation of alloantigen reactive cytotoxic T- lymphocytes in thymectomized mice, modulation of thymic natural killer (NK) cell activity in tumor-bearing and NZB mice, inhibi¬ tion of antibody-bearing lymphocyte production at late stages of differentiation, and suppression of Experimental Allergic Encephalomyelitis in guniea pigs. (Kaiserlian et al., Cellular Immunology 64:93 (1981); Kaiserlian et al., Cellular Immunology 66:360 (1982); Bardos et al., Clin. Im un. and Immunopath. 23:570 (1982); Kaiserlian et al., Clin. Immun. and Immunopath. 28:192 (1983); Immunology Today 4:16 (1983); Lenfant et al., Immunology 48:635 (1983); Nagai et al., J. Exp. Med. (Japan) 52(4) :213 (1982).) Goldstein et al. have reported in U.S. Patent Nos. 4,215,112 and 4,232,008 that both T-lymphocyte and B-lymphocyte differentiation, as measured by antigen marker induction, may be induced with tripeptides and longer peptides containing the sequence ys-X-Gln, where X is chosen from specified amino acid residues. The sequence of these peptides resembles that of part of the thymulin molecule, but no determination of the mechanism of activity of the peptides is stated. Imaizumi et al. concluded in 1981 that the pentapeptide portion Lys-Ser-Gln-Gly-Gly is the minimum essential part of the thymulin molecule which retains full theta-antigen induction capability for T-lymphocyte pre- . cursors. (Imaizumi et al., FEBS Letters, 128:108 (1981).) Later studies found that other thymulin segments, namely Glu-Ala-Lys- Ser-Gln and Glu-Ala-Lys-Ser, act as antagonists to thymulin activity. (Gyotoku et al.. Int. J. Peptide Protein Res. 21:135 (1983).) Goldstein et al. have described polypeptides which mimic the ability of the thymic hormones thymopoeitin and splenin to induce the differentiation of T-lymphocytes and/or B-lymphocytes. U.S. Patent No. 4,190,646 discloses the pentapeptide Arg-Lys-Asp- Val-Tyr and certain derivatives capable of inducing the differen¬ tiation of bone marrow cells to T-lymphocytes. The dipeptide Gln-Lys and certain derivatives thereof are reported in U.S. Patent No. 4,215,111 to be capable of inducing dif erentiation of both T- and B-lymphocytes. Other pentapeptides capable of induc¬ ing T- and/or B-lymphocyte differentiation are described in U.S. Patent Nos. 4,261,886 and 4,505,853. A family of tetra- and pentapeptides which promote the differentiation of T-lymphocytes was described by Konig et al. i U.S. Patent No. 4,487,764. These peptides are composed of basic and aromatic amino acids in the sequence Basic-Basic-Aromatic- Aromatic-Optional. Tuftsin and Related Peptides The tetrapeptide tuftsin, isolated by Najjar and descri- ' bed in U.S. Patent No. 3,778,426, has the sequence Thr-Lys-Pro- Arg. Tuftsin has been shown to stimulate iτ_ vitro phagocytosis by granulocytes, monocytes and macrophages. Other studies have shown tuftsin to be active in nanomolar concentrations in many species including humans, cows, dogs, rabbits, guinea pigs and mice. In addition to its phagocytosis stimulating properties, tuftsin has been shown to stimulate such immune response func- 0 tions as antibody-dependent cell-mediated cytotoxicity (ADCC) and Natural Killer cell activity in mouse splenic cells, anti-bacter¬ ial activity of PMN-leukocytes and tissue macrophages, antigen- specific macrophage-dependent T-lymphocyte education and antibody synthesis to T-lymphocyte-dependent and- independent antigens i_n 15 vivo and i_n vitro. Fridkin et al., Molecular and Cellular Bio¬ chemistry 41:73 (1981); Najjar et al., in Pick (ed.), Lymphokine Reports (Academic Press 1980), p. 157; Nishioka, Life Sciences 28:1081 (1981). A number of active analogs of tuftsin have been identified, as well as inhibitors for tuftsin such as Lys-Pro- __0 Arg, Ala-Lys-Pro-Arg and Ser-Lys-Pro-Arg. Peptide analogs which inhi/it the immunostimulatory activity of tuftsin do not, however, reduce the basal phagocytic activity of the cells. (Najjar, Annals New York Academy of Sciences (1982), p. 1; Najja et al., in Pick (ed.), Lymphokine Reports (Academic Press 1980), 25 p. 157.) This suggests that immunosupp ession could only be achieved via a mechanism distinct from that associated with tuftsin or its structural analogs. Rigin, a tetrapeptide analog of tuftsin having the peptide sequence Gly-Gln-Pro-Arg, has been shown to have 8 phagocytosis-stimulating properties similar to those of tuftsin. (Veretennikova et al.. Int. J. Peptide Protein Res., 17:430 (1981); U.S. Patent No. 4,353,823.) SUMMARY OF THE INVENTION It has been discovered that a number of very short pep¬ tides and peptide derivatives, including certain single-aminoaci derivatives, have a surprising ability to regulate T cell func¬ tions, and in particular to suppress T cell proliferation, and provide thereby potentially significant therapeutic benefits in the treatment of human or animal disease. Moreover, the peptide are capable of suppressing the growth of various neoplastic cells. Due to their short length, these peptides are relatively easy and inexpensive to manufacture. In addition, they are effective at non-toxic pharmacological dosage levels. Accordingly, it is one object of the present invention to provide new peptides with important biological and pharmaco¬ logical activities, as well as related and novel methods for using these peptides in suppressing the mammalian immune system in vitro and i_n vivo. A further object of the invention is co provide new peptides and methods related to the therapeutic treatment of mammalian autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, and other diseases. A further object of the invention is to provide new peptides and methods related to the therapeutic treatment of diseases involving a deficient, excessive or otherwise malfunc¬ tioning mammalian immune system response, including such condi¬ tions as organ transplantation rejection and bone marrow trans lantation re ection. A still further object of the invention is to provide new peptides and methods related to the treatment of neoplastic diseases. Other objects and advantages of the invention will become apparent from an examination of the present disclosure The peptides of the present invention are characte¬ rized by the formula I wherein X and Y are residues of amino acids or amino acid derivatives with positively charged side chains. preferably lysine,* ornithine, arginine, or histidine, or D-enantiomers of any of these residues; A and C are any substituents , including amino acid residues, that serve to preserve or augment the immunoregulatory activity of the peptide; B is a residue of an amino acid or amino acid derivative that preserves or augments the immunoregulatory activity of the peptide; and n is 0 or 1. Thus, the peptides of the present invention can be characterized either by formula A-X-C (la) or by formula A-X-B-Y-C (lb). Compounds of formula la are preferred. Most preferably, in la, X will be chosen from among the amino acids lysine, ornithine, D-lysine and D-ornithine; in lb, X will be most preferably lysine, arginine, histidine or ornithine, while Y will most preferably be lysine, arginine or histidine. A may be, for example, hydrogen or an N-acetyl, N-acyl, N-aliphatic, or N-aromatic group; or A may be an amino acid such as alanine, glycine, leucine, valine, phenylalanine, tyrosine, asparagine, aspartic acid, sarcosine, glutamine, glutamic acid, serine, or threonine, or an amino acid derivative including D-enantiomers of these amino acids, such as D-alanine or D-aspartic acid. B may be, for example, a residue of an amino acid such as valine, leucine, glutamic acid, glutamine, serine, threonine, glycine, alanine, proline, asparagine, aspartic acid, arginine, histidine, isoleucine, tyrosine, phenyl¬ alanine, lysine, ornithine, or tryptophan, or of a • D-enantiomer or other derivative of an amino acid, such as D-valine or D-serine. C preferably will be a small uncharged chemical constituent, for example -NH„, -NHR or -OR, where R is preferably H or a lower alkyl; or C may be a residue of an amino acid such as glycine, alanine, leucine, valine, serine, cysteine, sarcosine, threonine, proline, glutamine, phenylalanine, tyrosine, ho oserine or a D-enantiomer or other derivative of an amino acid. It wil be apparent from the following disclosure that significant immunoregulatory activity will be achieved for a large number of diverse substituents in the A, B and C positions, so long as the constituents X and Y are as defined above. Thus, f.e., in lb,' immunoregulatory activity may be retained where either or both of the terminal groups A and C comprise multiple amino acids that do not interfere substantially with the immuno¬ regulatory activity associated with the central tripeptide sequence X-B-Y. Accordingly, the present invention speci¬ fically contemplates that derivatives, including homologs, analogs, enantiomers, extensions, or other substitutions not specifically disclosed herein are within the scope and spirit of the present invention. DETAILED DESCRIPTION QF THE INVENTION In the following discussion, ' the amino acid components of immunoregulatory peptides are frequently identified with abbreviations for convenience. Unless otherwise specified, the following abbreviations designate L-enantiomeric forms of the amino acids, as follows: Amino Acid Abbreviation glycine Gly L-alanine Ala L-valine Val L-leucine Leu L-isoleucine He L-proline Pro L-methionine Met L-cysteine Cys L-phenylalanine Phe L-tyrosine • Tyr L-tryptophan Trp L-histidine His L-lysine Lys L-arginine Arg L-aspartic acid Asp L-asparagine Asn L-glutamic acid Glu L-glutamine Gin L-serine Ser L-threonine Thr L-ornithine Orn sarcosine Sar L-homoserine HomoSer In addition, the following abbreviations for chemica substitutes are used: Substituent Abbreviation N α -substituted amino acid N-R-(amino acid) M α -acylated amino acid RCO-(amino acid) N -acetyl amino acid Ac-(amino acid) N α -methyl amino acid N-Me-(amino acid) des-c -amino acid desamino-(amino acid) Amino acid amide (Amino acid)-NH 2 , -NHR, -NR Amino acid ester (Amino acid)-0R- 13 As used herein, the term "amino acid derivative" refers to homologs, analogs, D-enantiomers, and chemically substituted or otherwise modified forms of amino acids such as those listed above. As will be seen from the following description of the invention, it has been shown that a wide range of derivatives ma be substituted for naturally-occurring amino acids in the pep¬ tides of the present invention while still preserving or augmen¬ ting immunoregulatory activity. For example, chemical substitu¬ tion of acyl, alkyl, and other substituents at the N-terminus, o formation of esters or amides at the C-terminus, will frequently yield peptide derivatives with preserved or augmented immunoregu latory activity. Furthermore, the present invention contemplates that certain amino acids within the disclosed peptides may be substi- " tuted by amino acids which are chemically similar by virtue of similar side chain size, charge, -shape, solubility, or other chemical characteristics while still retaining the peptide's immunoregulatory activity. Amino acids with such chemical similarity are termed "functionally conserved." Functional classes of the common genetically-coded amino acids have been specified by Dayhoff, et al. in Atlas of Protein Sequence and Structure, volume 5 (National Biomedical Research Foundation, 1972), page 98. Derivatives of the naturally-occurring amino acids, such as ornithine, homoserine, homolysine, des-N α -amino lysine and homoarginine, have chemical structures and properties comparable to their naturally-occurring analogs or homologs, and 14 thus may, in proper cases, be substituted in the peptides of th present invention to preserve or even increase immunoregulatory activity. One aspect of the immunoregulatory activity of the subject peptides resides in the capability of the peptides to suppress autoimmune responses, to suppress organ transplantatio rejection responses, or to suppress neoplastic cell growth. As will be discussed below, such immunoregulatory activity may be realized in ijn vitro systems that are modeled after iτ_ vivo mammalian disease conditions, as well as in iji vivo systems. The immunoregulatory peptides of the present invention are characterized by the formula wherein X and Y are residues of amino acids or amino acid deriva¬ tives with positively charged side chains at physiological pH (i.e., pH 6 to 8) or D-enantiomers of any of these residues; A and C are amino acid residues or other sub- stituents, that preserve or augment the immunoregulatory activity of the peptide; B is a residue of an amino acid or amino acid derivative that preserves or augments the immunoregulatory activity of the peptide; and n is 0 or 1. Thus, in la, X may be chosen from among residues of such naturally-occurring positively charged amino acids as Lys, Arg and His. In addition, however, it has been discovered that residues of positively charged amino acids other than those naturally-occurring acids listed above may be used successfully in the X position. For example, sub¬ stitution of the D-enantiomeric form of the amino acid X will, in some cases, augment, and, in many cases, substantially preserve the immunoregulatory activity. of the subject peptide. As another example, residues of desamino forms of the central amino acid X, wherein the N -f .