bluuebunny/crossref_metadata_2025 huggingface dataset:
STUDIES ON THE MECHANISM OF PENICILLIN-INDUCED FEVER
Authors: Chusid Michael J. , Atkins Elisha
Published: June 2004

Rabbits immunized to benzylpenicillin G responded with fever when challenged with a penicillin-serum protein conjugate, but not with penicillin itself. After one or two challenges with conjugate, the rabbits became unresponsive (tolerant) to further injections. This form of hypersensitivity was transferable with plasma of immunized donors to normal rabbits. Blood leukocytes of immunized rabbits incubated with penicillin-protein conjugate and hypersensitive serum released endogenous pyrogen in vitro. Spleen cells from the same animals, on the other hand, were inactive when incubated with this antigen in vitro. These experiments appear to be the first to demonstrate in vitro a possible mechanism of drug-induced fever.
TUMOR DORMANCY IN VIVO BY PREVENTION OF NEOVASCULARIZATION
Authors: Gimbrone Michael A. , Leapman Stephen B. , Cotran Ramzi S. , Folkman Judah
Published: June 2004

Dormant solid tumors were produced in vivo by prevention of neovascularization.

When small fragments of anaplastic Brown-Pearce carcinoma were implanted directly on the iris in susceptible rabbits, they always vascularized. A characteristic growth pattern, consisting of prevascular, vascular, and late phases, was observed, which terminated with destruction of the eye within 2 wk. The beginning of exponential volume increase was shown to coincide with vascularization of the implant, as demonstrated by perfusion with intravenous fluorescein and by histologic sections.

In contrast, implants placed in the anterior chamber, at a distance from the iris, did not become vascularized. After initial growth into spheroids, they remained arrested at a small size comparable to prevascular iris implants, for periods as long as 6 wk. Although dormant in terms of expansion, these avascular tumors contained a population of viable and mitotically active tumor cells. When reimplanted on the iris, vascularization was followed by rapid, invasive growth.

These observations suggest that neovascularization is a necessary condition for malignant growth of a solid tumor. When a small mass of tumor cells is prevented from eliciting new vessel ingrowth from surrounding host tissues, population dormancy results. These data suggest that the specific blockade of tumor-induced angiogenesis may be an effective means of controlling neoplastic growth.
MATURATION OF THE IMMUNE RESPONSE IN VITRO
Authors: Macario Alberto J. L. , de Macario Everly Conway , Franceschi Claudio , Celada Franco
Published: June 2004

We have cultivated lymph node microfragments from ß-D-galactosidase (Escherichia coli) primed rabbits and have measured their secondary response directed towards the whole molecule (precipitating antibodies) and to a single determinant (activating antibodies) of the antigen. By decreasing the size of the fragments to 105 cells, we began to observe heterogeneity among identical cultures in terms of positivity of response, antibody specificity, and titers. The affinity of "early" activating antibodies was inversely proportional to the dose of challenge. While no maturation was seen in low and excessive challenge, in all cultures receiving intermediate doses the association constant was raised several orders of magnitude within periods of 20 days. The relevance of these data to the mechanism of affinity selection of antigen-sensitive cells is discussed.
B CELL ACTIVATION IN VIVO BY NONANTIGEN-SPECIFIC INTERACTION WITH T CELLS
Authors: Tito T. , Shearer G. M. , Trizio D. , Cudkowicz G.
Published: June 2004

The number of direct (γM) hemolytic plaque responses of irradiated mice, repopulated with relatively small and limiting numbers of bone marrow and thymus cells, was increased by the simultaneous immunization with two antigen complexes instead of one. Anti-sheep responses were augmented by the following antigen combinations: SRBC + HRBC, SRBC + BRBC, and SRBC + CRBC. Limiting either thymocytes or bone marrow cells indicated that the antigen mixtures acted at the level of T cells increasing severalfold the number of triggered antigen-reactive cells. It was concluded that one of the antigens could have influenced the triggering of antigen-reactive cells specific for the other by promoting synergistic or derepressive T-T cell interactions. Moreover, bone marrow precursor cells could have been activated by the thymic inducers specific for the test antigens as well as by those specific for the second of the priming antigens.
HAPTEN-SPECIFIC TOLERANCE
Authors: Davie Joseph M. , Paul William E. , Katz David H. , Benacerraf Baruj
Published: June 2004