-amino group of X is absent, may preserve or augment the immunoregulatory activity of the peptide. Other amino acid derivatives, including homologs, analogs, enantiomers and otherwise modified forms of naturally occurring positively charged amino acids, can also be .expected yield significant immunoregulatory activity. As an example, ornithine, which is closely homologous to lysine, demonstrates significant activity despite the fact the ornithine does not occur naturally in proteins or in other molecular constituents the immune system. Especially preferred for X are Lys and Orn. The D-enantiomeric form of these amino acids (D-Lys, D-Orn) as well as the dea inated forms (desamino-Lys, desamino-Orn) may be substituted for the naturally occurring L-enantiomer in proper cases, with the result that immunoregulatory activity or the peptide is substantially preserved or augmented . In lb, the structure of the three central constituents of the subject polypeptides is of central importance. In its simplest from, lb countenances a tripeptide of the form X-B-Y wherein X and Y are any positively-charged amino acids separate by any single amino acid, B, which tripeptide has immunoregula¬ tory activity. In this form of the present invention; terminal constituent A is hydrogen and terminal constituent C is a hydroxyl group. X and Y may be the same or different positivel charged amino acids, preferably chosen from among Lys, Arg, His and Orn. J ' Lys and Arg are particularly preferred in the X and Y positions. Thus, the following tripeptide sequences are particularly preferred in the present invention: Lys-B-Lys Arg-B-Arg Lys-B-Arg Arg-B-Lys In addition to the tripeptide sequences given above, immunoregulatory activity may be achieved through the use of His or Orn in the X or Y positions. His or Orn may be substituted in the X position, while His is preferred in the Y position. In addition to the common forms of the amino acids di cussed above, the present invention contemplates that modified homologous, analogous or artificial forms of positively charge amino acids may be utilized in the X and Y positions of lb. Thus, D-enantiomeric forms of positively charged amino acids may, in appropriate combination with other constituents of the subject polypeptides, substantially preserve or augment the immunoregu tory activity of the peptide. Constituent B comprises the residue of any aminό acid or amino acid derivative which preserves or augments the immunoregulatory activity of the sub ect • polypeptides. It has been discovered that a very broad range of amino acids may be incorporated into the B po¬ sition to yield polypeptides with significant immuno¬ regulatory activity. Preferably, B will be chosen from among the residues of the following amino acids or their D-enantiomers: Val, Leu, Glu, Gin, Ser, Thr, Gly, Ala, Pro, Asn, Asp, Arg, His, He, Tyr, Phe, Lys, Orn, Trp. Most preferably, B will be chosen from among the following amino acids or their D-enantiomers: Val, Leu, Glu, Gin, Ser, Thr, Gly, Ala. As discussed above, the B position amino acids listed are preferably used in conjunction with the positive¬ ly charged amino acids Lys or Arg in the X und Y positions. In peptides in which both X and Y are Lys, the amino acids Val, Glu and Gin are especially preferred in the B position, When both X and Y are Arg, Asp and Ser are highly active substituents in the B position. Ser and Thr are examples of suitable B substituents when X is Lys and Y is Arg, while G.ly , Ala, Ser and Thr are all active when X is Arg and Y is Lys. The terminal constituent A, which is substituted at the N -position of X, may be chosen from a number of chemical groups or substituents. For example, terminal constituent A may be hydrogen (H-) alone, yielding a peptide of the general formula X-(B-Y) -C. As another example, constituent A may be an N^acetyl sub- stituent, thus yielding a peptide of the general formula . Ac-X-(B-Y) -C. n Other substituents in the A position that may preserve or augment immunoregulatory activity include aliphatic and aromatic acyl substituents of the form RC0-, as well as substituents of the form R-, where R is prefer¬ ably an unbranched or branched alkyl group of one to eight carbons, and may also be C-,-C R alkenyl, C 2 -C R alkynyl, C 6~ C 14 aryl > C 7 _C 14 alkar y 1 ' c 7 - C 14 aralkyl, or C 3 -C 14 cycloalkyl. Furthermore, constituent A may be an amino acid. Ala and D-Ala are especially preferred amino acids for constituent A. Also preferred as amino acids for terminal constituent A are the following: Gly, Leu, Val, Phe, Tyr, 5 Asn, Asp, Sar, Gin, Glu, Ser and Thr as well as the D-enan¬ tiomers of these amino acids. In addition to single amino acid substitutions in the A terminal position, substitutions of more than one amino acid have been shown to yield active polypeptides, ■ _r, particularly of formula lb. In particular, A terminal constituents of the form Val-Asp-, Gly-Asp-, Ala-Asp-, Ser-Asp-, Thr-Val-Asp- and Leu-Thr-Val-Asp- have been successfully used in the A position. Thus, it is believed that the immunoregulatory activity of the present poly- 15 peptides may be preserved with a large number of diverse substituents, including sequences containing multiple amino acids, in the A position as well as in the C terminal position. It will be apparent to those skilled in the art that 20 modifications, additions, deletions, or substitution to the chemical groups named above as A terminal constituents may preserve activity without departing from the spirit of the invention described herein. Terminal constituent C also may be chosen from a 25 number of chemical groups or substituents which preserve or augment the immunoregulatory activity of the subject peptides. In general, it is preferred that C be a relati¬ vely small, uncharged species (including a hydroxyl -(-OH) group )• Furthermore, amidation, esterification and addition of one or more amino acids is possible in the terminal group C. For example, one preferred em¬ bodiment of C is of the form -NHR wherein R is hydrogen or a lower alkyl, such as C,-C fl alkyl substituent. As an example of the latter, wherein R is ethyl, and where X is Lys and A is hydrogen, Lys-NHCH ^ CH, is representative. Other substituents in " the £ terminal position may preserve or augment immunoregulatory activity,, most preferably relatively small and uncharged species. Thus, R groups such as C 2 -Cg alkenyl, C 2 -Cg alkynyl, C 8 -C 14 aryl, C -C-^^ alkaryl, C 7 -C aralkyl and C ~C 14 cycloalkyl may be utilized in c terminal substituents of the form -NHR or -OR to yield amides and esters respectively. Secondary amino groups of the form -NR 2 may also be expected to yield active peptide amides. Particularly significant immunoregulatory activity may be obtained by using lower alkyl R groups in the polypeptide amides described above. lower alkyl groups are particu¬ larly preferred. In particular, significant activity has been obtained in tripeptide amides of the form Lys-B-Lys-NH 2 wherein B is Val, Leu, Pro, Glu, Gin or Gly. Contrarily, amidation where the B position amino acid is Asp, Ala, Thr, Arg, or His yields peptides with lower, although still significant, immunoregulatory activity. Amino acids and derivatives thereof may also be used a C terminal constituents. In general, it is particularly preferred that such amino acids have relatively small, uncharge side chains. Thus, Ser, Gly, Ala, Leu, Val and Gys, are particularly preferred as C- terminal constituents. Ser has been shown to yield a particularly high immunoregulatory activity, particularly in the combination Lys-Ser. Gly and Ala are especially preferred in the combinations Orn-Gly, Lys-Gly and Orn-Ala. As with the examples discussed above with respect to amino acid constituents at the A and . X positions, the D-enantiomeric form of amino acids in the C cerminal position demonstrate significant immunoregulatory activity. The combination Orn-D-Ala is especially preferred. Although amino acids having relatively small, uncharg side chains are particularly preferred as C constituents in th present invention, significant immunoregulatory activity is al achieved using amino acids with relatively larger uncharged si chains as C terminal constituents. Also preferred, therefore, C terminal constituents are the following amino acids, as well their D-enantiomers: Thr, Pro, Gin, Phe, Tyr. O ther amino acids, or derivatives thereof, including homologs, analogs, enantio ers, or combinations thereof, as wel as other non-amino acid chemical constituents, may likewise be incorporated into the C terminal position to substantially preserve or augment the immunoregulatory activity of the subjec peptides. For example, HomoSer and Sar respectively, may be utilized successfully in the present invention as C terminal constituents. In addition, amides or esters of C terminal amino acids may be so used. The peptide Lys-Ser-NH ^ is parti- - cularly preferred. Furthermore, combinations or sequences of amino acids which substantially preserve or augment. the immunoregulatory activity of the subject peptides may be incorporated as C terminal constituents. It is believed that it is within the skill of the applicable art to identify and utilize as C terminal constituents those chemical substituents, including amino acids and their derivatives, that substantially preserve or augment the immunoregulatory activity of the subject peptides, and which are not disclosed specifical herein. It is apparent from the foregoing discussion that a peptide of the present invention may incorporate one, two, thre or more amino acids. In its simplest form, the present inventi contemplates a single, positively charged amino acid (the centr amino acid, X) flanked by non-amino acid terminal constituents and C. Certain of these "monopeptides" demonstrate extremely high immunoregulatory activity. Particularly preferred are lo alkyl amides of Lys, Orn, D-Lys and D-Orn. Thus, the following monopeptides are particularly preferred: Lys-NH 2 Lys-NHCH 2 CH 3 D-Lys-NH 2 D-Lys-NHCH 3 D-Lys-NHCH 2 CH 3 Orn-NH 2 Orn-NHCH 3 Orn-NHCH 2 CH 3 D-Orn-NH 2 D-Orn-NHCH 3 D-Orn-NHCH 2 CH 3 The present invention countenances a large number of highly active dipeptides. Many of these are characterized by A terminal constituent that comprises a non-amino acid specie and a C terminal constituent that comprises an amino acid or homolog, analog, or other derivative thereof. In particular, is particularly preferred that the C terminal constituent be Ser, Lys, Ala or Cys, and that the central amino acid X be Lys or Orn. The A terminal constituent is preferably hydrogen (H-) or an acetyl group. In addition, the C terminal constituent may be amidated to form a lower alkyl amide. Thus, dipeptides of the following general form are particularly preferred: X-C X-C-NH-, X-C-NHCH 3 X-C-NHCH 2 CH 3 Ac-X-C Ac-X-C-NH 2 Ac-X-C-NHCH 3 Ac-X-C-NHCH 2 CH 3 wherein C is preferably Ser, Gly, Ala, or Cys, and X is preferably Lys or Orn. The combinations Lys-Ser, Lys-Gly, Lys-Ser-NH 2 , Orn-Gly and Orn-Ala are especial preferred. The use of D-enantiomeric forms of amino acids in the and C positions has been shown, to substantially preserve or augment immunoregulatory activity in a number of cases. Particularly preferred D-enantiomeric substitutions include, in the central amino acid X position, D-lysine_ and D-ornithine, an in the C terminal position, D-alanine. D-Lys-Ser and Orn-D-Ala have been shown to have particularly high immunoregulatory activity. 25 In addition to the foregoing class of dipeptides, in which the A terminal constituent is not an amino acid, the present invention contemplates that class of dipeptides charac terized by an amino acid A terminal constituent in conjunction with a non-amino acid C terminal constituent. In general, for la, preferred that the C terminal constituent be a group other tha hydroxyl group (-OH), although dipeptides such as Asp-Lys and Ser-Lys, in which C is a hydroxyl group, have been shown to exhibit immunoregulatory activity. A c terminal substituent o the form -NHR, wherein R is preferably hydrogen or a lower alk accompanied by an A-position amino acid as discussed below, wi yield a dipeptide amide of the central positively charged amin acid X. Amides of this central amino acid have been shown to have particularly significant immunoregulatory activity. Particularly preferred as A terminal amino acids are Ala, Gly, Val, Phe, Tyr, Asp and Sar, as well as the D-enan¬ tiomers of these amino acids. Ala is especially preferred as an A terminal constituent in peptides of the form Ala-X-C wherein X is preferably Lys, D-Lys, Orn, or D-Orn, and C is preferably Gly, Ala, D-Ala, or Ser. In addition the use of D-Ala as an A terminal constituent is preferred, yielding, f.e. a peptide of the form D-Ala-X-C, wherein X and C are preferably as defined immediately above. Modifications of the C terminal constituent, as for example, by amidation to a lower alkyl amide, may also yield peptides having potent immunoregulating activity. Other modifications to the constituents of the subject peptides will be recognized by those skilled in the art and can readily be synthesized, tested and utilized within the scope of the present invention as described herein. Specifically preferred are peptides of formulae laa to lam, lama to lamz and Ian to lat which correspond to formula la, but wherein in laa: X is a residue of an amino acid or amino acid derivative with a positively charged side chain; A is H, R, RCO, or a residue of an amino acid or amino acid derivative; C is NH 2 , NHR, NR-,, OR, or a residue of an amino acid or amino acid amide or ester formed by sub¬ stitution of an amino acid with a substituent of the form NH 2 , NHR, NR 2 , or OR; and R is a C,-C fl aliphatic, C--C, . aryl . aralkyl or alkaryl, or C,-C, . cycloalkyl; in lab: X is a residue of an amino acid or amino acid derivative with a positively charged side chain; A is H, acetyl, Ala, Gly, Val, Phe, Tyr, Asp, Sar, Ser, Thr, D-Ala, D-Val, D-Phe, D-Tyr, D-Asp, D-Ser or D-Thr; and C is any chemical substituent, residue of an amino acid or amino acid derivative that preserves the immuno¬ regulatory activity of said peptide; in- lac: X is a residue of an amino acid or amino acid derivative with a positively charged side chain; A is any chemical substituent, residue of an amino acid or amino acid derivative that preserves the immuno¬ regulatory activity of said peptide; and C is NH 2 , NHR, OR, Gly, Ala, Ser, Cys, Sar, Thr, Pro, Gin, Phe, Tyr, Ho oSer, D-Ala, D-Ser, D-Cys, D-Thr, D-Pro, D-Gln, D-Phe, D-Tyr,' D-HomoSer, or a residue of an amino aci ' d amide or ester formed by substitution of one of the foregoing amino acids with a substituent of the form NH 2 , NHR or OR ' , where .R is a C- ^ -Cg alkyl; in lad: X is a residue of an amino acid or amino acid derivative with a positively charged side chain; A is H, R, RCO, Ala, Gly, Val, Phe, Tyr, Asp, Sar, Ser, Thr, D-Ala, D-Val, D-Phe, D-Tyr, D-Asp, D-Ser or D-Thr; C is NH 2 , NHR, OR, Gly, Ala, Ser, Cys, Sar, Thr, Pro, Gin, Phe, Tyr, HomoSer, D-Ala, D-Ser, D-Cys, D-Thr, D-Pro, D-Gln, D-Phe, D-Tyr, D-HomoSer, or a residue of an amino acid amide or est er formed by substitution of one of the foregoing amino acids with a substituent of the form NH 2 , NHR, or OR; and R is a C* | _- C 8 all< y**-; in Iae: X is a residue of an amino acid or amino acid derivative with a positively charged side chain; A is H, acetyl, Ala, and D-Ala; and C is NHR, Gly, Ala, Ser, D-Ala, D-Ser, Gly-NHR, Ala-NHR, Ser-NHR, D-Ala-NHR, or D-Ser-NHR, where R is a C- ^ -Cg alkyl; in Iaf: X is Lys, Orn, Arg, His, D-Lys, D-Orn, D-Arg, or D-His; A is any chemical substituent, residue of an amino acid or amino acid derivative that preserves the immunoregulatory activity of said peptide; and C is any chemical substituent, residue of an a ' mino acid or amino acid derivative that preserves the immunoregulatory activity of said peptide; In lag: X is Lys, Orn, Arg, His, D-Lys, D-Orn, D-Art or D-His; A is H, R, RCO, a residue of an amino acid or an amino acid derivative; C is NH 2 , NHR, NR 2> -OR, or a residue of an amino acid or amino acid amide or ester formed by sub¬ stitution of an amino acid with a substituent of the form NH 2 , NHR, NR 2 , or OR; and R is a C,-C-. aliphatic, C,-C, . aryl, aralkyl or alkaryl, or C,-C, . cycloalkyl; in Iah: X is Lys, Orn, Arg, His, D-Lys, D-Orn, D-Arg, or D-His; A is H, R, RCO, Ala, Gly, Val, Phe, Tyr, Asp, Sar, Ser, Thr, D-Ala, D-Val, D-Phe, D-Tyr, D-Asp, D-Ser and D-Thr; C is NH 2 , NHR, OR, Gly, Ala, Ser, Cys, Sar, Thr, Pro, Gin, Phe, Tyr, HomoSer, D-Gly, D-Ala, D-Ser, D-Cys, D-Ser, D-Thr, D-Pro, D-Gln, D-Phe, D-Tyr, D-HomoSer, or a residue of an amino acid amide and or ester formed by substitution of one of the foregoing amino acids with a substituent of the form NH«, NHR, or OR; and R is a C,-C fl lower al yl; in Iai: X is Lys,. Orn, Arg, His, D-Lys, D-Orn, D-Arg, or D-His; A is H, acetyl, Ala, or D-Ala; and C is NHR, Gly, Ala, Ser, D-Ala, D-Ser, Gly-NHR, Ala-NHR, Ser-NHR, D-Ala-NHR, or D-Ser-NHR, where R is a C λ - Q alkyl; in Iaj: X is Lys, Orn, D-Lys or D-Orn; A is any chemical substituent, residue of an amino acid, or amino acid derivative that preserves the immunoregulatory activity of said peptide; and C is any chemical substituent, residue of an amino acid, or amino acid derivative that preserves the immunoregulatory activity of said peptide; in Iak: X is Lys, Orn, D-Lys or D-Orn; A is H, R, RCO, or a residue of an amino acid or amino acid derivative; C is NH 2 , NHR, NR 2 , OR, or a residue of an amino acid or amino acid amide or ester formed by substitution of an amino acid with a substituent of the form NH 2 , NHR, NR 2 , or OR; and R is a ^-Cg aliphatic, C 6 ~C 14 aryl, aralkyl or alkaryl, or C-.-C, . cycloalkyl; in Ial: X is Lys, Orn, D-Lys or D-Orn; A is H, R, RCO, Ala, Gly, Val, Phe, Tyr, Asp, Sar, Ser, Thr, D-Ala, D-Val, D-Phe, D-Tyr, D-Asp, D-Ser or D-Thr; and C is H 2 , NHR, Gly, Ala, Ser, Cys, Sar, Thr, Pro, Gin, Phe, Tyr, HomoSer, D-Ala, D-Ser, D-Cys, D-Thr, D-Pro, D-Gln, D-Phe, D-Tyr, D-HomoSer, or a residue of an amino acid amide or ester formed by substitution of one of the foregoing amino acids with a substituent of the form NH 2 , NHR, or OR; and R is a CI _C B alkyl; in lam: X is Lys, Orn, D-Lys or D-Orn; A is H, acetyl, Ala, or D-Ala; and C is NHR, Gly, Ala, Ser, D-Ala, D-Ser, Gly-NHR, Ala-NHR, Ser-NHR, D-Ala-NHR, or D-Ser-NHR, where R is C-L-Cg alkyl; in lama: X is Lys or D-Lys; A is H; and C is -NHR,where R is H, methyl or ethyl; in Iamb: X is Orn or D-Orn, A is H; and C is NHR, where R is H, methyl or ethyl; in lame: X is Lys; A is H or acetyl; and C is Gly or Gly-NHR, where R is H, methyl or ethyl; in Iamd: X is Lys; A is Ala; and C is Gly or Gly-NHR, where R is- H, methyl or ethyl; in lame: X is D-Lys; A is H or acetyl; and C is Gly or Gly-NHR, where R is H, methyl or ethyl; in Iamf: X is Orn; A is H or acetyl; and C is Gly or Gly-NHR, where R is H, methyl or ethyl; in Iamg: X is D-Orn; A is H or acetyl; and C is Gly or Gly-NHR, where R is H, methyl or ethyl; in Iamh: X is Lys; A is H or acetyl; and C is Ala or Ala-NHR, where R is H, methyl or ethyl; in Iami: X is D-Lys; A is H or acetyl; and C is Ala or Ala-NHR, where R is H, methyl or ethyl ; in Iamj: X is Lys; A is H or acetyl; and C is D-Ala or D-Ala-NHR, where R is H, methyl or ethyl; in Iamk: X is D-Lys; A is H or acetyl; and C is D-Ala or D-Ala-NHR, where R is H, methyl or ethyl; in Iaml: X is Orn; A is H or acetyl; and C is Ala or Ala-NHR, where R is H, methyl or ethyl ; in Iamm: Y is D-Orn; A is H or- acetyl; and C is Ala or Ala-NHR, where R is H, methyl or ethyl; in Ia π: X is Orn; A is H or acetyl; and C is D-Ala or D-Ala-NHR, where R is H, methyl or ethyl; in I amo : X i s D-Orn ; A is H or acetyl; and C is D-Ala or D-NHR, where R is H, methyl or ethyl ; in lamp: X is Lys; A is H or acetyl; and C is Ser or Ser-NHR, where R is H, ethyl or ethyl ; in Iamq: X is D-Lys; A is H or acetyl; and C is Ser or Ser-NHR, where R is H, methyl or ethyl ; in Iamr: X is Lys; A is H or acetyl; and C is D-Ser or D-Ser-NHR, where R is H, methyl or ethyl; in lams: X is D-Lys; A is H or acetyl; and C is D-Ser or D-Ser-NHR, where R is H, methyl or ethyl; in Iamt: X is Orn; A is H or acetyl; and C is Ser or Ser-NHR, where R is H, methyl or ethyl; in Iamu: X is D-Orn; A is H or acety; and C is Ser or Ser-NHR, where R is H, methyl or ethyl ; in lav: X is Orn; A is H or acetyl; and C is D-Ser or D-Ser-NHR, where R is H, methyl or ethyl; in Iamw: X is D-Orn; A is H or acetyl; and C is D-Ser or D-Ser-NHR, where R is H, methyl or ethyl; in Iamx: X is Lys or D-Lys; A is Ala or D-Ala; and C is Gly; in Iamy: X is Lys or D-Lys A is Ala or D-Ala and C is Ala or D-Ala in lamz: X is Lys or D-Lys A is Ala or D-Ala; and C is Ser or D-Ser in Ian: X is a residue of an amino acid or amino acid derivative with a positively charged side chain; A is Ala, Val, Tyr, Asp, Sar, Ser, Thr, D-Ala, D-Val, D-Phe, D-Tyr, D-Asp, D-Ser or D-Thr; C is Cys, Sar, Thr, HomoSer, D-Ala, D-Ser, D-Cys, D-Thr, D-Pro, D-Gln, D-Phe, D-Tyr, D-HomoSer, or a residue of an amino acid amide or ester formed by substitution of one of the foregoing amino acids with a substituent of the form NH_, NHR or OR; and R is a C,-C 8 aliphatic, C.-C, . aryl, aralkyl or alkaryl, or C- j -C, . cycloalkyl; in Iao: X is Lys, Orn, Arg, His, D-Lys, D-Orn, D-Arg, or D-His; A is Ala, Val, Tyr, Asp, Sar, Ser, Thr, D-Ala, D-Val, D-Phe, D-Tyr, D-Asp, D-Ser or D-Thr; C is Cys, Sar, Thr, HomoSer, or a residue of an amino acid amide or ester formed by substitution of one of the foregoing amino acids with a substituent of the form NH 2 , NHR or OR; and R is a C,-C-. aliphatic, C--C, . aryl, aralkyl or alkaryl, or C,-C, . cycloalkyl; in lap: X is-Lys or D-Lys; A is R, RCO, Ala, Gly, Val, Phe, Tyr, Asp, Sar, Ser, Thr, D-Ala, D-Val, D-Phe, D-Tyr, D-Asp, D-Ser, or D-Thr; C is NH 2 , NHR, OR, Gly, Ala, Ser, Cys, Sar, Thr, Pro, Gin, Phe, Tyr, HomoSer, D-Ala, D-Ser, D-Cys, D-Thr, D-Pro, D-Gln, D-Phe, D-Tyr, D-HomoSer, or a residue of an amino acid amide or ester formed by substitution of one of the foregoing amino acids with a substituent of the form NH„, NHR or OR; and R is a C,-Cg lower alkyl; in Iaq: X is Lys or D-Lys; A is acetyl, Ala or D-Ala; and C is NH 2 , NHR, Gly, Ala, Ser, D-Ala, D-Ser, Gly-NHR, Ala-NHR, Ser-NHR, D-Ala-NHR, or D-Ser-NHR, where R is a C,-C 8 alkyl; in Iar: X is Orn or D-Orn; A is H, R, RCO, Ala, Gly, Val, Phe, Tyr, Asp, Sar, Ser, Thr, D-Ala, D-Val, D-Phe, D-Tyr, D-Asp, D-Ser or D-Thr; C is NH 2 , NHR, NR 2 , OR, or a residue of an amino acid or amino acid amide or ester formed by substitution of an amino acid with a substituent of the form NH 2 , NHR, NR 2 , or OR; R is a C,-C Q aliphatic, C,-C, . aryl, aralkyl or alkaryl, or C,-C, . cycloalkyl; provided that Orn-Ala and 0rn-NH 2 are not included; in las: X is Orn or D-Orn; A is H, R, RCO, Ala, Gly, Val, Phe, Tyr, Asp, Sar, D-Ala, D-Val, D-Phe, D-Tyr or D-Asp; and C is H 2 , NHR, Gly, Ala, Ser, Cys, Sar, Thr, Pro, Gin, Phe, Tyr, HomoSer, D-Ala, D-Ser, D-Cys, D-Thr, D-Pro, D-Gln, D-Phe, D-Tyr, D-HomoSer, or a residue of an amino acid amide or ester formed by substitution of one of the foregoing amino acids with a substituent of the form NH 2 , NHR or OR; R is a C ^ -Cg alkyl; provided that Orn-Ala and 0rn-NH„ are not included; in l at : X is Orn or D-Orn ; A is H, acetyl, Ala or D-Ala; and C is NH 2 , NHR, Gly, Ala,. Ser, D-Ala, D-Ser, Gly-NHR, Ala-NHR, Ser-NHR, D-Ala-NHR or D-Ser-NHR, wehre R is a C,-C R alkyl; provided that Orn-Ala and Orn-NH 2 are not included. Specifically preferred are, furthermore, peptides of formulae Iba to Ibz and Ibza to Ibzo which correspond to formula lb but wherein in Iba: X and Y are residues of amino acids or amino acid derivatives with positively charged side chains; A is H, R, RCO, amino acids, and amino acid derivatives formed by N -sυbstitution of an amino acid with a substituent of the form R or RCO; B is a residue of an amino acid or amino acid derivative that preserves the immunoregulatory activity of said peptide; C is OH, NH 2 , NHR, NR 2> OR, or a residue of an amino acid or amino acid amide or ester formed by substitution of an amino acid with a substituent of the form NH 2 , NHR, NR 2 , or OR; and R is a C,-Cg aliphatic, C,-C, . aryl, aralkyl or alkaryl, or C,-C, . cycloalkyl; in Ibb: X and Y are residues of amino acids or amino acid derivatives with positively charged side chains; A is H, R, RCO, or a residue of any amino acid or amino acid derivative that preserves the immunoregu¬ latory activity of said peptide; B is a residue of an amino acid or amino acid derivative that preserves the immunoregulatory activity of said peptide; C is OH, NH 2 , NHR, NR 2 , OR, or a residue of an amino acid or amino acid derivative that preserves the immunoregulatory activity of said peptide; and R is a C,-C R aliphatic, C,-C, . aryl, aralkyl or alkaryl, or C,-C, . cycloalkyl; in Ibc: X and Y. are each residues of amino acids or amino acid derivatives with positively charged side chains ; A is H, R, RCO, Asp, Gly, Ala, Val, Leu, Asn, Glu, Ser, Thr, D-Asp, D-Ala, D-Val, D-Leu, D-Asn, D-Glu, D-Ser, D-Thr, or a residue of a derivative of one of the foregoing amino acids formed by N—— substi¬ tution with a substituent of the form R or RCO; B is Val, Leu, Glu, Gin, Ser, Thr, Gly, Ala, Pro, Asn, Asp, Arg, His, lie, Tyr, Phe, Lys, Orn, Trp, or a residue of a D-enantiomer o_f one of the foregoing amino acids; C is OH, NH-,, NHR, NR 2> OR, Gly, Ser, Ala, Val, Leu, D-Ser, D-Ala, D-Val, D-Leu, or a residue of an amino acid amide or ester formed by substitution of one of the foregoing amino acids with a substituent of the form NH 2 , NHR, NR £ , or OR; and R is a C,-Cg aliphatic, C.-C, . aryl, aralkyl or alkaryl, or C,-C, . cycloalkyl; in Ibd: X and Y are each residues of amino acids or amino acid derivatives with positively charged side chains ; A is H, R, RCO, Asp, Gly, Ala, Val, Leu, Asn, Glu, Ser, Thr, D-Asp or a residue of a derivative of *_t < one of the foregoing amino acids formed by N - substitu¬ tion with a substituent of the form R or- RCO; B is Val, Leu, Glu, Gin, Ser, Thr, Gly, Ala, Pro, Asn, Asp, Arg, H-is, lie, Tyr, Phe, Lys, ' Orn, Trp, D-Val, D-Ser, or D-Ala; C is OH, NH 2 , NHR, Gly, or Ser; and R is a C,- Cg alkyl; in Ibe: X and Y are each Lys, Arg, His, Orn, D-Lys, D-Arg, D-His, or D-Orn; A is a chemical substituent, residue of an amino acid or amino acid derivative, or sequence of amino acids or amino acid derivatives, that preserves the immuno¬ regulatory activity of said peptide; B is a residue of an amino acid or amino acid derivative that preserves the immunoregulatory activity of said peptide; and C is a chemical substituent, residue of an amino acid or amino acid derivative, or sequence of amino acids or amino acid derivatives, that preserves the immunoregulatory activity of said peptide; in Ibf: X an Y are each Lys, Arg, His, Orn, D-Lys, D-Arg, D-His, or D-Orn; A is H, R, RCO, or a residue of an amino acid or amino acid derivative formed by N^-substitution of an amino acid with a substituent of the form R or RCO; B is a residue of an amino acid or amino acid derivative that preserves the immunoregulatory activity " of said peptide; C is OH, NH 2 , NHR, NR 2 , OR,or a residue of an amino acid or amino acid amide or ester formed by sub¬ stitution of an amino acid with a substituent of the form NH 2 , NHR, NR 2 , or OR; and R is a C,-C-. aliphatic, C,-C, , aryl, aralkyl or alkaryl, or C,-C, . cycloalkyl; in Ibg: X and Y are each Lys, Arg, His, Orn, D-Lys, D-Arg, D-His, or D-Orn; A is H, R, RCO, or a residue of amino acid or amino acid derivative that preserves the immunoregulatory activity of said peptide; B is a residue of an amino acid or amino acid derivative that preserves the immunoregulatory activity of said peptide; C is OH, NH 2 , NHR, NR 2 , OR, or a residue of an amino acid or amino acid derivative that preserves the immunoregulatory activity of said peptide; and R is a C,-Cg aliphatic, C,-C-^ aryl, aralkyl or alkaryl, or C-.-C, . cycloalkyl; in Ibh: X and Y are each Lys, Arg, His, Orn, D-Lys, D-Arg, D-His, or D-Orn; A is H, R, RCO, Asp, Gly, Ala, Val, Leu, Asn, Glu, Ser, Thr, D-Asp, D-Ala, D-Val, D-Leu, D-Asn, D-Glu, D-Ser, D-Thr, or a residue of a derivative of one of the foregoing amino acids formed by N "-sub¬ stitution with a substituent of the form R or RCO; B is Val, Leu, Glu, Gin, Ser, Thr, Gly, Ala, Pro, Asn, Asp, Arg, His, lie, Tyr, Phe, Lys, Orn, Trp," or a residue of one of the D-enantiomers of the fore¬ going amino acids; C is OH, NH 2 , NHR, NR 2 , OR, Gly, ' Ser, Ala, Val, Leu, D-Ser, D-Ala, D-Val, D-Leu, or a residue of an amino acid amide or ester formed by substitution of one of the foregoing amino acids with a substituent of the form NH 2 , NHR, NR 2 , or OR; and R is a C,-C_ aliphatic, C,-C, . aryl, aralkyl or alkaryl, or C,-C, . cycloalkyl; in Ibi: X and Y are each Lys, Arg, His, Orn, D-Lys, D-Arg, D-His, or D-Orn; A is H, R, RCO, Asp, Gly, Ala, Val, Leu, Asn, Glu, Ser, Thr, D-Asp or a residue of a derivative of one of the foregoing amino acids formed by N -substitution with a substituent of the form R or RCO; B is Val, Leu, Glu, Gin, Ser, Thr, Gly, Ala, Pro, Asn, Asp, Arg, His, lie, Tyr, Phe, Lys, Orn, Trp, D-Val, D-Ser, or D-Ala; C is OH, NH 2 , NHR, Gly or Ser; and R is a t-^-Cg alkyl; • in Ibj: X and Y are each Lys, Arg, His, or Orn; A is a chemical substituent, a residue of an amino acid or amino acid derivative, or sequence of amino acids or amino acid derivatives, that preserves the immunoregulatory activity of said peptide; B is a residue of an amino acid or amino acid derivative that preserves the immunoregulatory activity of said peptide; and C is a chemical substituent, a residue of an amino acid or amino acid derivative, or sequence of amino acids or amino acid derivatives, that preserves the immunoregulatory activity of said peptide; in Ibk: X and Y are each Lys, Arg, His, or Orn; A is H, R, RCO, or a residue of an amino acid or amino acid derivative formed by N -substitution of an amino acid with a substituent of the form R or RCO; B is a residue of an amino acid or amino acid derivative that preserves the immunoregulatory activity of said peptide; C is OH, NH 2 , NHR, NR 2 , OR, or a residue of an amino acid or amino acid amide or ester formed by substitution of an amino acid with a substituent of the form NH ? , NHR, R 2 , or OR; and R is a C j -Cg aliphatic, Cg-C, . aryl, aralkyl or alkaryl, or cycloalkyl; in Ibl: X and Y are each Lys, Arg, His, or Orn; A is hydrogen, R, RCO, or a residue of amino acid or amino acid derivative that preserves the immunoregulatory activity of said peptide; B is a residue of an amino acid or amino acid derivative that preserves the immunoregulatory activity of said peptide; C is OH, NH 2 , NHR, NR 2 , OR, or a residue of an amino acid or amino acid derivative that preserves the immunoregulatory activity of said peptide; and R is a C,-C_ aliphatic, C..