The induction of tolerance in guinea pigs with a 2,4-dinitrophenyl (DNP) derivative of a copolymer of copolymer of D-glutamic acid and D-lysine (D-GL) leads to a preferential depression of the capacity to produce high affinity anti-DNP antibody in response to immunization with DNP-guinea pig albumin. Thus, immunization 2 wk after tolerance induction with 3 mg of DNP-D-GL results in an immune response in which individual plaque-forming cells (PFC) secreting high affinity anti-DNP antibody are absent and in which the affinity of circulating anti-DNP antibody is reduced. A similar, but less marked, suppression is seen when 0.3 mg of DNP-D-GL is used for tolerance induction. If immunization is delayed until 2 months after tolerance induction, then suppression is restricted to the highest avidity PFC group. Our data is consistent with a state of tolerance in the pool of precursors of anti-DNP antibody-secreting cells induced as a result of their interaction with DNP-D-GL in the absence of specific "helper" cells, which appear to be lacking for DNP-D-GL. In such a situation, the affinity of receptors on precursor cells for tolerogen and the concentration of tolerogen appear to be crucial determinants of whether an individual cell will become tolerant.
THE SPECIFIC SELECTION OF RECIRCULATING LYMPHOCYTES BY ANTIGEN IN NORMAL AND PREIMMUNIZED RATS
Authors: Rowley D. A. , Gowans J. L. , Atkins R. C. , Ford W. L. , Smith Marilyn E.
Published: June 2004

Thoracic duct lymphocytes (TDL) from normal rats will restore a primary antibody response to sheep erythrocytes (SRBC) in irradiated recipients and cause a graft-versus-host reaction in F1 hybrid rats; lymphocytes from rats immunized with either tetanus toxoid or dinitrophenylated bovine gamma globulin (DNP BGG) will generate specific antibody after cell transfer and challenge. The ability of TDL to mediate each of these responses is severely depressed by giving a single intravenous dose of the specific antigen shortly before cannulation of the thoracic duct, although the lymphocyte donors themselves respond normally. The injection of antigen does not decrease the output of lymphocytes in the thoracic duct and the effect is specific for the antigen injected. The findings are most readily accounted for by assuming that small subpopulations of specific lymphocytes are selected from the recirculating pool by antigen which has localized in lymphoid tissue. The observation that passive antibody abolishes selection by SRBC supports this interpretation.

The strong selection exerted by a subcutaneous injection of SRBC in Freund's complete adjuvant, which induces delayed hypersensitivity but little early antibody, suggests that a common cell type may be involved in the induction of both delayed hypersensitivity and antibody formation. The anti-DNP antibody response generated by TDL from rats immunized with DNP BGG was abolished by a selecting injection of the homologous conjugate. The response was depressed to a smaller degree by injections of either BGG or dinitrophenylated human serum albumin, suggesting that carrier-specific (T) and hapten-specific (B) lymphocytes could be separately selected from the recirculating pool.

The regional selection of recirculating lymphocytes by antigen may explain a number of phenomena in which the prior injection of antigen has been found to inhibit a subsequent immune response.
INDUCTION OF IMMUNITY AND TOLERANCE IN VITRO BY HAPTEN PROTEIN CONJUGATES
Authors: Feldmann Marc
Published: June 2004

The capacity of dissociated spleen cell suspensions to be immunized by dinitrophenylated polymeric flagellin (DNP POL), in the absence of thymus-dependent lymphocytes or macrophages, provided a simple experimental system to investigate the mechanism of binding of antigen molecules to nonthymus-dependent lymphocyte (B cell) receptors during the induction of immunity or tolerance. Various nonimmunogenic DNP compounds were used to inhibit the anti-DNP response to DNP POL. By performing inhibition experiments of brief duration at 4°C, it was established that the inhibition of the anti-DNP response by nonimmunogenic compounds was due to competitive blockade of receptors, and not tolerance or receptor modulation. It was found that univalent DNP compounds were much less efficient inhibitors of the antibody response than multivalent DNP conjugates. The difference in inhibitory capacity between univalent and multivalent DNP human globulin (DNP HgG) suggested the importance of interaction with both combining sites of a single receptor antibody molecule. Nonimmunogenic highly conjugated DNP3POL was a more efficient inhibitor of the anti-DNP response to immunogenic DNP1POL than DNP12HgG, indicating that interactions at more than one receptor molecule are involved in immunization of B cells. Recent demonstrations of the rapid metabolic turnover of receptor antibody molecules suggests that the requirement for multipoint binding (to different receptors) may simply be to maintain the antigen at the cell surface in a dynamic system.