-C, . aryl, aralkyl or alkaryl, or 0-,-C, . cycloalkyl; in Ibm: X and Y are each Lys, Arg, His, or Orn; A is H, R, RCO, Asp, Gly, Ala, Val, Leu, Asn, Glu, Ser, Thr, D-Asp, D-Ala, D-Val, D-Leu, D-Asn, D-Glu, D-Ser, D-Thr, or a residue of a derivative of one of the foregoing amino acids formed by N -substitution with a substituent of the form R or RCO; B is Val, Leu, Glu, Gin, Ser, Thr, Gly, Ala, Pro, Asn, Asp, Arg, His, lie, Thr, Phe, Lys, Orn, Trp, or a residue of a D-enantiomer of one of the foregoing amino acids; C is OH, NH 2 , NHR, NR 2 , OR, Gly, Ser, Ala, Val, Leu, D-Gly, D-Ser, D-Ala, D-Leu, or a residue of an amino acid amide or ester formed by substitution of one of the fore¬ going amino acids with a substituent of the form NH„, NHR, NR 2 , or OR; and R is a C,-Cg aliphatic, C--C, . aryl, aralkyl or alkaryl, or C,-C, . cycloalkyl; in Ibn: X and Y are each Lys, Arg, His, or Orn; A is H, R, RCO, Asp, Gly, Ala, Val, Leu, Asn, Glu, Ser, Thr, D-Asp or a residue of a derivative of one of the foregoing amino acids formed by N -substitution with a substituent of the form R or RCO; B is Val,- Leu, Glu, Gin, Ser, .Thr*, Gly, " Ala, Pro, Asn, Asp, Arg, His, lie, Tyr, Phe, Lys, Orn, Trp, D-Val, D-Ser, or D-Ala; t . C is OH, NH 2 , NHR, Gly or Ser; and R is a C,-Cg alkyl; in Ibo: X is Lys, Arg, His, or Orn; Y is Lys, Arg, or His; A is Ac, Gly, Ala, Val, Asp, Asn, Glu, Arg, Ser, Thr, D-Asp, Ac-Asn, Val-Asp-, Gly-Asp-, Ala-Asp-, Ser-Asp-, Thr-Val-Asp-, or Leu-Thr-Val-Asp- ; B is Val, Ser, Thr, Gly, Ala, Asp, Lys, or D-Ser; and C is OH, or NHR, where R is H or C,-Cg alkyl; in Ibp: X and Y are each Lys; A is H; B is Val, Leu, Glu, Gin, Ser, Thr, Gly, Ala, Pro, Asn, Asp, Arg, His, lie, Tyr, Phe, Lys, Orn, D-Ala, or D-Ser; and C is OH. in Ibq: X and Y are each Lys; A is H; B is Val, Leu, Glu, Gin, Ser, Gly, Pro, Tyr, Phe, Lys, Trp, or D-Val; and C is NHR, where R is H or a C,-Cg alkyl; in Ibr: X is Lys; Y is Arg; A is H, B is Ser, Thr, Gly, or Ala; and C is OH or NHR, where R is hydrogen or a C--C-. alkyl ; in lbs: X is Arg; Y is Lys ; A is H; B is Val, Ser, Thr, Gly, or Ala; and C is OH or NHR, where R is H or a C- ^ -Cg alkyl; in Ibt: X is Arg; Y is Lys; A is H; B is Asp or Ser; C is OH or NHR, where R is H or a alkyl; in Ibu : X i s Lys ; Y is Lys or Arg ; A is Gly, Ala, Ser, Thr, Val, or Ac-Asn; B is Val; and C is OH or NHR, where R is H or a C^-Cg alkyl; in Ibv: X is Lys, y is Lys or Arg; A is Ala, Val, Ser, Thr, or Ac-Asn; B is Thr; and C is OH or NHR, where R is H or a C^g alkyl; in Ibw: X is Lys; Y is Lys or Arg; A is Ac-, Ala, Asn, Glu, Gly, Arg, Ac-Asn, Gly-Asp-, Ala-Asp-, Val-Asp-, Ser-Asp-, or Thr-Val-Asp- ; B is Ser; and C is OH or NHR, where R is H or a C,-Cg alkyl; in Ibx: X and Y are residues of amino acids or amino acid derivatives with positively charged side chains; A is H, R, RCO, a residue of an amino acid or _ amino acid derivative formed by N -substitution of an amino acid with a substituent of the form R or RCO, provided, that A is not Thr if X is Lys and Y is Arg or a derivative of Arg; B is Val, Leu, Gin, Ser, Thr, Gly, Ala, Asp, Arg, His, He, Tyr, Phe, Lys, Sar, D-Thr, or D-Pro; C is OH, NH 2 , NHR, NR 2 , OR, Gly, Ser, Ala, Val, Leu, D-Ser, D-Ala, D-Val, D-Leu, or a residue of an amino acid amide or ester formed by substitution of one of the foregoing amino acids with a sub¬ stituent of the form NH 2 , NHR, NR 2 , or OR; and R is a C, -Cg aliphatic, C^-C- I A aryl, aralkyl or alkaryl, or a C,-C, . cycloalkyl; in Iby: X and Y are residues of amino acids or amino acid derivatives with positively charged side chains: A is H, R, RCO, a residue of an amino acid or amino acid derivative formed by N^-substitution of an amino acid with a substituent of the form R or RCO; B is Glu, Asn, Orn, Trp, D-Val, D-Ser, D-Ala, D-Leu, D-Glu, D-Gln, D-Ala, D-Asn, D-Asp, D-Arg, D-His, , D-Ile " , D-Tyr, D-Phe, D-Lys, D-Orn, D-Trp, or a residue of a derivative of one of the foregoing amino acids; C is OH, NH-,, NHR, NR 2 , OR,Gly, Ser, Ala, Val, Leu, D-Ser, D-Ala, D-Val, D-Leu, or a residue of an amino acid amide or ester formed by substitution of one of the foregoing amino acids with a substituent of the form NH 2 , NHR, R 2 , or OR; and R is a C-i-Cg aliphatic, C,-C,^ aryl-, aralkyl or alkaryl, or a C 3 -C,. cycloalkyl; in Ibz: X and Y are residues of amino acids or amino acid derivatives with positively charged side chains; A is H, R, RCO, Asp, Gly, Ala, Val, Leu, Asn, Glu, Ser, D-Asp or a residue of a derivative of one of the foregoing amino acids formed by Nr ^ -substitution with a substituent of the form R or RCO; B is Val, Leu, Glu, Gin, Ser, Thr, Gly, Ala, Asp, Arg, His, He, Tyr, Phe, Lys, Orn, Trp, D-Val, D-Ser, or D-Ala; C is OH, NH 2 , NHR, Gly or Ser; and R is a 0,-Cg alkyl ; in I bza: X and Y are each Lys, Arg, His, Orn, D-Lys, D-Arg, D-His or D-Orn; A is H, R, RCO, a residue of an amino acid or amino acid derivative formed by N -substitution of- an amino acid with a substituent of the form R or RCO, provided that A is not Thr if X is Lys and Y is Arg or a derivative of Arg; B is Val, Leu, Gin, Ser, Thr, Gly, Ala, Asp, Arg, His, He, Tyr, Phe, Lys, Sar, D-Thr, or D-Pro; C is OH, NH 2 , NHR, NR 2 , OR, Gly, Ser, Ala, Val, Leu, D-Ser, D-Ala, D-Val, D-Leu, or a residue of an amino acid amide or ester formed by substitution of one of the foregoing amino acids with a substituent of the form NH 2 , NHR, NR 2 , or OR; and R is a C,-C R aliphatic, C--C, . aryl, aralkyl or alkaryl, or a C,-C, . cycloalkyl; in Ibzb:X and Y are each Lys, Arg, His, Orn, D-Lys, D-Arg, D-His or D-Orn; A is H, R, RCO, a residue of an *amino acid or amino acid derivative formed by N -substitution of an amino acid with a substituent of the form R or RCO; B is Glu, Asn, Orn, Trp, D-Val, D-Ser, D-Ala, D-Leu, D-Glu, D-Gln, D-Ala, D-Asn, D-Asp, D-Arg, D-His, Dτlle, D-Tyr, D-Phe, D-Lys, D-Orn, D-Trp, or a residue of a derivative of one of the foregoing amino acids; C is OH, NH 2 , NHR, NR 2 , OR, Gly, Ser, Ala, Val, Leu, D-Ser, D-Ala, D-Val, D-Leu, or a residue of an amino acid amide or ester formed by substitution of one of the foregoing amino acids with a substituent of the form NH 2 , NHR, NR £ , or OR; and R is a C,- C R aliphatic, C--C,. aryl, aralkyl or alkaryl, or a 0,-C,^ cycloalkyl; in Ibzc: X and Y are each. Lys, Arg, His, Orn, D-Lys, D * -Arg, D-His, or D-Orn ' ; A is H, R, RCO, Asp, Gly, Ala, Val, Leu, Asn, Glu Ser, D-Asp or a residue of a derivative of one of the foregoing amino acids formed by N -substitution with a substituent of the form R or RCO; B is Val, Leu, Glu, Gin, Ser, Thr, Gly, Ala, Asn, Asp, Arg, His, He, Tyr, Phe, Lys, Orn, Trp, D-Val, D-Ser, or D-Ala; C is OH, NH 2 , NHR, Gly or Ser; and R is a C--C Q alkyl; 1 o in Ibzd: X and Y are each Lys, Arg, His, or Orn; A is H, R, RCO, a residue of an amino acid or amino acid derivative formed by N -substitution of an amino acid with a substituent of the form R or RCO, provided that A is not Thr if X is Lys and Y is Arg or a derivative of Arg; B is V al , Le u , Gin , Ser , Thr , Gly , Ala , Asp , Ar g , His , He , Tyr , Phe , Lys , Sar , D- Thr , or D-Pro ; C is OH, NH 2 , NHR, NR £ , OR, Gly, Ser, Ala, Val, Leu, D-Ser, D-Ala, D-Val, D-Leu, or a residue of an amino acid amide or ester formed by substitution of one of the foregoing amino acids with a substituent of the form NH ? , NR 2 , or OR; and R is a C.-C R aliphatic, C.-C- . aryl, aralkyl or alkaryl, or a 0,-C, . cycloalkyl; in Ibze: X and Y are each Lys, Arg, His, or Orn; A is H, R, RCO, a residue of an amino acid or amino acid derivative formed by N -substitution of an amino acid with a substituent of the form R or RCO; B is Glu, Asn, Orn, Trp, D-Val, D-Ser, D-Ala., D-Leu, D-Glu, D-Gln, D-Ala, D-Asn, D-Asp, D-Arg, D-His, D-Ile, D-Tyr, D-Phe, D-Lys, D-Orn, D-Trp, or a residue of a derivative of one of the foregoing amino acids; C is OH, NH 2 , NHR, NR 2 , OR, Gly, Ser, Ala, Val, Leu, D-Ser, D-Ala, D-Val, D-Leu, or a residue of an amino acid amide or ester formed by substitution of one of the foregoing amino acids with a substituent of the form NH 2 , NHR, NR 2 , or OR; and R is a C,-Cg aliphatic, C--C aryl, aralkyl or alkaryl, or a C,-C,^ cycloalkyl; in Ibzf: X and Y are each Lys, Arg, His, or Orn; A is H, R, RCO, Asp, Gly, Ala, Val, Leu, Asn, Glu, Ser, D-Asp or a residue of a derivative of one of the foregoing amino acids formed by N -substitution with a substituent of the form R or RCO; B is Val, Leu, Glu, Gin, Ser, Thr, Gly, Ala, Asn, Asp, Arg, His, He, Tyr, Phe, Lys, Orn, Trp, D-Val, D-Ser, or D-Ala; C is OH, NH 2 , NHR, Gly or Ser; and R is a C 2 -Cg alkyl; in Ibzg: X is Lys, Arg, His, or Orn; Y is Lys, Arg, or His; A is Ac, Gly, Ala, Val, Asp, Asn, Glu, Arg, Ser, Thr, D-Asp, Ac-Asn, Val-Asp-, Gly-Asp-, Ala-Asp-, Ser-Asp-, Thr-Val-Asp-, or Leu-Thr-Val-Asp- ; B is Val, Ser, Thr, Gly, Ala, Asp, Lys, or D-Ser; and C is OH, or NHR, where R is H or alkyl ; C 1 "C 3 in Ibzh: X and Y are each Lys; A is H; B is Val, Leu, Glu, Gin, Ser, Thr, Ala, Asn, Arp, Arg, His, He, Tyr, Phe, Lys, Orn, D-Ala, or D-Ser; and C is OH; in Ibzi: X and Y are each Lys; A is H; B is Val, Leu, Glu, Gin, Ser, Gly, Pro, Tyr, Phe, Lys, Trp, or D-Val; and C is NHR, where R is H or a C,-C 3 alkyl; in Ibz : X is Lys ; Y is Arg; A is H; B is Ser, Thr, Gly, or Ala; and C is OH or NHR, where R is H or a C^-C.- alkyl; in Ibzk : X is Arg ; Y is Lys; A is H; B is Val, Ser, Thr, Gly or Ala; and C is OH or NHR, where R is hydrogen or a C,-C lower alkyl; in Ibzl:X is Arg; Y is Lys; B is Asp or Ser; C is OH or NHR, where R is hydrogen or a C.-C, alkyl ; in Ibzm:X is Lys; Y is Lys or Arg; A is Gly, Ala, Ser, Val, or Ac-Asn; B is Val; and C is OH or NHR, where R is hydrogen or a C,-C 3 alkyl; in Ibzn: X is Lys; Y is Lys or Arg; A is Ala, Val, Ser, or Ac-Asn; B is Thr; and C is OH or NHR, where R is H or a C.-C, alkyl; in Ibzo: X is Lys; Y is Lys or Arg; A is Ac, Ala, Asn, Glu, Gly, Arg, Ac-Asn, Gly-Asp-, Ala-Asp-, Val-Asp-, Ser-Asp-, or Thr-Val-Asp- ; B is Ser; and C is OH or NHR, where R is H or a C 2 -C 3 alkyl. The peptides of formula I can be prepared by usual methods of peptide synthesis. In particular, a peptide of formula I is prepared by liberating it from its corresponding functional derivative which may be bound by a covalent bond to a solid resin by treatment under acidic or basic conditions, and, if desired, the peptide thus obtained is esterified, amidated and/or acylated to yield a corresponding ester, N- and/or O-acyl derivative or is transformed into one of its pharmacologically acceptable salts by treatment with a base or an 'acid. Immunoregulatory Activity of the Subject Peptides As discussed above, T-lymphocytes (T cells) play a powerful role in the rn vivo induction, suppression, and regula¬ tion of immune responses leading to a number of autoimmune and other disease conditions. In order to examine the effect of peptides or other drugs on T cell function, i_n vitro assays have been developed which are predictive of in vivo T cell function. In the usual in vitro assays of T cell function, lymphoid cells from peripheral blood or from the spleen, lymph nodes or other organs are isolated and cultured with or without potential ' immunoregulatory drugs. The,extent to which lymphocyte function in general and T cell function in particular are regulated may b assessed by many measurement techniques. The most common techni que measures the amount of a radioactive precursor of DNA (tri i ated thymidine) incorporated into newly synthesized DNA of lymphocytes. Since only "activated" cells that are preparing to divide synthesize new DNA, the amount of tritiated thymidine in ¬ corporated in cells and the resultant incorporated radioactivity is directly related to the extent of cell activation and resultant proliferation. In order to predict whether a potential immunoregulatory drug will be useful in treating a particular disease or class of diseases, it is important that it be tested in in vitro or in vivo system that are reflective of the particular disease or diseases in question. Several in vitro assays of T cell function in particular are highly predictive of In vivo efficacy in treating organ transplantation rejection and autoimmune disease. The mixed lymphocyte response (MLR) is an iτ_ vitro analog of the i_n vivo organ transplantation rejection response. To perform the MLR, T cell-containing lymphocyte preparations from two humans or animals are cultured together for five to seven days under standard cell culture conditions. During the culture, T cells from both subjects recognize histocompatibility • molecules of the other subject. If both subjects are genetically identical, their histocompatiblity molecules will also be identi¬ cal and no activation or cell proliferation will occur. The radioactivity incorporated into cells will therefore be very low since few cells are stimulated to divide. By contrast, if both subjects are genetically non-identical,- both subjects' cells will recognize the foreign histocompatibility molecules of the other and will divide and proliferate. The level of cellular radioac¬ tivity will therefore be increased over that of control, unstimu- lated cultures and will be directly proportional to the magnitude of the genetic difference between the two subjects. This assay is termed a two-way MLR since each subject's cells respond to the other's proliferative stimuli. If one of the subject's cells is prevented from dividing by, for example, exposure to gamma ir- radiation or raitomycin C, then the observed proliferation and incorporated radioactivity will be due only to the other sub¬ ject's cellular proliferation. This assay is termed a one-way MLR. During a MLR, some of the proliferating T cells differ¬ entiate into T cells able to kill the target cells which produced- the initial stimulus. These sensitized cytotoxic or Killer T cells are primarily