Competitive inhibition experiments were also performed to investigate the mechanism of binding of DNP3POL in the induction of B cell tolerance. It was found that monovalent DNP compounds or multivalent DNP12HgG did not prevent the induction of tolerance, unlike their capacity to inhibit immunity, suggesting that a tolerance-inducing antigen binds more avidly to the cell membrane than an immunogen. The inhibition data obtained here, together with prior results describing the differential immunogenicity of DNP conjugates of different structure, and the importance of epitope density on DNP POL conjugates, permit certain conclusions about the details of antigen-receptor interaction in immunity and tolerance. Distinctions between the mechanisms of immune and tolerance induction are discussed.
DECREASED PERCENTAGE OF POLYMORPHONUCLEAR NEUTROPHILS IN MOUSE PERIPHERAL BLOOD AFTER INOCULATION WITH MATERIAL FROM MULTIPLE SCLEROSIS PATIENTS
Authors: Carp Richard I. , Licursi Pamela C. , Merz Patricia A. , Merz George S.
Published: June 2004

Mice inoculated with brain homogenates from multiple sclerosis (MS) cases showed marked changes in their leukocyte differential counts, with a decrease in per cent polymorphonuclear neutrophils (PMN) and an increase in the per cent lymphocytes. These changes were based upon an absolute decrease in the number of circulating PMN. The decrease in PMN percentages was apparent at 16 hr after infection and persisted for at least 11 months. The factor responsible for the decrease in PMN was (a) recoverable from 12 hr to 8½ months after inoculation, (b) present in human brain homogenate at a concentration of 3 x 1012, and (c) between 25 and 50 nm in diameter. Inoculation of 100 units of factor into mice and subsequent titration showed that the factor had undergone a net increase in the mouse of at least 109-fold. The factor causing the PMN decrease was found in all MS material thus far tested: three brains, one spleen, three sera, and two cerebrospinal fluid (CSF) from nine cases of MS. The factor was not found in normal human material that included two brains, one spleen, two sera, and two CSF.
THE ORIGIN OF ALVEOLAR MACROPHAGES IN MOUSE RADIATION CHIMERAS
Authors: Godleski John J. , Brain Joseph D.
Published: June 2004

This investigation attempted to determine whether the primary source of alveolar macrophages is pulmonary or hematopoietic. We have utilized an antigenic marker to identify cells of hematopoietic origin. Mouse chimeras were produced by irradiating C57B6/AF1 mice (900 R) and then injecting them intravenously with B10D2/AF1 bone marrow. The donor animal has an antigenic specificity on the H-2 locus, not shared by the recipient. Alveolar macrophages were obtained by repeated lung washings with physiologic saline at 37°C. Cytotoxic tests were done on bone marrow and alveolar macrophages using anti-31 mouse antibody, absorbed rabbit serum as complement, and trypan blue exclusion as a test for viability. Animals were studied at 7, 14, 21, 28, and 35–50 days and 4, 5, 8, and 11 months after irradiation and bone marrow replacement. By 21 days after irradiation, 90% of the animals had greater than 80% replacement of marrow with donor tissue; and white blood cell and alveolar macrophage counts approached normal. At this time and at later intervals the per cent of donor cells in the lung free cell population was not significantly different from the per cent of donor cells in the bone marrow. Similarly, after aerosol particulate exposure, the percentage of marrow cells and alveolar macrophages of donor origin were not significantly different. This immunologic approach suggests that alveolar macrophages in radiation chimeras are entirely of hematopoietic origin.
CELL SURFACE IMMUNOGLOBULIN
Authors: Vitetta Ellen S. , Uhr Jonathan W.
Published: June 2004

Turnover and release of cell surface Ig and secretion of total intracellular Ig has been studied in small lymphocytes from normal mouse spleen. The major findings to emerge are: (a) small lymphocytes secrete 8S IgM and IgG. A small portion of the 8S IgM, but virtually none of the IgG appears to have a cell surface phase. (b) Cell surface IgM is actively turned over with a half-life of 6–8 hr, and turnover can be accounted for by release into the incubation medium. Release is temperature dependent. (c) Released cell surface Ig is noncovalently bound to a fragment of plasma membrane. (d) H-2 antigens are not released during short-term incubation. Based on the above findings, we propose a model for the transport and release of both cell surface and conventionally secreted Ig.
GENETIC FACTORS CONTROLLING ANTI-SHEEP ERYTHROCYTE ANTIBODY RESPONSE AND IMMUNOGLOBULIN SYNTHESIS IN BACKCROSS AND F2 PROGENY OF MICE GENETICALLY SELECTED FOR "HIGH" OR "LOW" ANTIBODY SYNTHESIS
Authors: Lieberman R. , Stiffel C. , Asofsky R. , Mouton D. , Biozzi G. , Benacerraf B.
Published: June 2004

Agglutinin responses to sheep erythrocytes and immunoglobulin heavy chain phenotypes determined in F1, F2, and backcross progeny of mice genetically selected for high and low antibody synthesis indicated that an immune response gene for sheep erythrocytes is linked to the immunoglobulin heavy chain allotype. Mice homozygous for the phenotype of the high line had significantly higher titers than mice homozygous for the phenotype of the low line. An association was also observed in some progeny of the backcross of the F1 generation with the low line. However, the control of the immune response was clearly multigenic since heterozygous mice of the same phenotype (2/3, 5) resulting from the two backcrosses (high and low) had very different immune responses.

Immunoglobulin levels in the same progeny showed no linkage to the immunoglobulin allotype but a rather simple pattern of inheritance.
OCCURRENCE OF 19S AND 7S ANTI-IGGS DURING HYPERIMMUNIZATION OF RABBITS WITH STREPTOCOCCI
Authors: Bokisch Viktor A. , Bernstein David , Krause Richard M.
Published: June 2004

All 110 rabbits immunized with Group A, A-variant, and C streptococcal vaccines produced 19S anti-IgG in addition to antibodies to the streptococcal carbohydrates. 19S anti-IgG was detected by hemagglutination of rabbit red blood cells coated with rabbit anti-blood group F antibody. Antisera of 88 of these animals were also tested for 7S anti-IgG with a coprecipitation assay. This assay is based on the coprecipitation of 7S anti-IgG with complexes of streptococcal carbohydrate and anti-carbohydrate antibody. 50 of the 88 anti-Group C streptococcal antisera contained 7S anti-IgGs. In eight antisera the concentration was greater than 5 mg/ml.

The data suggest a genetic influence on the occurrence of 7S anti-IgG. The eight rabbits which produced more than 5 mg/ml of 7S anti-IgG belonged to three related families. Moreover, there were families in which almost every member produced 7S anti-IgG and other families in which only 30% of the members manufactured 7S anti-IgG.

The streptococcal vaccine was an especially efficient stimulus for the production of 19S anti-IgG, whereas the pneumococcal vaccine was much less effective in this respect. Furthermore, 7S anti-IgGs were not detected in antipneumococcal antisera, although the concentration of anti-capsular antibodies was similar to that of anti-carbohydrate antibodies in antistreptococcal antisera.
STUDIES IN PORPHYRIA
Authors: Kappas Attallah , Bradlow H. Leon , Gillette Peter N. , Gallagher T. F.
Published: June 2004

A variety of 5ß steroid metabolites derived from hormones natural to man are potent inducers experimentally of δ-aminolevulinate synthetase, the rate-limiting enzyme in porphyrin-heme formation. This mitochondrial enzyme is found at high levels of activity in the livers of patients with the genetic disease, acute intermittent porphyria (AIP). In this study the metabolism of 14C-labeled testosterone was examined in AIP patients to determine whether there was a disproportionate conversion of the hormone to its 5ß, compared to its 5α metabolite. The results indicate that AIP subjects do generate a substantially greater than normal fraction of 5ß metabolite from this steroid; the excessive degree of ring A reduction of testosterone taking place via the 5ß pathway in the porphyric patients averages 350% greater than in the nonporphyric subjects. In one asymptomatic AIP patient the disproportionate generation of 5ß metabolite from the hormone reached a level 10 times the normal mean. Studies with a second 14C-labeled hormone, dehydroisoandrosterone, whose metabolism in man resembles that of testosterone, confirmed the derangement in reductive transformation of steroids found in the individuals carrying the genetic lesion of AIP.

These findings define a new endocrine abnormality in AIP patients and raise the possibility that endogenously derived 5ß steroids may contribute by an induction mechanism to the increased levels of hepatic δ-aminolevulinate synthetase activity found in AIP patients.
PREPARATION AND FURTHER CHARACTERIZATION OF THE MN GLYCOPROTEIN OF HUMAN ERYTHROCYTE MEMBRANES
Authors: Cleve Hartwig , Hamaguchi Hideo , Hütteroth Thomas
Published: June 2004

Human erythrocyte membrane glycoproteins were solubilized and recovered in the aqueous phase after extraction of red cell ghosts with a mixture of chloroform and methanol. The major glycoprotein, the so-called MN glycoprotein, was prepared from this phase by gel filtration on Sepharose 4B columns in 6 M guanidine hydrochloride. By SDS-acrylamide gel electrophoresis the MN glycoproteins from the three major genetic types, MM, MN, and NN, were found to be relatively free from minor glycoprotein contaminants. The carbohydrate and amino acid composition did not reveal significant differences between the three MN genotypes. The specific activities of the purified glycoproteins were determined for inhibition of agglutinating anti-M and anti-N rabbit antisera and for inhibition of myxovirus hemagglutination. It was, furthermore, established that the purified MN glycoproteins contain a receptor for Phaseolus vulgaris phytohemagglutination. The red cell MN glycoprotein inhibits partially lymphocyte stimulation induced by unfractionated Phaseolus vulgaris phytohemagglutinin; the red cell MN glycoprotein does not influence the lymphocyte stimulation induced by purified Phaseolus vulgaris mitogen.
H-2-LINKED IMMUNE RESPONSE (Ir) GENES
Authors: Lieberman R. , Paul W. E. , Humphrey W. , Stimpfling J. H.
Published: June 2004