directed toward the target cell's histocom¬ patibility molecules and produce T cell-mediated destruction which closely resembles the destruction which occurs during organ transplantation rejection. If T cells from a transplant recipi¬ ent are sensitized to the histocompatibility antigens of a trans¬ planted organ mi vitro and then injected into the recipient, the sensitized T cells will cause the organ to be rejected. Sensi- tized T cells alone are therefore both necessary and sufficient to cause organ transplant rejection. As demonstrated in Table 1, the peptides of the present invention can substantially suppress the MLR without significantly affecting cell viability. This indicates that such peptides have therapeutic usefulness since they can suppress the immune response responsible for the irrununo- logic rejection of transplanted organs and autoimmune diseases. It should be noted that suppression of T cell activities in vitro by peptides of the present invention is but one manifes¬ tation of the complex immunoregulation which occurs i_n vitro and _in vivo and which leads to reduction or prevention of autoimmune disease or of the rejection of transplanted organs. For example, while the peptides of the present invention can suppress a MLR at concentrations listed in table 1, lower peptide concentrations typically result in stimulation of tritiated thymidine uptake which is reflective of the peptides' ability to activate certa immunoregulatory processes. Administration of the subject peptides to animals, for example, can in certain cases result in stimulation of certain lymphocyte subsets, which can in turn lead to net suppression o a clinical disease or condition. It is thus entirely within th scope of the peptides of the present invention that certain immunostimulatory properties, in addition to the suppressive properties described herein, will be expressed in alternate in vitro and ύi vivo tests of the subject peptides. The MLR is a specific example of a more general T cell response toward "foreign" antigens. In a MLR, T ' cells recogniz and proliferate in response primarily to antigens located on histocompatibility molecules of the stimulator .cells. Molecule unrelated to histocompatibility antigens may also serve as pote stimulators of T cell proliferative and killing responses. In fact virtually any molecule, if presented to T cells in an appropriate manner, may stimulate T cell proliferative, regula¬ tory and killing responses directed toward the stimulating antigen. Such antigen-specific T cell responses in humans are thought to be responsible for many of the autoimmune diseases listed earlier when immune tolerance is reduced or lost. Specific in vitro assays exist which can measure a T cell response directed toward any specific antigen. In particular, the therapeutic and immunoregulatory utility of the peptides of the present invention is further demonstrated by an antigen-specific T cell proliferation assay which uses mice tha have been immunized with a particular antigen such as Bovine Serum Albumin (BSA). Upon immunization, T cells in lymph nodes which drain the injection site are activated and stimulated to proliferate. During this immune response, regulatory and Kill T cells which specifically recognize BSA are generated. ' At si days post-immunization when the T cell response is sufficientl mature, the draining lymph nodes are removed and cells eluted from them are placed into a standard culture. BSA or a second, unrelated antigen is then added to the cultures with or without the immunoregulatory peptides of the present invention. Quanti tation of antigen-induced T cell activation and proliferation i assessed by cellular tritiated thymidine incorporation at the e of the culture incubation in a manner similar- to that used in M cultures. Cultures containing BSA will produce high levels of tritiated thymidine incorporation because the BSA-sensitized T cells recognize the BSA molecules and become stimulated to prol ferate. Cultures containing an unrelated antigen, by contrast, have low stimulation levels because they lack receptors directe toward the unrelated antigen. As demonstrated in Table 2, the peptides of the present invention substantially suppress the T cell proliferative response toward specific molecular or cellular antigens without significantly affecting cellular viability. This observation is of therapeutic importance because it indicates that such pepti can suppress an abnormal T cell immune response directed towar wide range of unrelated antigens different from those found on histocompatibility antigens. As previously discussed, abnorma Killer T cell responses directed against either foreign or nor "self" antigens on various organs are thought to be responsibl for many autoimmune diseases. Other autoimmune diseases may result from an abnormal regulatory T cell response towards specific antigens that result in an imbalanced response of oth T cell-regulated portions of the immune system. It is possible to develop in vivo models of human aut immune disease in which animals are immunized with organ tissu from healthy genetically identical animals. Animals immunized against one of their organs develop an autoimmune response whi may result in destruction of the organ. T cells isolated from such an immunized animal may be very specific for molecules and cells of the injected organ showing that the T cells have receptors for organ-specific antigens. By using organs or their preparations as immunizing agents as described, it is possible to develop animal models of autoimmune diseases involving virtually any organ system, some which were previously enumerated. The peptides of the present invention are efficacious reducing or preventing the tissue destruction characteristic of autoimmune disease ^n vivo. Figures 1 and 2 demonstrate the efficacy of one peptide and one of its peptidomimetic analogs i treating an animal model of human multiple sclerosis (MS). In this model, termed Experimental Allergic Encephalomyelitis (EAE) SJL/J mice were immunized with a homogenate of spinal cord from SJL/J mice in a Complete Freund's Adjuvant medium. This homo- genate contains cells and molecules representative of the many potential antigens which are present in the central nervous system (CNS). Such animals typically develop vestibular and occular disturbances, weakness, paralysis, and other signs of central nervous system destruction characteristic of both EAE a MS ten to fifteen days after initial immunization. The EAE mod is discussed in Brown et al.. Lab. Invest. 45(3) :278-284 (1981). Like the majority of human MS cases, the disease sever ity in this animal MS model waxes and wanes during the disease course. Mice receiving only- saline injections two to three tim per week exhibit high peaks and troughs of disease severity. B contrast, mice receiving peptide or peptidomimetic demonstrated very mild disease initially and were clinically disease free by the study's end. Microscopic analysis of brain sections from both peptide and saline-treated mice is presented in Table 3. O ne h undred percent of saline-treated mice demonstrated substan¬ tial numbers of visible lesions which represent physical brain destruction in all portions of the CNS examined. By contrast, sixty percent of peptide-treated mice were lesion-free while the remaining forty percent of peptide-treated mice had few, scat- tered lesions confirming the clinically-elicited observations. In addition to the immunoregulatory properties of the peptides of the present invention, the peptides may also be used to regulate the growth of neoplastic (cancer) cells in vivo. Al cancer cells have in common the property of unregulated cell replication. Whereas normal cells replicate at a rate consiste with the normal functioning of the organ in which the cells reside, cancerous cells replicate in an unregulated manner, whi leads to tumor formation and possible destruction of adjacent healthy tissue. As demonstrated in Tables 4 and 5, the peptides of the present invention can suppress or prevent the growth of a varie of neoplastic cells iri vitro. Figure 3 demonstrates the anti- cancer properties of one of the peptides of the present inventi in mice with lymphoma/leukemia of T cell origin. Whereas salin treated mice had a median survival of 23.5 days after injection of lymphoma/leukemia cells, peptide-treated mice had a median survival of 30.5 days. Additionally, all saline-treated mice were dead by day 31 while one peptide-treated mouse was tumor-free at day 50. The peptides of the present invention may be adminis¬ tered to humans or other mammals by a variety of means commonly utilized with respect to other therapeutic agents. Injected subcutaneously, a dosage range of from about 25ug/kg to about 5 mg/kg of body weight may be employed, with a preferred range of about 2.5 to 50 mg/kg. Sterile saline, aqueous dextrose and glycols are preferred liquid carriers, particularly (when iso- tonic) for injectable solutions. Intravenous, intraperitoneal, and intramuscular injections may also be used at dosages compar¬ able to those of subcutaneous injections. The peptides may be administered orally at dosages generally ranging from one to 100 times that of an injected dose, although greater dosages may be required depending on factors such as food intake. The peptides may be combined with appropriate pharmaceutical carriers in the form of pills, capsules, elixers, suspensions, aerosols, powers, or in other forms. Intranasal administration may be achieved by using an appropriate amphipathic vehicle such as, for example, glycocholic acid or EDTA, Administration may be achieved topi¬ cally or transdermally, using an appropriate carrier in the form of, for example, an ointment. Sublingual, rectal, or topical ocular administration using appropriate pharmaceutical media may )- be employed. Sustained-release formulations using, for example, liposome delivery media, are also appropriate vehicles for administering the subject peptides. TABLE 1 PERCENT INHIBITION OF DNA PROLIFERATION OF MURINE AND HUMAN LYMPHOCYTES DURING MIXED LYMPHOCYTE CULTURES IN THE PRESENCE OF THE SUBJECT PEPTIDES Murine MLR Human MLR [Peptide] [Pept.ide] Peptide Sequence ( ug/ml) % inhib-t (ug/ml) % Inhib . desam N- Orn-Ala 50 99 100 91 Orn-D-Ala 50 98 100 94 Orn-Gly 100 99 200. 97 Arg-D-Ala 200 99 400 88 Arg-Sar 200 98 400 97 Arg-Thr 400 83 50 -32 His-Ser 100 99 400 97 Lys-Cys 200 99 100 93 Lys-Phe 100 99 400 99 Lys-D-Phe 400 -61 400 54 Lys-Tyr 200 99 400 95 Lys-Asp 100 99 100 -41 Lys-Gln 100 99 400 55 Lys-Leu 100 99 200 26 Lys-Pro 200 99 200 -19 Lys-HomoSer 200 99 200 93 Ala-Lys-Ser 50 99 50 90 Ala-Lys-Gly 50 99 200 90 D- -Ala-D-Lys-D-Ser 50 96 200 90 Gly-Lys-Ser 200 89 400 94 Val-Lys-Ser 100 -59 400 99 Phe-Lys-D-Ala 50 99 Phe-Lys-Sar 400 99 100 -100 Tyr-Lys-Gly 200 99 400 94 Asp-Lys-Ser 50 99 400 99 [Table 1 continues next page] [Table 1, continued] 1 Murine MLR Human MLR [Peptide] [Peptide] _ Peptide Sequence ( g/ml) % Inhibi (ug/ml) % Inhib Sar-D-Lys-Ser 100 99 400 58 Lys-Ser-Tyr 200 95 400 99 Lys-Ser-Ala 200 98 400 99 Phe-Lys-Ser-Tyr 200 98 400 96 Lys-Val-Lys 400 99 100 96 Lys-Glu-Lys 50 99 400 84 Lys-Gln-Lys 100 98 100 85 Lys-Arg-Lys 100 99 100 76 Lys-His-Lys 100 99 100 77 Lys-D-Ala-Lys 200 99 200 43 Lys-Val-Lys-NH 2 100 99 100 96 Lys-Leu-Lys-NH 2 50 99 100 89 Lys-Pro-Lys-NH 2 50 - 99 100 ■ 92 Lys-Tyr-Lys-NH 2 100 99 400 98 • Lys-D-Val-Lys-NH 2 400 99 400 63 Lys-Ser-Arg 100 92 100 49 Lys-Thr-Arg 200 98 200 -47 Arg-Gly-Lys 200 98 400 -31 Arg-Ala-Lys 100 92 50 -39 Arg-Asp-Arg 50 99 200 92 Ac-Lys-Ser-Lys 400 97 400 99 Val-Lys-Val-Lys-NH 2 100 99 200 99 Ala-Lys-Val-Lys-NH 2 50 98 100 90 Ala-Lys-Ser-Arg 400 99 400 -132 Arg-Lys-Ser-Arg 100 96 100 -141 Asn-Lys-Ser-Arg 50 70 400 99 Ac-Asn-Lys-Ser-Arg 200 99 400 99 Gly-Asp-Lys-Ser-Arg 100 90 400 51 Asp-Lys-Lys-Arg 100 99 100 86 Asp-Lys-Ile-Arg 200 99 400 42 Ser-Lys-Val-Arg 100 98 400 85 Gly-Lys-Val-Arg 100 99 100 60 Asp-Orn-Ser-Arg 100 99 200 99 Asp-His-Ser-Arg 400 95 400 -36 Asp-Lys-Ser-His 100 90 400 26 /Table 1 continues next page /Table 1, continued/ 1/ Percentage inhibition as compared to cultures in the absence of peptide. NOTE: Splenocytes from Balb/c mice were cocultured with spleno¬ cytes from C57B/6 mice and one healthy human donor were cultured with irradiated stimulator cells from a second healthy human donor for seven days at 37 β C and 5% C0 2 . Cultures were pulsed with 1 uCi 3 H-thymidine for six hours. The concentrations of the subject peptides which produce inhibition or stimulation of proliferation may occasion¬ ally vary from the concentrations listed depending on, many factors including age of the donor, time of day of blood drawing, food intake and other factors. 66 TABLE INHIBITION OF ANTIGEN-SPECIFIC DNA PROLIFERATI ON OF SENSITIZED MURINE LYMPHOCYTES IN THE PRESENCE OF THE SUBJECT PEPTIDES Concentration Peptide Sequence <ug/ml) % Inhibition. Lys-NH 2 100 98 D-Lys-NH 2 100 99 D-Lys-NH 2 CH 2 CH 3 100 36 Lys-Ser 50 99 D-Lys-Ser 12. 5 96 Lys-Ser-NH 2 25 92 desamino-Lys-Ser 100 68 Ac-Lys-Ser 50 98 Ac-Lys-Ser-NH 2 50 99 N-Ch 3 -Lys-D-Ser 100 99 Orn-D-Ala 50 99 Orn-Gly 12. 5 94 Arg-DτAla 12. 5 36 Arg-Sar 100 99 Arg-Thr 25 22 His-Ser 100 -13 Lys-Cys 100 74 Lys-Phe 50 99 Lys-Tyr 100 75 Lys-Asp 100 ■ 92 Lys-Pro 100 44 Ala-Lys-Ser 50 98 Ala-Lys-Gly 100 99 D-Ala-D-Lys-D-Ser 100 -31 Phe-Lys-D-Ala 100 99 Asp-Lys-Ser 100 99 Sar-D-Lys-Ser 100 18 Lys-Ser-Tyr 100 60 Lys-Ser-Ala 12. 5 -57 Table 2 continues next page/ 67 [_ Table 2 continued/ Concentration Peptide Sequence (μg/ml) Jόlnhibition— Lys-Val-Lys 50 -96 Lys-Glu-Lys 12.5 98 Lys-Arg-Lys 50 100 Lys-His-Lys 100 99 Lys-D-Ala-Lys 100 62 Lys-Val-Lys-NH 2 50 97 Lys-Leu-Lys-NH 2 50 94 Lys-Thr-Arg 25 -7 Arg-Gly-Lys 50 11 Arg-Ala-Lys 100 7 Arg-Asp-Arg 25 99 Val-Lys-Val-Lys-NH 2 50 99 Ala-Lys-Val-Lys-NH 2 50 99 Asn-Lys-Ser-Arg . 100 99 Asp-Orn-Ser-Arg 25 94 1/ Percentage inhibition as compared to cultures in the absen peptide. NOTE: Balb/c mice were immunized with ovalbumin (OVA) in Complet Freund's Adjuvant. Seven days later lymphocytes from superficial inguinal lymph nodes were cultured with 100 ug OVA and peptide. Cultures were pulsed with 1 μCi 3 H-thym for 24 hours from day 4 to day 5. The concentrations of the subject peptides which produce inhibition or stimulation of proliferation may occasionall vary from the concentrations listed depending on many fact including age of the donor, time of day of blood drawing, intake and other factors. TABLE 3 PATHOLOGICAL LESIONS PRESENT IN CENTRAL NERVOUS TISSUE OF MICE DURING EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS TREATED WITH SALINE OR SUBJECT PEPTIDE LYS-SER SUBCUTANEOUS INJECTIONS* CNS TISSUE SALINE (8) LYS-SER (10) Spinal Cord 8.1 + 3.9 1.2 ± 1.0 (85) Cerebellum 20.1 ± 6.7 0.6 + 0.4 (97) Brainstem 12.3 ± 6.5 0.4 + 0.2 (97) Basal Nuclei 2.6 ± 2.1 1.2 + 0.9 (54) Cerebral White Matter 2.8 ± 0.9 1.8 + 1.2 (36) Cerebral Grey Matter 4.6 + 2.2 1.3 + 0.9 (72) */ Mean ± standard error of lesions detected per mouse. NOTE: SJL/J mice were injected subcutaneously with mouse spinal cord homogenate in Complete Freund's Adjuvant on days 0 and 7 and injected with saline or 1 mg peptide 3 times per week from day 11 to 32. The number of mice in each group is enclosed within parentheses. Tissue was sectioned, the sample identity was coded and was examined microscopically by an uninformed observer. The percent inhibition of lesions is given in the last column in parentheses. 69 TABLE 4 PERCENT INHIBITION OF DNA PROLIFERATION OF MURINE LEUKEMIC CELLS IN THE PRESENCE OF THE SUBJECT PEPTIDES L 1210 Cells [Peptide] Peptide Sequence (ug/ml) % Inhib.i/ Lys-NH 100 98 200 2 D-Lys-NH 2 200 98 200 7 Lys-Ser 200 78 200 3 D-Lys-Ser 200 • 13 200 2 desamino-Lys-Ser 200 21 200 Ac-Lys-Ser 200 44 200 2 Ac-Lys-Ser-NH 2 50 ■ 57 200 1 N-CH 3 -Lys-D-Ser 200 37 200 7 Orn-Ala 100 71 100 8 Orn-D-Ala 100 89 100 8 Orn-Gly 100 95 100 8 Arg-D-Ala 200 89 200 8 Arg-Sar 200 97 100 7 His-Ser 200 67 200 7 Lys-Cys 50 94 100 9 Lys-Phe 200 99 Lys-D-Phe 200 19 200 -2 Lys-Asp 200 38 200 Lys-Gln 200 •34 200 Lys-Leu 200 69 200 4 Lys-Pro 100 8 100 2 Ala-Lys-Ser 100 49 200 9 Ala-Lys-Gly 200 83 200 5 D-Ala-D-Lys-D-Ser 100 29 100 4 Gly-Lys-Ser 200 91 200 9 Val-Lys-Ser 200 80 200 7 Phe-Lys-Sar 200 16 200 1 Tyr-Lys-Gly 50 ■ 18 100 -1 Asp-Lys-Ser 100 3 Sar-D-Lys-Ser 200 81 200 7 Lys-Ser-Tyr 100 10 Lys-Ser-Ala 200 98 200 8 Phe-Lys-Ser-Tyr 50 -7 50 -3 . Table 4 continues next page/ 70 /Table 4, continue dj L 1210 Cells WEHI-22 Cells [Peptide] [Peptide] Peptide Sequence (uκ/πιl) % Inhib.±/ (ug/ml) % Inhib Lys-Val-Lys 100 64 200 85 Lys-Glu-Lys 200 43 200 43 Lys-Gln-Lys 200 99 200 94 Lys-Arg-Lys 200 73 100 50 Lys-His-Lys 200 99 200 94 Lys-D-Ala-Lys 25 -19 100 -83 Lys-Val-Lys-NH 2 200 93 100 82 Lys-Leu-Lys-NH 2 200 96 200 96 Lys-Pro-Lys-NH 2 100 95 100 90 Lys-Tyr-Lys-NH 2 200 85 200 81 Lys-D-Val-Lys-NH 2 200 28 100 24 Lys-Ser-Arg 100 28 100 19 Lys-Thr-Arg 200 17 200 10 Arg-Gly-Lys 200 19 25 30 Arg-Ala-Lys 100 -13 200 -22 Arg-Asp-Arg 100 88 100 94 Ac-Lys-Ser-Lys __ _.— 200 58 Val-Lys-Val-Lys-NH 2 200 - 88 200 85 Ala-Lys-Val-Lys-NH 2 • 200 65 200 76 Ala-Lys-Ser-Arg —— _.— 100 16 Arg-Lys-Ser-Arg — — 100 -31 Asn-Lys-Ser-Arg — — 100 16 Ac-Asn-Lys-Ser-Arg —- — 100 -41 Gly-Asp-Lys-Ser-Arg —- — 100 -14 Asp-Lys-Lys-Arg —— ——. 100 81 Asp-Lys-Ile-Arg — — 100 21 Ser-Lys-Val-Arg — — 100 72 Gly-Lys-Val-Arg —— — 100 6 Asp-Orn-Ser-Arg 200 98 200 84 Asp-His-Ser-Arg 50 -28 100 -14 1/ Percentage inhibition as compared to cultures in the absence peptide. NOTE : Cells were cultured at 37 β C and 5% CO, for 48 hours and then pulsed with 1 uCi J H-thymidine for 6 hours. The concentrations of the subject peptides which produce inhibition may occasionally vary from the concentrations list 0 depending on many factors including age of the cells, culture conditions and other factors. 7i -:. * ^ TABLE 5 PERCENT INHIBITION OF DNA PROLIFERATION OF HUMAN MENINGIOMA TUMOR CELLS IN THE PRESENCE OF THE SUBJECT PEPTIDES EFc Tumor Cells LG Tumor Cells [Peptide] .. [Pept:Lde] Peptide Sequence (ug/ml) % Inhib.i/ (ug/ml) % Inhib. Lys-NH 2 200 74 200 84 D-Lys-NH 2 200 93 200 96 Lys-Ser 200 88 200 88 Lys-Ser-NH 2 100 65 100 78 desamino-Lys-Ser 200 20 200 25 Ac-Lys-Ser-NH 2 200 N-CH 3 -Lys-D-Ser 100 82 50 -439 Orn-D-Ala 200 88 100 52 Orn-Gly 200 72 200 48 Arg-D-Ala 200 37 100 50 Arg-Sar 200 82 50 50 His-Ser 200 31 200 -10 ι - Lys-Cys 200 91 100 97 Lys-Phe 100 63 200 77 Lys-Tyr 200 46 100 -42 Ala-Lys-Ser 200 90 200 95 Ala-Lys-Gly 50 79 50 72 1 D-Ala-D-Lys-D-Ser 200 23 200 45 Gly-Lys-Ser 50 -12 50 53 Phe-Lys-D-Ala 200 16 — — Lys-Ser-Tyr 100 37 100 -9 Lys-Ser-Ala 200 46 200 58 1 Lys-Arg-Lys 100 70 50 72 Lys-Val-Lys-NH 2 200 54 200 76 Lys-Ley-Lys-NH 2 200 49 Asp-Lys-Lys-Arg 100 65 200 79 1/ Percentage inhibition as compared to cultures in the absence peptide. NOTE: Cells were cultured at 37 β C and 5% C0 2 for 48 hours and then pulsed with 1 uCi H-thymidine for 6 hours. The concentrations of the subject peptides which produce inhibition may occasionally vary from the concentrations list depending on many factors including age of the cells, culture conditions and other factors. EXAMPLE 1 Solution phase synthesis of Lys-Ser salts using t-butyloxy- carbonyl protection. L-Serine (157.6 g, 1.5 moles) and sodium bicar¬ bonate (168 g, 2 moles) were dissolved in distilled water (2 1) and treated with a solution of N,N*-bis-t-butyloxycarbonyl-L-lysine N-hydroxysuccinimide ester (444 g, 1 mole) in tetrahydrofuran (2 1). The resulting solution (pH approx. 9) was stirred overnight at room temperature. The pH was then adjusted to 6.5 with 1 N sodium bisul¬ fate and the mixture evaporated to approximately half the volume under reduced pressure. The residue was extracted twice with ether before adjusting the pH to 3.0 (1 N sodium bisulfate) and extracting the product three times with ethyl acetate (2 1, 1 1, 1 1). The combined organic extracts were washed with 5% brine and then dried over sodium sulfate. The solution was then concentrated under reduced pressure to approximately 1.5 1, dicyclohexylamine (199.2 ml, 1 mole) added and the mixture stirred at room temperature for 0.5 hours. The product, N,N'-bis-t-butyloxycarbony1-L-lysyl-L-serine dicyclohexylammonium salt, crystallized out of the solution and was recrystallized from isopropanol. Yield: 464 g (76%), m.p. 126-129 β C [ ]^ 5 = +4.48° (c = 1, ethanol) . The dicyclohexylammonium salt (73 g) was dissolved in ice- water (800 ml), the pH adjusted to 3 with 1 N sodium bisulfate and the product extracted into ethyl acetate (500 ml, 200 ml, 100 ml). The combined organic extracts were dried over sodium sulfate and the solu- tion evaporated to give N,N'.-bis-t-butyloxycarbonyl-L-lysyl-L-serine (46.3 g). 73 Deprotection to bis-trifluoroacetate salt. N,N'-bis-t- butyloxycarbonyl-L-lysyl-L-serine (17.8 g) was dissolved in dichlo methane (70 ml), anhydrous trifluoroacetic acid (50 ml) added and th mixture stirred at room temperature for 0.5 hours. The solution wa evaporated under reduced pressure and the residue triturated three times with dichloromethane and three times with ether to give the bis-trifluoroacetate salt of L-lysyl-L-serine in quantitative yield a colorless, hygroscopic solid. Deprotection to dihydrochloride salt. N,N'-Bis-t-butyloxy carbonyl-L-lysyl-L-serine (20 g) was dissolved in an anhydrous solu tion of hydrogen chloride in ethyl acetate (3.5 N, 200 ml) and the mixture stirred at room temperature for 0.5 hours. The solution wa evaporated under reduced pressure and the residue triturated our times with ether to give the dihydrochloride salt of L-lysyl-L-seri in quantitative yield as a white hygroscopic solid. Alternately, N,N'-bis-t-butyloxycarbonyl-L-lysyl-L-serine (25 g) was dissolved in dioxane (50 ml) and treated with a solution hydrogen chloride in anhydrous dioxane (4 N, 250 ml). The mixture stirred at room temperature for 0.5 hours, evaporated under reduced pressure and the residue triturated four times with ether to give t dihydrochloride salt of L-lysyl-L-serine in quantitative yield as a colorless, glassy hygroscopic solid. EXAMPLE 2 Solution phase synthesis of Lys-Ser salts using benzyl- oxycarbonyl protection. Following the general procedure described i Example 1, L-serine, (15.76 g, 0.15 mole) and sodium bicarbonate (25 g, 0.3 mole) were dissolved in distilled water (325 ml) and treated with a solution of N,N*-bis-benzyloxycarbonyl-L-lysine N-hydroxysuc- ciniraide ester (51.56 g, 0.1 mole) in tetrahydrofuran (300 ml). Aft stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure to approximately half the volume, extracted with ether (2 x 500 ml) and poured, with rapid stirring, into ice-cold hydrochloric acid (l.N, 3.5 1). The white precipitate which separated was quickly extracted into ethyl acetate (3 1) and th organic phase washed with ice-cold 1 N HC1 (2 x 1 1), water (3 x 1 1) and dried over magnesium sulfate. The solution was evaporated to dryness under reduced pressure and the solid residue triturated with hexanes to give N,N'-bis-benzyloxycarbonyl-L-lysyl-L-serine as a colorless, hygroscopic solid, m.p. 143-145 β C. Yield: 45.03 g. Conversion to dicyclohexylammonium salt. The product was converted to the dicyclohexylamine salt by dissolving in a minimum volume of ethyl acetate (approx. 7 1) containing methanol (1 1) and treating with 1 equivalent of redistilled dicyclohexylamine (17.9 ml). The crystalline product ' was filtered, washed with ether, dried and recrystallized from isopropanol. The product was reconverted to the protected dipeptide by neutralizing with aqueous sodium bisulfate as described in Example 1. Yield: 31.5 g. Deprotection to acetate salt. N,N'-Bis-benzyloxycar- bonyl-L-lysyl-L-serine (3 g) was dissolved in a mixture of methan (20 ml) and water (20 ml) containing acetic acid (0.35 ml, 2 equivalents) and hydrogenated over 10% palladium on carbon (1 g) atmospheric pressure overnight. After removing the catalyst by filtration, the solution was concentrated to approximately half t volume under reduced pressure, and the residue lyophilized, to gi the acetate salt of L-lysyl-L-serine in quantitative yield as a colorless, hygroscopic solid. EXAMPLE 3 Automated solid-phase synthesis of Lys-Ser on chlorometh ted polystyrene resin. Tert-butyloxycarbonyl-amino acid resins, protected amino acid derivatives, and other peptide synthesis pro may be obtained from, e.g.. Peninsula Laboratories, Inc., 611 Tay way, Belmont, CA 94002, or Bachem, Inc., 3132 Kashiwa Street, Torrance, CA 90505. Tert-butyloxycarbonyl-O-benzyl-L-serine-resi (substitution = 0.85 mmoles/g; 4.0 g) was deblocked and coupled w t-butyloxycarbonyl-ε-benzyloxycarbonyl-L-lysine using an automate synthesizer (Beckman Model 990) programmed with the following protocol: 1. Wash with dichloromethane (50 ml), 3 x 1 minute. 2. Deblock with trifluoroacetic acid (35% v/v in dichloromethane, 50 ml), l x l minute, 1 x 20 minutes. 3. Wash with dichloromethane (50 ml), 3 x 1 minute; isopropanol (50 ml), 2 1 minute; and dichloromethane (50 ml), 3 minute. 4. Neutralize with triethylamine (10% v/v in dichlorometh¬ ane, 50 ml), l l minute and 1 x 5 minutes. 5. Wash with dichloromethane (50 ml), 4 x 1 minute. 6. Couple with t-butyloxycarbonyl-ε-benzyloxycarbonyl-L-lysine (2.59 g, 6.8 mmoles, 2 equivalents) in dichloromethane (30 ml), together with N,N-dicyclohexylcarbodiimide (0.5 M in dichloromethane, 13.6 ml, 2 equivalents), 1 x 90 minutes.' 7. Repeat step 3. 8. Repeat step 1. 9. Repeat step 2. 10. • Repeat step 3. (Note: Steps 1-7 constitute one complete coupling cycle.) The resin was collected on a sintered glass funnel, washed successively with ethanol and dichloromethane and dried under vacuum. Yield: 4.96 g. The peptide was cleaved from the resin by treatment with liquid hydrogen fluoride (10 ml per gram of dry resin) in the presenc of anisole (1 ml per gram of resin) and 0 β C for one hour. After removal of the hydrogen fluoride under vacuum, ether (10 ml per gram of resin) was added, the resin transferred to a sintered glass funnel and washed alternately with ether (4 x 40 ml) and chloroform (3 x 40 ml). The resin was sucked dry and the peptide extracted with 1 N aqueous acetic acid (4 x 30 ml). The combined extracts were lyophilized, redissolved in distilled water (7 ml) and relyophilized 77 to give 816 mg of the acetate salt of the crude peptide, Lys-Ser. Analogously Lys-Val-Lys is obtained from tert.- butoxycarbonyl-E-2-chlorobenzoxy-carbonyl-L-lysi.ne-resin with t- b utoxycar b onyl-L-valine and t-butαxycarbαnyl-£-benzoxycarbonyl- L-lysine. EXAMPLE 4 Purification of Lys-Ser using carboxymethyl cellulose chromatoqraphv. The crude peptide salt from Example 3 { 2 . 5 g) was dissolved in distilled water (1 1), the pH adjusted to 5.0-6.5 (1 M aqueous ammonia) and the solution applied to a column (2..5 x 30 cm) Whatman CM-52 which had been equilibrated with 0.01 M ammoniαm ace¬ tate, pH 5.0-6.5. The column was washed copiously with the equili¬ bration buffer and then eluted with a linear gradient of 0.01 M amm ium acetate, pH 4.5-6.5 (350 ml) to 0.30 M ammonium acetate, pH 6.5 ( 350 ml). The pH of the column and the starting buffer was adjuste to equal that of the peptide solution before loading. The fraction containing the pure product were combined and lyophilized to give L-lysyl-L-serine as a colorless, hygroscopic solid. Analogously, Lys-Val-Lys is purified. EXAMPLE 5 Purification of Lys-Ser using carboxymethyl Sephadex chroma- tography. Following the general procedure described in Example 4, th crude peptide from Example 2 (2 g) was dissolved in distilled water ( 1), the pH adjusted to 4.5-6.5 (1 M aqueous ammonia) and the solution applied to a column (2.5 x 30 cm) of CM-Sephadex (Pharmacia, Inc.) which had been equilibrated with 0.01 M ammonium acetate, pH 4.5-6.5. The column was then eluted with a linear gradient of 0.01 M ammonium acetate, pH 4.5-6.5 (350 ml) to 0.30 M ammonium acetate, pH 6.5 (350 ml). The pH of.the column and the starting buffer was adjusted to equal that of the peptide solution before loading. Fractions con¬ taining the pure product were combined and lyophilized to give L-lysyl-L-serine as a colorless, glassy, hygroscopic solid. Analogously, Lys-Val-Lys is purified. EXAMPLE 6 Purification of Lys-Ser using reverse-phase chromatoqraphy o C-18 silica. The crude peptide from Example 1 (5.0 g) was dissolved in a minimum volume of distilled water (approximately 10 ml) and applied to a column (5 x 50 cm) of C-18 silica gel (Separation Tech- nologies. Inc.) which had been previously equilibrated with 0.5% aqueous hydrochloric acid. The column was eluted with the same solvent and the fractions containing the pure product combined and lyophilized to give L-lysyl-L-serine hydrochloride salt as a colorless, hygroscopic, glassy solid. Analogously, Lys-Val-Lys is purified. 19 EXAMPLE 7 Purification of Lys-Ser using Sephadex G-10 chromatograph The peptide from Example 2 (1.0 g) was dissolved in a minimum volum of distilled water (5 ml) and applied to a column (2.5 x 100 cm) of 5 Sephadex G-10 (Pharmacia) which had been equilibrated with 3% aque acetic acid. The column was eluted with the same solvent and the fractions which contained the pure product combined and lyophilize give L-lysyl-L-serine acetate salt as a colorless, glassy, hygrosc solid. 