Two H-2-linked autosomal dominant immune response (Ir) genes Ir-IgG and Ir-IgA were demonstrated to be at separate loci. Ir-IgG controls the immune response to IgG (γ2a) myeloma proteins and Ir-IgA the immune response to IgA meyloma proteins. Both genes are associated with the H-2K region specificities of the H-2 chromosome, specifically Ir-IgG with H-2b and Ir-IgA with H-2a. Different recombinants derived from H-2a/H-2b crossovers were examined for their immune responsiveness to BALB/c IgG (γ2a) and IgA myeloma proteins. B10 (H-2b) parental type responded only to IgG; B10.A (H-2a) responded only to IgA. All the recombinants except for B10.A (4R) responded to either IgG or IgA. B10.A (4R), however, responded to both IgG and IgA. This indicated that the crossover event giving rise to B10.A (4R) occurred between the Ir-IgG and Ir-IgA loci.
THYMUS-DERIVED (T) CELL IMMUNOGLOBULINS
Authors: Grey Howard M. , Kubo Ralph T. , Cerottini Jean-Charles
Published: June 2004

Quantitation of surface and total cell Ig obtained after lysis by detergent, urea-acid treatment, and freeze-thawing were determined on spleen cells, thymus cells, and spleen cells specifically depleted of B cells. A two- to four-fold increase in measurable Ig was found after cell lysis. All cell populations showed a similar increase in measurable Ig indicating that no discordantly large amounts of buried Ig determinants were associated with the surface of T cells. The lack of appreciable amounts of T cell Ig was confirmed by immunoprecipitation of radioiodinated cells. A theta-positive lymphoma was described which, when grown in culture, lacked detectable surface Ig but contained a receptor site for IgG. This resulted in appreciable amounts of surface IgG being associated with the tumor line when isolated from ascitic fluid of tumor-bearing mice or after preincubation of cultured cells with either heat-aggregated IgG or normal mouse serum.
IMMUNOLOGIC PROPERTIES OF MOUSE THYMUS CELLS
Authors: Konda Susumu , Nakao Yoshinobu , Smith Richard T.
Published: June 2004

The functional attributes of minor subpopulations of mouse thymus cells derived by bovine serum albumin density gradient centrifugation, cortisone treatment, or selective depletion by anti-TL or anti-θ treatment have been examined. A subpopulation derived in each fashion contains the cells required to evoke graft-versus-host reactions in neonatal F1 hybrid recipients and to be stimulated by alloantigens in vitro in one-way mixed lymphocyte cultures and by phytohemagglutinin. The functions of this subpopulation are abrogated by treatment with anti-H-2 plus complement and by high concentrations of anti-θ. A tentative ordering of the various thymus cell subpopulations, on the basis of these and other data, is described.
ANTIGEN-INDUCED STIMULATION OF GLUCOSAMINE INCORPORATION BY GUINEA PIG PERITONEAL MACROPHAGES IN DELAYED HYPERSENSITIVITY
Authors: Hammond M. Elizabeth , Dvorak Harold F.
Published: June 2004

The interaction between sensitized lymphocytes and specific antigen occurring in delayed hypersensitivity causes bystander macrophages to undergo a variety of light-microscopic, ultrastructural, and biochemical changes, which are reflected in alterations in cell movement and intercellular contacts. Since such alterations involve functions of the cell periphery, we postulated that metabolic changes in this polysaccharide-rich zone would accompany the expression of delayed hypersensitivity.

We here demonstrate that the incorporation of radioactive glucosamine by peritoneal macrophages into TCA-precipitable, membrane-associated material is regularly enhanced when these are cultured in the presence of specific antigen and nonadherent cells (lymphocytes) primed for delayed hypersensitivity. Lymphocytes from unsensitized animals, or from animals immunized so as to form antibody but not delayed hypersensitivity, do not stimulate such incorporation. Antigen-induced glucosamine incorporation is maximal at 2 or 3 days of culture and is not observed earlier; it may be elicited with as little as 0.1 µg/ml PPD, and affords an exceedingly reproducible and sensitive index of delayed hypersensitivity.

Radioautographic studies indicate that nearly all plastic adherent cells (90% macrophages) incorporate glucosamine and that grains are concentrated in the regions of the perinuclear zone and cell membrane. Subcellular fractionation indicates that nearly 30% of counts and the highest specific activity are associated with the membrane-rich microsomal fraction; the microsomal distribution of counts increases in both absolute and relative terms when macrophages are cultured in the presence of specific antigen and sensitized lymphocytes.