10 Analogously, Lys-Val-Lys is purified. EXAMPLE 8 Automated solid-phase synthesis of Lys-NH 2 on benzhydryla resins. N-t-butyloxycarbonyl-ε-benzyloxycarbonyl-L-lysine (2.31 g 6.08 mmole) was coupled to preswollen benzhydrylamine resin (1% cr 15 linked, substitution = 0.76 meq. amine per gram) in dichloromethan (30 ml) using a solution of dicyclohexylcarbodiimide in dichloro¬ methane (0.5 M, 12.2 ml; 2 equivalents) in an automated synthesize as described in Example 3. The mixture was stirred for 90 minutes the resin thoroughly washed (see protocol in Example 3, steps 7-10 '20 transferred to a sintered glass funnel, washed successively with ethanol and dichloromethane and dried under vacuum. Yield: 4.7 g. The crude peptide, Lys-NH 2 , was cleaved from the resin us liquid hydrogen fluoride, following the procedure described in Exa 3. Yield: 693 mg. 25 Analogously, Lys-Val-Lys-Nh is prepared. Peptide amides may be synthesized by an identical procedu using 4-methylbeπzhydrylamine resin in place of benzhydrylamine res EXAMPLE 9 Synthesis of N a -acetyl-Lys-Ser (Ac-Lys-Ser) by acetylation of a peptide resin. The dipeptide was assembled by the solid-phase method, as described in Example 3, starting with 2.9 g of t-butyloxy- carbonyl-O-benzyl-L-serine resin (substitution = 0.65 mmole/g) . After cleavage of the N-terminal t-butyloxycarbonyl group from the dipeptide-resin, it was acetylated using the following protocol: 1. Wash with dichloromethane (50 ml), 3 x 1 minute; ethanol (50 ml), 2 x 1 minute; and dichloromethane (50 ml), 3 x 1 minute. 2.. Neutralize with triethylamine (10% in dichloromethane, 50 ml), 1 x 1 minute and 1 5 minutes. 3. Acetylate by adding dichloromethane (40 ml), followed by acetic anhydride (1.9 ml per mmole- of peptide-resin) and triethylamine (2.8 ml per mmole of peptide-resin) for 20 minutes. 4. Repeat step 1. The reS j in was collected on a sintered glass funnel, washed successively with ethanol and dichloromethane and dried under vacuum. The peptide was cleaved from the resin using liquid hydrogen fluoride at 0°C, as described in Example 3 and purified by chromato- graphy on C-18 silica, as described in Example 6 to give N°-acetyl- L-lysyl-L-serine acetate as a colorless, glassy hygroscopic solid. Yield: 304.7 mg. EXAMPLE 10 Synthesis of D-Lysine N-ethylamide ( D-Lys-NHCH 2 CH 3 ) via aminolysis of an amino acid resin. N α -t-Butyloxycarbonyl-ε -benzyloxy- carbonyl-D-lysine-resin ( substitution = 0.67 mmole/g , 1.5 g ) was 81 suspended in dimethylformamide (15 ml) and anhydrous ethylamine gas bubbled slowly through the solution until saturation was achieved the mixture stored in a stoppered flask for 24 hours at room temperature. The resin was removed by filtration, washed with dimethylformamide and the filtrate evaporated under reduced pressure. The residue was triturated with ether to give crude N-t-butyloxycarbonyl-ε -benzyloxycarbonyl-D-lysine N-ethylamide as white solid. Yield: 0.4 g. The product was deprotected using liquid hydrogen fluorid ml) at 0°C in the presence of anisole (2 ml), as described in Exam 3. Purification was accomplished by chromatography on Sephadex G- as described in Example 7 to give D-lysine N-ethylamide as a white hygroscopic solid. Yield: 70 mg. EXAMPLE 11 » General method for the preparation of t-butyloxycarbonyl amino acid resins. Chloromethylated polystyrene beads (Biobeads S Bio-Rad; 1% crosslinked; substitution = 1.25 milliequivalents Cl/g are added to a solution of the t-butyloxycarbonyl-amino acid deri tive (1 equivalent) in dimethylsulfoxide (3 ml per gram of resin) round bottom flask, and the mixture treated with a solution of potassium t-butoxide (1 equivalent) in dimethylsulfoxide (1.5 ml gram of resin; centrifuged to remove insolubles). The mixture is heated with agitation at 80 β C using an oilbath for two hours and allowed to stand at room temperature overnight. The resin is transferred to a sintered glass funnel, washed with dimethylsulfo (3 times), alternately with methanol and dichloromethane (3 times each) and finally with methanol (2 times) and dried under vacuum. Degree of substitution is calculated from the weight gain of the resin. EXAMPLE 12 Acetate salts of the peptides listed in Table 6 were prepar and purified under the protocols described in the foregoing examples, using the materials and protocols specified in the table. Peptide R and specific rotation data are given in Table 7. EXAMPLE 13 Solution-phase synthesis of Lys-Val-Lys acetate salt. Tert-butyloxycarbonyl-L-valine (22.8 g, 0.105 moles) is dissolved in dry tetrahydrofuran (400 ml), the solution cooled to -15°C and treated with N-methylmorpholine (11.0 ml, 0.1 mole), followed by isobutyl chloroformate (13.0 ml, 0.1 mole). The mixture is stirred at -15" for 10 minutes and then treated with a precooled colution of ε-benzyloxycarbonyl-L-lysine benzyl ester hydrochlo- ride (40.65 g, 0.1 mole) in tetrahydrofuran (200 ml) and di¬ methylformamide (50 ml). The reaction mixture is allowed to warm slowly to room temperature and stirred overnight. The solvent is evaporated under reduced pressure, the residue redissolved in ethyl acetate (2 1) and washed with 1 N hydrochloric acid (3 x 500 ml), 5% sodium chloride (3 x 500 ml), 5% sodium bicarbonate (3 x 500 ml) and finally with water (3 x 500 ml). The organic phase is dried over magnesium sulfate, concentrated under reduc pressure and crystallization of the product induced by additio of hexane to the cloud point. Yield: 46.7 g (82%). Tert-butyloxycarbonyl-L-valyl-ε-benzyloxycarbonyl-L- lysine benzyl ester from the previous step (46.7 g) is depro- tected by dissolving in dichloromethane (250 ml) and treating with cold (0 β C) trifluoroacetic acid (150 ml) for 30 minutes. The solvent is evaporated under reduced pressure and the residu triturated several times with ether to give L-valyl-ε-benzyloxy carbonyl-L-lysine benzyl ester trifluoroacetate salt in quanti¬ tative ' yield, which may be used without further purification. N,N-bis-benzyloxycarbonyl-L-lysine (35.6 g, 0.086 mole is dissolved in tetrahydrofuran (350 ml), the solution cooled t -15°C and treated with N-methylmorpholine (9.02 ml, 0.082 mole) followed by. isobutyl chloroformate (10.64 ml, 0.082 mole). The mixture is stirred for 10 minutes and then treated with a pre- cooled solution of L-valyl-ε-benzyloxycarbonyl-L-lysine benzyl ester trifluoroacetate (46.4 g, 0.082 mole) in tetrahydrofuran (200 ml) and dimethylformamide (50 ml), followed by N-methylmor pholine (9.02 ml, 0.082 mole). The mixture is allowed to warm slowly to room temperature and stirred overnight. The product worked up as described above to give N,N-bis-benzyloxycarbonyl- lysyl-L-valyl-ε-benzyloxycarbonyl-L-lysine benzyl ester. Yield 49.0 g (78%) . The protected tripeptide (49.0 g) is dissolved in glacial acetic acid (1 1) and hydrogenated over palladium on carbon (10%, 10 g) overnight at atmospheric pressure. The catalyst is removed by filtration, the filtrate evaporated and the residue redissolved and lyophilized to give L-lysyl-L-valyl- L-lysine acetate salt in quantitative yield (37.0 g). Purification may be achieved by the methods of Examples through 7. T A B L E 6 Product Peptide S* Starting Resin Coupling Cycle Reagents P D-Lys-NH 2 8 Boc-ε-Cbz-D-Lys benzhydrylamine LysrSer-NH 2 8 Boc-OBzl-L-Ser Boc-ε -Cbz-L-Ly s 4 benzhydrylamine D-Lys-Ser 3 Boc-OBzl-L-Ser Boc-ε -Cbz-D-Lys 4 Desamino-Lys-Ser 3 Boc-OBzl-L-Ser t-Boc-des-β-amino-Lys Orn-D-Ala 3 Boc-D-Ala Boc-δ -Cbz-L-Orn 4 , Arg-D-Ala 3 Boc-D-Ala Boc-N^-tosyl-L-Arg 4 , His-Ser 3 Boc-OBzl-L-Ser Boc-N im -tosyl-L-His Lys-Cys 3 Boc-δ-MeCbz-Cys Boc-ε -Cbz-L-Lys . 4 , Orn-Gly 3 Boc-Gly Boc-δ -Cbz-L-Orn 4 , Lys-Phe 3 Boc-L-Phe " Boc ' -ε -Cbz-L-Lys 6 Lys-Asp 3 Boc-e-Cbz-L-Asp Boc-ε -Cbz-L-Lys 7 Lys-Pro 3 Boc-L-Pro Boc-ε -Cbz-L-Lys 4 , Ac-Lys-Ser-NH 2 8,9 Boc-OBzl-L-Ser Boc-ε -Cbz-L-Lys __ benzhydrylamine N-Me-Lys-D-Ser Boc-OBzl-L-Ser Boc-N -Me- ε -Cbz-L-Lys 6 , (threefold excess) Ala-Lys-Ser Boc-OBzl-L-Ser Boc-ε -Cbz-L-Lys ; 6 Boc-L-Ala D-Ala-D-Lys-D-Ser Boc-OBzl-D-Ser Boc-ε -Cbz-D-Lys. ; Boc-D-Ala Val-Lys-Ser Boc-OBzl-L-Ser Boc-ε -Cbz-L-Lys ; 6 Boc-L-Val Phe-Lys-D-Ala Boc-D-Ala Boc-ε -Cbz-L-Lys ; Boc-L-Phe Lys-Ser-Tyr 3 Boc-OBzl-L-Tyr Boc-OBzl-L-Ser ; 6 Boc-ε -Cbz-L-Lys Phe-Lys-Ser-Tyr 3 Boc-OBzl-L-Tyr Boc-OBzl-L-Ser ; Boc-ε -Cbz-L-Lys ; Boc-L-Phe Zϊable 6 continues an next page_7 /.Table 6, continued/ Lys-Glu-Lys 3 Boc-ε-Cbz-L-Lys Boc-γ-Bzl-L-Glu; Boc-ε-Cbz-L-Lys Lys-Gln-Lys 3 Boc-ε-Cbz-L-Lys Boc-X-L-Gln; Boc-ε-Cbz-L-Lys Lys-Arg-Lys Boc-ε-Cbz-L-Lys Boc-N^-tosyl-L-Arg; Boc-ε-Cbz-L-Lys Lys-His-Lys 3 Boc-ε-Cbz-L-Lys Boc-N im -tosyl-L-His; Boc-e-Cbz-L-Lys Lys-D-Ala-Lys Boc-e-Cbz-L-Lys Boc-D-Ala; 4,7 Boc-e-Cbz-L-Lys Lys-Leu-Lys-NH 2 8 Boc-e-Cbz-L-Lys Boc-L-Leu; 7 benzhydrylamine Boc-ε-Cbz-L-Lys Lys-Pro-Lys-NH 2 8 Boc-ε-Cbz-L-Lys Boc-L-Pro; benzhydrylamine Boc-ε-Cbz-L-Lys Lys-Tyr-Lys-NH 2 8 Boc-e-Cbz-L-Lys Boc-OBz1-L-Tyr; 6 3 > benzhydrylamine Boc-ε-Cbz-L-Lys Lys-Ser-Arg 3 Boc-N^- Boc-OBzl-L-Ser; 7 tosyl-L-Arg Boc-ε-Cbz-L-Lys Lys-Thr-Arg 3 BOC-N9- Boc-OBzl-L-Thr 7 ' tosyl-L-Arg Boc-ε-Cbz-L-Lys Arg-Gly-Lys Boc-ε-Cbz-L-Lys Boc-Gly; 4,7 Boc-N^-tosyl-L-Arg Arg-Ala-Lys 3 Boc-ε-Cbz-L-Lys Boc-L-Ala; 4,7 Boc-N^-tosyl-L-Arg Arg-Asp-Arg 3 Boc-N^- Boc-8-Bzl-L-Asp; tosyl-L-Arg Boc-N^-tosyl-L-Arg •4) Ala-Lys-Val-Lys-NH 8 Boc-ε-Cbz-L-Lys Boc-L-Val; benzhydrylamine Boc-ε-Cbz-L-Lys; Boc-L-Ala Arg-Lys-Ser-Arg 3 Boc-N^- , Boc-OBzl-L-Ser; 1) tosyl-L-Arg Boc-ε-Cbz-L-Lys; Boc-N^-tosyl-L-Arg Ac-Asn-Lys-Ser-Arg 3 , 9 BO C -N^- Boc-OBzl-L-Ser; tosyl-L-Arg Boc-ε-Cbz-L-Lys; Boc-Xan-L-Asn /Table 6 continues on next page./ [Table 6 continued] Gly-Asp-Lys-Ser-Arg 3 Boc-N^- Boc-OBzl-L-Ser; 7 tosyl-L-Arg Boc-e-Cbz-L-Lys; Boc-S-Bzl-L-Asp; Boc-Gly Asp-Lys-Lys-Arg 3 Boc-N^- Boc-ε-Cbz-L-Lys; 7 tosyl-L-Arg Boc-ε-Cbz-L-Lys; Boc-S-Bzl-L-Asp Asp-Lys-Ile-Arg 3 Boc-N^- Boc-L-Ile; 7 tosyl-L-Arg Boc-ε-Cbz-L-Lys; Boc-S-Bzl-L-Asp Gly-Lys-Val-Arg 3 Boc-N^- Boc-L-Val; 6 tosyl-L-Arg Boc-ε-Cbz-L-Lys; Boc-Gly Asp-Orn-Ser-Arg 3 Boc-N^- Boc-OBzl-L-Ser; 7 tosyl-L-Arg Boc-δ-Cbz-L-Orn Boc-S-Bzl-L-Asp Asp÷Lys-Ser-His ' 3 Boc-N ιm - Boc-OBzl-L-Ser; 7 tosyl-L-His Boc-e-Cbz-L-Lys; Boc-S-Bzl-L-Asp * S refers to the synthesis protocol followed, as described in the Example number(s) given in this column. ** P refers to the purification protocol followed, as described in the Example number(s) given in this column. Where two protocols are listed, these were utilized in the order listed. 1) 0-60?ό acetonitrile gradient in 0.5?ό aqueous HC1 used for elution. 2) 0-60.0 acetonitrile gradient in 0.1 M ammonium acetate, pH 4.5, used for elution. 3) 0-30 % acetonitrile gradient in 0.5?ό aqueous HC1 used for elution. 4) 0-50?. acetonitrile gradient in 0.5.0 aqueous HC1 used for elution. Note: The following abbreviations apply to Table 6: Boc, tert- butyloxycarbonyl; Cbz, benzyloxycarbonyl; Ofizl, O-benzyl; MeBzl, 4-methylbenzyl; Bzl, benzyl; Me, methyl; Xan, xanthydryl. TABLE 7 PEPTIDE R_ AND SPECIFIC ROTATION DATA P roduct Peptide κ Rj.I/ [o ](c)l/ Lys-Ser 0.15 + 20.42 (4.26) Lys-NH 2 0.15 + 16.21 (4.38) D-Lys-NH 2 0.14 - 13.39 (3.66) Lys-Ser-NH 2 0.16 + 20.32 (4.92) D-Lys-Ser 0.15 - 42.54 (4.00) Desamino-Lys-Ser 0.34 + 2.36 (6.78) Orn-D-Ala 0.15 + 64.36 (5.36) Arg-D-Ala 0.28 + 56.15 (6.50) His-Ser 0.16 - 31.44 (3.60) Lys-Cys 0.18 + .9.70 (3.40) Orn-Gly 0.16 + 44.20 (4.14) Lys-Phe 0.37 + 1.46 (3.20) Lys-Asp 0.20 + 24.11 (11.60) Lys-Pro 0.14 - 55.60 (4.04) Ac-Lys-Ser-NH 2 0.26 - 35.50 (4.00) N-Me-Lys-D-Ser 0.13 + 51.23 (4.06) Ala-Lys-Ser 0.15 - 17.25 (4.00) D-Ala-D-Lys D-Ser 0.10 + 17.88 (3.41) Val-Lys-Ser 0.16 + 0.61 (14.8) Phe-Lys-D-Ala 0.32 + 16.67 (4.50) Lys-Ser-Tyr 0.08 + 18.78. (4.10) Phe-Lys-Ser-Tyr 0.05 + 7.01 (4.28) /Table 7 continues on next page 1/ TLC analysis on Silica Gel 60 plates (MERCK) in the solvent system n-butanol:acetic acid:water:ethyl acetate (1:1:1:1). __ r 2/ Specific rotation /_ r_/ measured in water at the concen- — tration (in mg/ml) indicated in parentheses. /.Table 7, continued/ Lys-Val-Lys 0.10 - 4.78 (3.56) Lys-Val-Lys-NH 2 0.09 -10.78 (4.64) Lys-Glu-Lys 0.09 + 1.84 (5.42) Lys-Gln-Lys 0.06 nd Lys-Arg-Lys 0.07 + 2.57 (15.8) Lys-His-Lys 0.03 + 9.86 .(5.36) Lys-D-Ala-Lys 0.07 +45.03 (6.44) Lys-Leu-Lys-NH-, 0.09 - 5.46 (4.60) Lys-Pro-Lys-NH 2 0.05 -41.67 (5.04) Lys-Tyr-Lys-NH-, 0.14 +30.88 (4.34) Lys-Ser-Arg 0.06 nd ( Lys-Thr-Arg 0.09 - 1.36 (5.88) Arg-Gly-Lys 0.08 +10.38 (5.20) Arg-Ala-Lys 0.10 - 4.59 (3.92) Arg-Asp-Arg 0.14 + 3.95 (18.0) Ala-Lys-Val-Lys-NH 2 0.07 -45.57 (4.06) Arg-Lys-Ser-Arg 0.01 nd Ac-Asn-Lys-Ser-Arg 0.13 nd Gly-Asp-Lys-Ser-Arg 0.03 -32.50 . (32.4) Asp-Lys-Lys-Arg 0.03 nd Asp-Lys-Ile-Arg 0.10 nd Gly-Lys-Val-Arg 0.12 nd Asp-Orn-Ser-Arg 0.06 -20.49 (3.49) Asp-Lys-Ser-His 0.03 nd 90 In addition to the peptides mentioned above, the following preferred compounds can be prepared in analogy to the G1u-Thr Thr Thr- NH„ Pro Lys-Ala-Tyr Phe-Lys-Ser Lys-Asp-Lys Sar-Lys-Ser Lys-Gln-Lys-NH 2 Sar-D-Lys-Ser Lys-Glu-Lys-NH 2 Thr-Gln-Glu-Lys Lys-Gly Thr-Gln-Glu-Lys-Asn-Pro-Leu-Pr Lys-Gly-Lys Thr-Glu-Thr Lys-Gly-Lys-NH 2 Thr-Glu-Thr-Gln-Glu-Lys Lys-Gly-Tyr Val-Lys-Thr-Arg. Lys-Lys-Lys Lys-Lys-Thr Lys-Lys-Thr-Glu-Thr Lys-Phe-Lys-NH 2 Lys-Ser-Lys D-Lys-Ser-NH 2 Lys-Ser-NH-CH 3 D-Lys-Ser-NH-CH 3 Lys-Ser-NH-C 2 H 5 D-Lys-Ser-NH-C 2 H 5 Lys-Thr-Glu Lys-Thr-Glu-Thr Lys-Thr-Glu-Thr-Gln-Glu-Lys Lys-Thr-Lys N-Me-Lys-Ser N-Me-Lys-Ser-NH 2 N-Me-Lys-Ser-NH-CH 3 N-Me-Lys-Ser-NH-C 2 H 5 Orn-Ser D-Orn-Ser Orn-Ser-NH- D-0rn-Ser-NH 2 Orn-Ser-NH-CH, D-0rn-Ser-NH-CH 3 0rn-Ser-NH-C 2 H 5 D-Orn-Ser-NH-C H Phe-Lys-Gly In the syntheses described in the foregoing examples, the solvents and reagents were invariably of the highest, commercially-available grade and were used without purification, except in the following cases: Triethylamine was dried over solid potassium hydroxide, decanted and distilled from ninhydrin (1 g per liter of triethylamine) at atmospheric pressure. Trifluoroacetic Acid was distilled from phosphorus pen- toxide at atmospheric pressure. Dicyclohexylamine was dried over solid potassium hydroxide and distilled under vacuum. Dioxane was dried over metallic sodium pieces (freshly cut) and distilled at atmospheric pressure. Dimethylformamide was dried over, solid potassium hydroxide, decanted and distilled from ninhydrin (1 g per liter of solvent) under vacuum. Pyridine was dried over potassium hydroxide, decanted and distilled from ninhydrin (1 g per liter of solvent) at atmospheric pressure. EXAMPLE 14 Methods for assessing purity of intermediates and final products. The purity of intermediates, column fractions (from purifications) and final products was assessed by a combination of techniques. Thin layer chromatography (TLC) was carried out on glass-backed Silica Gel 60 plates (Merck) using the following solvent systems: 1. n-butanol:acetic acid:water:pyridine (30:6:20:24); 2. n-butanol.*acetic acid:water:ethyl acetate (1:1:1:1); and 3. isopropanol:ammonia (3%) (1:1). Products were visualized by spraying the plates with ninhydrin (l% solution in ethanol) or chlorine peptide spray (1% solution of t-butyl hypochlorite in cyclohexane, followed by a 1% solution of o-toluidine in 10% acetic acid). High performance liquid chromatography (HPLC) was carried out on C-18 reverse-phase columns (5 ym particle size, 4.6 mm i.d. x 25 cm) using gradients of acetonitrile in 5 rαM aqueous hexanesulfonic acid or octanesulfonic acid. Flow-rates were typically 1 ml/min., chromatogra s were monitored at 215 nm and 10-20 ugloads of samples were injected. High voltage electrophoresis was carried out in pyridine:acetic acid:water (10:0.4:90) buffers on Whatman 3MM paper at 2 kV. Products were visualized by spraying the chromatograms with ninhydrin (1% solution in ethanol). Final, purified peptide products were packaged under sterile conditions in vials containing 1 ml of 0.01M phosphate buffer, pH 7.4, per milligram of peptide and lyophilized to a dry powder for storage. EXAMPLE 15 Murine Mixed Lymphocyte Response Assay Procedure. The murine MLR assay procedure is described in Dutton, R.W., J. Exp. Med., 123:655-671 (1966). The spleen is removed from mice of two different strains, and the spleen cells from each strain are dis¬ bursed and separately suspended in human serum albumin in RPMI- 1640 (2% HSA-RMPI, Irvine Scientific). ' The cell suspensions are then centrifuged at 400 G for ten minutes at 15 β C, and the cell pellets resuspended in 2% HSA-RPMI.to a total volume of 50 ml. The cell concentration is ascertained using, e.g., a hemacyto- meter. Cell viability, as measured by trypan blue dye exclusion, should be at least 95%. A stimulator cell suspension is prepared by incubating the cells of one strain with 25 ug mitomycin C per ml for 30-60 minutes at 37 β C or irradiation with a total of 3200 roentgens in order to inhibit DNA synthesis. After washing the stimulator cells three times with 2% HSA-RPMI, both the stimu¬ lator cells and the untreated responder cells are suspended in KC 2000 (KC Biologicals) to a concentration of 4 x 10° cells/ml. Equal portions of each suspension are then combined, and a con¬ trol group is prepared in a microtiter plate well by " transferring 0.1 ml aliquots each of the cell mixture and KC 2000. An experi- mental group is prepared by transferring to a microtiter plate well 0.1 ml of the cell mixture and 0.1 ml of the test peptide diluted to twice the experimental concentration. The microtiter plates are incubated in a humidified 37°C incubator with an atmosphere of 5% C0 2 for seven days, whereupon 1 uCi 3 H-thymidine is added in 0.025 ml/well. The control and experimental groups are incubated for six hours and then harvested using a 12-channel SCATRON cell harvester or the equivalent. After the filter pods have air dried, the radioactivity count due to incorporated 3 H-thymidine is ascertained in a LKB minivial scintillation counter using 3 ml Cytoscint (Westchem). The amount of cell-associated radioactivity is used to estimate the degree to which the responding cells in the experimental and control groups are stimulated to proliferate in the presence and in the absence of the subject peptide. EXAMPLE 16 Human Mixed Lymphocyte Response Assay Procedure. The human MLR assay is discussed in "Lymphocyte Transformation in Cultures of Mixed Leukocytes," Lancet 1:1184-1186 (1965), and in Walthe, W.I. et al. (Weir, D.M., ed.). Handbook of Experimental Immunology (3d ed.), pp. 26.1-26.10, Blackwell Scientific Publi¬ cations (London 1978). In this assay, venous blood is extracted from two unrelated human subjects (A and B) in sterile syringes containing 0.15 ml heparin (10,000 units/ml) per 60 cc blood. The mononuclear cells are isolated by centrifuging 40 ml of a 1:1 mixture of blood and sterile RPMI-1640 (Irvine Scientific), underlaid with 8 ml Ficoll-Paque (Pharmacia Fine Chemicals), for 30 minutes at 400 G and 15°C. The plasma is discarded and the mononuclear cell band adjusted to 40 ml with 2% human serum albumin in RPMI-1640 (2% HSA-RPMI, Irvine Scientific). The cell mixture is centrifuged for 8 minutes at 40 G and 15°C, residual plasma discarded, and the cell band rediluted and recentrifuged as immediately above. The cell pellet is resuspended in 10.0 ml KC 2000 (KC Biologicals) , and the mononuclear cells counted using a Coulter counter or the equivalent. Stimulator cells (A* and B*) are prepared by treating 20 X 10° mononuclear cells with irradiation or mitomycin C as described above in the murine MLR assay procedure. Responder cells (A and B) are prepared by washing the untreated cells once with 2% HSA-RPMI. Both respon- der and stimulator cells are adjusted to a final concentra on of 2 X 10° mononuclear cells/ml in KC 2000. In a typical one way human MLR assay, experimental and control groups are assayed by incubating equal-volume mixtures of, e.g., responder cells A and stimulator cells B* for seven days with and without the subject 96 peptide, as described in the murine MLR procedure. 3 H-thymidine is then added to each sample, followed by incubation for six hours, harvesting, and counting of the incorporated labelled DNA in the newly replicated cells as in the murine assay. EXAMPLE 17 Antigen-Specific T Cell Proliferation Assay Procedure. The antigen-specific T-cell proliferation assay consists of injecting a live mouse with a specific antigen for a period suf¬ ficient to allow sensitization to the antigen, culturing the sensitized lymph node cells,, and then reexposing the lymph node cells to the antigen after treatment with the subject peptide. Following an appropriate incubation period, the amount of immuno- responsive T-cell proliferation is measured using labelled-DNA uptake methods, e.g., tritiated thymidine incorporation, thus providing a measure of the immunoregulatory activity of the sub¬ ject peptide with respect to a specific antigen. The data in Table 2 reflect peptide-induced inhibition of T-cell prolifera¬ tion in response to the antigen ovalbumin. Similar assays may be performed using such antigens as bovine serum albumin, human IgG, sheep, chicken or bovine erythrocytes, or haptens such as dinitrophenol. The antigen-specific T cell proliferation assay is de¬ scribed in "Antigen Induced Proliferation Assay for Mouse T- Lymphocyte Response to Monovalent Antigens," Eur. J. Immuno. 8:112-118 (1978). A mouse is injected subcutaneously at the base 97 of the tail with 0.1 mg ovalbumin in 0.05 ml Complete Freund's Adjuvant. After seven days, the mouse is sacrificed and its superficial inguinal lymph nodes removed aseptically. Excess f is removed, and the lymph node cells are dispersed into 15 ml of 2% human serum albumin (HSA) in phosphate-buffered saline (PBS) by, e.g., gentle teasing between the frosted surfaces of two sterile microscope slides. The dispersed single cells are then gently resuspended three to five times using a sterile plastic pipet, transferred to a sterile centrifuge tube, and the super- natent transferred to a new centrifuge tube, free of settled debris, after three minutes. The single cell suspension is cen- trifuged for ten minutes at 400 G and 15 β C, and the pellet resus pended and tested for cell viability by measuring the exclusion of trypan blue dye (0.5% solution, 0.020 ml) from cells of the cell suspension (0.100 ml). The cells should measure at least about 95% viable. The cells are then washed twice in 2% HSA-PBS and resuspended at approximately 8 x 10° lymph node cells/ml in Complete Click's Medium. The cell count is determined and the lymph node cell solution diluted to a final concentration of 4 x 10 6 cells/ml with Complete Click's Medium. 0.1 ml aliquots of the culture suspension are transferred into microtiter plate wells, and 0.1 ml of the subject peptide in Complete Click's Medium in the concentrations specified in Table 2 is added to c experimental groups. Control groups receive Complete Click's Medium. After at least 15 minutes, 100 ug/ml of ovalbumin is added to groups with and without the subject peptide. Control groups are prepared without antigen and with 100 ug/ml of anti- gens unrelated to ovalbumin (e.g., human IgG) or with mitogens such as concanavalin A, phytohemagglutinen, and polkweed mitogen. The plates are incubated at 37°C and 5% C0 2 . On day four to day five, 1 uCi of J H-thymidine is added in 0.025 ml/well, and the plates are incubated for 24 hours before harvesting and counting as described with respect to the murine MLR assay procedure. EXAMPLE 18 Leukemia and Tumor Cell Proliferation Assay. Mouse leukemia/lymphoma and human tumor cell lines are available from, e.g., American Type Culture Collection, 12301 Parklawn Drive, Rockville MD 20852-1776. The individual cells are gently and sterilely dispersed to suspension in PBS. Cell viability is ascertained using the trypan blue dye exclusion method described in Example 16, and should be at least about 85%. The cells are washed 2-3 times in PBS and then twice in RPMI 1640. The cells are then resuspended in a sufficient quantity of approximately 10% FCS-RPMI or HSA-RPMI to yield a final cell concentration of 1 x 10 cells/ml. 0.1 ml aliquots of the tumor cell suspension are transferred to microtiter plate wells. 0.1 ml aliquots of appropriately-diluted peptide in RPMI 1640 are added as indicated in Tables 4 and 5. After incubation for 48 hours at 37°C and 5% C0 2 , the cells are pulsed for six hours with 1 uCi 3 H-thymidine, harvested, and counted as described in the foregoing examples. General procedures relating to the measurement of neoplastic cell proliferation may be found in Sample et al., Clin. Exp. Immunol. 9:419 (1971) and in Shellekens et al., Clin. Exp. Immunol. 3:571 (1968).

Claims: C L A I S 1. Use of a peptide of formula I A-X-(B-Y) -C n wherein X and Y are residues of amino acids or amino acid derivatives with positively charged side chains,- A and C are substituents that preserve or augment the immunoregulatory activity of the peptide, B is a residue of an amino acid or amino acid derivative that preserves or augments the immunoregula¬ tory activity of the peptide, and n is 0 or 1 , for- he manufacture of a medicament for regulating immune system responses. 2. Use of a peptide of formula I for the manu¬ facture of a medicament for suppressing autoimmune disease responses. 3. Use of a peptide of formula I for the manu¬ facture of a medicament for suppressing organ trans¬ plantation rejection responses. 4. Use of a peptide of formula I for the manu¬ facture of a medicament for suppressing neoplastic cell growth . 5. Use of a peptide of formula I for the manu¬ facture of a medicament for suppressing T-lymphocyte proliferation in mixed lymphocyte response cultures or in antigen-specific T-lymphocyte proliferation assay cultures. 6. A peptide of formula I. 7. A peptide of any of formulae la, lb, laa to lam, lama to lamz, Ian to lat, Iba to Ibz or Ibza to Ibzo as defined above. 8. A peptide selected from the group consisting of Ala-Lys-Ser, Ala-D-Lys-D-Ser , Arg-Asp-Arg, Asp-Lys-Ser, Des-*!-amino-Lys-Ala-Lys, Des- -amino-Lys-Arg-Lys, Des-oC-amino-Lys-Asp-Lys , Des-oL-amino-Lys-Cys , Des---A.-an.ino- Lys-Gln, Des- -amino-Lys-Gln-Lys , Des--=_-amino-Lys-Gly-Lys , Des- -amino-Lys-His-Lys , Des-σ-v-amino-Lys-HomoSer , Des->_Nramino-Lys-Lys-Lys, Des-θ.-amiπo-Lys-Lys-fhr-Glu-Thr , Des-Cr-a ino-Lys-Pro, Des-^a ino-Lys-Ser , Des-*-\_. amino- Thr-Glu-Thr, Des- j -amino-Lys-Thr-Glu-Thr-Glπ-Glu-Lys, Des-j(_-amino-Lys-Thr-Lys . Des-'.X_-amino-Lys- al-Lys , Des-J.-amino-Lys-Val-Lys-NH„ , Gln-Glu-Lys, Glu-Lys-Asn- Pro-Leu-Pro, Glu-Thr-Gln-Glu-Lys , Gly-Lys-Ser, HomoLys-Gly, HomoLys-Ser, Leu-Lys-Lys-Thr-Glu-Thr , Lys-Ala-Tyr , Lys-Arg-Lys, Lys— Cys, Lys-Gln, Lys-Gln-Lys, Lys-Gly-Tyr, Lys-His-Lys, Lys-HomoSer, Lys-Lys-Thr-Glu-Thr, Lys-Thr-Glu, Lys-Thr-Glu-Thr , Lys-Thr-Lys, Lys-Val-Lys, Lys-Val-Lys-NH 2 , Orn-Ala, Thr-Gln-Glu-Lys, Thr-Gln-Glu- Lys-Asn-Pro-Leu-Pro, Thr-Glu-Thr, and Val-Lys-Ser. 9. A peptide selected from the group consisting of Ae-Lys-Ser, Ac-Lys-Ser-Lys , Ac-Lys-Ser-NH 2 , Ala-Lys-Gly, D-Ala-D-Lys-D-Ser, Ala-Lys-Ser-Arg, Ala-Lys-Val-Lys-NH 2 , Arg-D-Ala, Arg-Ala-Lys, Arg-Gly-Lys, Arg-Lys-Ser-Arg , Arg-Sar, Arg-Thr, Asn-Lys-Ser-Arg, Asp-His-Ser-Arg, Asp-Lys-Ile-Arg, Asp-Lys-Lys-Arg, Asp-Lys-Ser-His, Asp-Orn-Ser-Arg, Gly-Asp-Lys-Ser-Arg, Gly-Lys-Val-Arg , Lys-D-Ala-Lys, Lys-Asp, Lys-Glu-Lys , Lys-Leu, Lys-Leu- Lys-NH 2 , D-Lys-NH 2 , D-Lys-NHCH 2 CH 3 , Lys-D-Phe, D-Lys-Ser, Lys-Ser-Ala, Lys-Ser-Arg, Lys-Ser-NH 2 , Lys-Thr-Arg, Lys-Tyr-Lys-NH 2 , Lys-D-Val-Lys-NH 2 , N-Me-Lys-D-Ser , Orn-D-Ala, Phe-Lys-D-Ala, Phe-Lys-Sar, Phe-Lys-Ser-Tyr , Sar-D-Lys-Ser , Ser-Lys-Val-Arg, Tyr-Lys-Gly and Val-Lys-Val-Lys-NH 2 . 10. A process for the preparation of a peptide of formula I characterized in that such peptide is liberated from its corresponding functional derivative which may be bound by a covalent bond to a solid resin by treat¬ ment under acidic or basic conditions, and, if desired, the peptide thus obtained is esterified, amidated and/or acylated to yield a corresponding ester, amide, N- and/or O-acyl derivative or is transformed* into one of its pharmacologically acceptable salts by treatment with a base or an acid. 11. A pharmaceutical preparation comprising a peptide of formula I and at least one pharmaceutically acceptable carrier. 12. Use of a peptide of formula I for regulating immune system responses. 13. Use of a peptide of formula I for suppressing autoimmune disease responses. 14. Use of a peptide of formula I for suppressing organ transplantation rejection responses. 15. Use of a peptide of formula I for suppressing neoplastic cell growth. 16. Use of a peptide of formula I for suppressing T-lymphocyte proliferation in mixed lymphocyte response cultures or in antigen-specific T-lymphocyte prolifera¬ tion assay cultures.

Inventors: HAHN GARY SCOTT, HAHN, GARY, SCOTT
Applicants: MERCK PATENT GMBH, MERCK PATENT GESELLSCHAFT MIT BESCHRAENKTER HAFTUNG
Application year: 1986
Main classification: C07K5
IPC codes: A61K38, C07K5, C07K14, C07K16