Taken together, these data indicate that a sizable fraction of incorporated glucosamine is localized to the vicinity of the cell periphery but lack sufficient resolution to determine whether this material is associated with the cell membrane itself or with the extramembranous cell coat. This last possibility is of particular interest since we have previously shown that macrophage cell coat material is lost or altered as a consequence of an interaction between sensitized lymphocytes and specific antigen.
DISTRIBUTION OF LABELED LYMPH NODE CELLS IN MICE DURING THE LYMPHOCYTOSIS INDUCED BY BORDETELLA PERTUSSIS
Authors: Taub Robert N. , Rosett Walter , Adler Andy , Morse Stephen I.
Published: June 2004

The mechanism by which Bordetella pertussis organisms and their products induce lymphocytosis in mice was analyzed in terms of the localization of syngeneic Cr-51-labeled lymph node cells. Labeled lymphoid cells incubated in vitro with the supernatant of B. pertussis cultures and then injected intravenously into normal recipients, or labeled cells injected into pertussis-treated recipients were unable to "home" to lymphoid organs but persisted for long periods in the blood. In animals "equipped" with a population of Cr-51-labeled lymphoid cells, administration of B. pertussis organisms or culture supernatant effected a shift of radioactivity from lymph nodes and spleen into the peripheral blood, coincident with the lymphocytosis.

In in vitro experiments it was found that the active principle could bind to both erythrocytes and lymphocytes and could spontaneously elute from these cells onto labeled lymphocytes which were then unable to home efficiently.

The data suggest that Bordetella pertussis-induced lymphocytosis involves a reversible attachment of the pertussis factor onto the surfaces of lymphocytes which prevents their recirculation to lymphoid organs. Recirculating lymphocytes are presumably affected as they emerge from lymphoid organs to enter the blood.
QUANTITATIVE EFFECTS OF NUTRITIONAL ESSENTIAL AMINO ACID DEFICIENCY UPON IMMUNE RESPONSES TO TUMORS IN MICE
Authors: Jose David G. , Good Robert A.
Published: June 2004

Mice were fed diets deficient in a single essential amino acid, and the primary immune responses to inoculation of allogenic tumor cells was measured by in vitro assay of cellular immunity. Moderate reduction of the amino acids phenylalanine-tyrosine, valine, threonine, methionine-cystine, isoleucine, and tryptophane in the diet produced profound depression of hemagglutinating and blocking antibody responses, although cytotoxic cell-mediated immunity remained intact. These diets had previously been shown to result in a selective depression of tumor growth in mice. Limitation of the amino acids arginine, histidine, and lysine in the diets gave rise to only slight depression of the immune responses. These diets had previously been shown to produce a proportional decrease in both tumor growth and host body weight. Moderate leucine restriction resulted in a paradoxical depression of cytotoxic cell-mediated immunity with little effect on serum blocking activity. Slight increases had previously been noted in the weight of tumors in mice fed leucine-restricted diets. Deficiency or imbalance of essential amino acids in the diet may produce profound depression of immune responses and apparent, marked changes in the immune resistance of the host animal to tumors.
EVIDENCE FOR THE LINKAGE OF THE IGCH LOCUS TO A GENE CONTROLLING THE IDIOTYPIC SPECIFICITY OF ANTI-p-AZOPHENYLARSONATE ANTIBODIES IN STRAIN A MICE
Authors: Pawlak Laura L. , Mushinski Elizabeth B. , Nisonoff Alfred , Potter Michael
Published: June 2004

Anti-p-azophenylarsonate (anti-Ar) antibodies elicited in all strain A/J mice tested share one or more idiotypic specificities. These specificities are also found in the anti-Ar antibodies of mice of the closely related strain, AL/N, but not in those of BALB/c mice.

Anti-Ar antibodies were elicited in congenic mice in which the IgCH locus of AL/N mice, which controls allotypic markers in the constant regions of heavy chains, had been introgressively backcrossed for nine generations onto a BALB/c background; the mice were then rendered homozygous for the AL/N allotypic determinant. On the average, these antibodies were quantitatively equivalent, with respect to content of the cross-reactive idiotype, to those of AL/N mice. This indicates that the gene controlling the idiotype is closely linked to the IgCH locus. Since idiotype must be a function of V region sequences, the results suggest close linkage of VH and CH genes. The cross-reactive idiotype was found in nearly all F1 mice (C57/BL x A/J or BALB/c x A/J) tested.
AN ENZYMATIC FUNCTION ASSOCIATED WITH TRANSFORMATION OF FIBROBLASTS BY ONCOGENIC VIRUSES
Authors: Unkeless J. C. , Tobia A. , Ossowski L. , Quigley J. P. , Rifkin D. B. , Reich E.
Published: June 2004

Chick embryo fibroblast cultures develop fibrinolytic activity after transformation by Rous sarcoma virus (RSV). This fibrinolytic activity is not present in normal cultures, and it does not appear after infection with either nontransforming strains of avian leukosis viruses or cytocidal RNA and DNA viruses. In cultures infected with a temperature sensitive mutant of RSV the onset of fibrinolysis appears after exposure to permissive temperatures and precedes by a short interval the appearance of morphological evidence of transformation.

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The rate of fibrinolysis in transformed cultures depends on the nature of the serum that is present in the growth medium: some sera (e.g., monkey or chicken serum) promote high enzymatic activity, while others (calf, fetal bovine) do not. Some sera contain inhibitors of the fibrinolysin.

Based on the effect of a small number of known inhibitors, at least one step of the fibrinolytic process shows specificity resembling that of trypsin.

The sera of sarcoma-bearing chickens contain an inhibitor of the fibrinolysin, whereas normal chicken sera do not.

For general discussion, conclusions, and summary see the accompanying paper, part II, (J. Exp. Med. 137:112).
REGULATION OF AUTOSENSITIZATION
Authors: Cohen Irun R. , Wekerle Hartmut
Published: June 2004

We studied the mechanisms underlying the natural tolerance of thymus-derived (T) lymphocytes for self-antigens. Lymphocytes from the thymus or lymph nodes of inbred rats were autosensitized in vitro against monolayers of autochthonous thymus reticulum cells or syngeneic fibroblasts. Receptors for self-antigens were detected by the specific adherence of normal lymphocytes to syngeneic cells. The achievement of active cell-mediated autosensitization was assayed by measuring the immunospecific lysis of syngeneic target cells in vitro, or graft-versus-host (GvH) reactions in vivo. The following observations were made using these systems.

(a) A fraction of normal lymphocytes was found to have specific surface receptors that are able to recognize self-antigens which seem to be accessible in vivo. These potentially self-reactive lymphocytes were activated by incubation with syngeneic or autochthonous cells in vitro. Hence, the elimination of potentially self-reactive lymphocytes cannot be the only basis for natural self-tolerance. Therefore, the maintenance of self-tolerance in vivo appears to involve suppression of the immune reactivity of such self-tolerant lymphocytes.

(b) We found that control of autosensitization depends upon the inhibition of the recognition of self-antigens. A GvH reaction in vivo could not be suppressed once recognition of self-antigens had occurred in vitro. Moreover, studies of the kinetics of antigen recognition indicated that several hours of incubation in vitro were needed for the inactivation of factors specifically inhibiting self-recognition.

(c) We found that factors which inhibit self-recognition are present in fresh autologous serum. Treatment of the lymphocytes, but not syngeneic adsorbing cells, with autologous serum prevented recognition of syngeneic antigens. Allogeneic serum did not prevent self-recognition, and autologous serum did not inhibit the recognition of foreign antigens.

These findings indicate that natural tolerance of T lymphocytes to self-antigens can be regulated by serum factors which act on the lymphocytes. The immunospecificity of the inhibitory effect suggests that these factors may be soluble self-antigens in a tolerogenic form.
CROSS-IDIOTYPIC SPECIFICITY AMONG MONOCLONAL IGM PROTEINS WITH ANTI-γ-GLOBULIN ACTIVITY
Authors: Kunkel H. G. , Agnello V. , Joslin F. G. , Winchester R. J. , Capra J. D.
Published: June 2004

Through the use of absorbed idiotypic antisera prepared against single isolated monoclonal IgM anti-γ-globulins, partial cross-idiotypic specificity was demonstrated with other IgM anti-γ-globulins. Such antisera classified these proteins into at least three groups. The major group which included 60% of the anti-γ-globulins was particularly homogeneous. The anti-γ-globulin specific antigens were detected best in hemagglutination and hemagglutination inhibition systems. They were not found in monoclonal IgM proteins that lacked anti-γ-globulin activity although related antigens were detected at low concentrations in pooled immunoglobulin preparations as well as in heterogeneous anti-Rh antibodies.

Several lines of evidence were obtained indicating that the antibody combining site was involved in the specific determinants. Attempts were made to analyze the fine specificity of each anti-γ-globulin for the Fc fragment of different subclasses of human immunoglobulins as well as those of other species. Differences were observed but these were not readily related to the cross-specificity antigens.

The anti-γ-globulin specific antigens were very analogous to those previously described for monoclonal IgM cold agglutinins. Although each protein could be distinguished from all the others on the basis of individual idiotypic antigens, the antigens common to the specific groups of proteins with each of these activities were prominent and readily detected with multiple antisera. The results indicate basic similarities between proteins of a given activity even in unrelated individuals.
EFFECTS OF SERUM ON MEMBRANE TRANSPORT
Authors: Strauss Phyllis R. , Berlin Richard D.
Published: June 2004

The effects of normal rabbit serum (NRS) on two transport systems in rabbit lung macrophages have been examined. A 20 min preincubation with serum was required for the effects, which were retained for at least 40 min after serum was removed. No serum was present during the transport studies. (a) Preincubation with 0.5 or 1.0% NRS resulted in depression of lysine transport to 59 ± 2.6% (SE, 31 observations) of control levels. The activity was heat stable to 100°C for 30 min and lost after dialysis. Pretreatment with serum did not alter the intracellular concentration of lysine attained when cells were then incubated with 10 mM lysine for 30 min. The relative depression of lysine transport by serum was unaltered by preloading with such high concentrations of lysine. (b) Preincubation with 5% NRS resulted in enhancement of adenosine transport by 35 ± 2.3% (SE, 60 observations). Activity was stable to heating at 65°C for 40 min but lost at 100°C for 20 min. It was nondialyzable. Total radioactivity accumulated after 30 min incubation with 1 mM adenosine was unaffected by serum pretreatment. The two activities were separable by passage over Sephadex G25.
FATE OF ANTIGEN-BINDING CELLS IN UNRESPONSIVE AND IMMUNE MICE
Authors: Louis J. , Chiller J. M. , Weigle W. O.
Published: June 2004

Antigen-binding cells (ABC) to the antigen human gamma globulin (HGG) were quantitated in lymphoid tissues of A/J mice at various times after the injection of deaggregated HGG (tolerogen), aggregated HGG (immunogen), or saline. The reaction of lymphoid cells with highly labeled HGG was specific to that antigen since binding could be inhibited by excess unlabeled HGG, but not by unrelated non-cross-reacting proteins. Compared with normal mice, there was a marked decrease in the numbers of ABC in the spleens of unresponsive animals evident as early as 12 h after the injection of tolerogen. A marked increase in ABC was observed in the spleens of immunogen-injected mice, beginning at 24 h and reaching a peak at 3 days. In bone marrow, no difference in the number of ABC was found among the three experimental groups until day 20, when a reduction in ABC was observed only in tolerogen-injected mice. No quantitative difference in the thymuses in the experimental groups could be determined because of the paucity of ABC displayed by normal thymus cells.
A SCANNING AND TRANSMISSION ELECTRON MICROSCOPE STUDY OF ANTIGEN-BINDING SITES ON ROSETTE-FORMING CELLS
Authors: Gudat Fred G. , Villiger W.
Published: June 2004

The ultrastructure of binding sites in rosette-forming cells of mice after immunization with sheep red cells was studied by means of scanning and transmission electron microscopy. It was found that the red cells were bound to the lymphocyte surface in circumscribed, immunoglobulin-containing areas, consistent with a spotlike or patchy distribution of antigen-binding immunoglobulin receptors. In these contact areas the cell membranes formed a gap of 80 Å (range 75–90 Å) which exhibited electron-opaque bridges at high magnification. These results are discussed in the light of the recent recognition of the formation of immunoglobulin spots on the lymphocyte surface after antigen contact. Morphological details suggest that the same mechanism is operating in rosette formation, possibly including the movement of the contact areas on the lymphocyte membrane.
INDEPENDENCE OF H-2K AND H-2D ANTIGENIC DETERMINANTS ON THE SURFACE OF MOUSE LYMPHOCYTES
Authors: Neauport-Sautes Catherine , Lilly Frank , Silvestre Danielle , Kourilsky François M.
Published: June 2004

At 37°C, fluorescein-conjugated anti-H-2 alloantibodies specifically induce, at the surface of living mouse lymphocytes, the redistribution of the corresponding H-2 antigens, which cluster as patches and sometimes single caps at one pole of the cell. This aggregation is inhibited at 0°C and the H-2 antigens, stained by fluorescent antibodies in the cold, appear evenly spread over the cell surface.

This phenomenon was used to define the relationships between the membrane structures bearing the antigens coded by the H-2K and the H-2D genes of the H-2 region. Monospecific anti-H-2 antibodies coupled to either tetramethyl rhodamine isothiocyanate or fluorescein isothiocyanate were used to induce the redistribution of H-2D and H-2K antigens of the H-2b and H-2k haplotype at the surface of lymph node cells from homozygous and F1 hybrid mice. It was observed that the diffuse distribution of H-2K antigens labeled at 0°C was not affected by the prior antibody-induced aggregation of H-2D antigens and vice versa. The results were the same for H-2 antigens governed by genes located either in cis or in trans position.

These data indicate that the H-2K and H-2D antigens migrate independently at the cell surface, and suggest that the gene products from the D and the K end of the H-2 region are expressed on independent molecules or structures at the cell membrane.
THE GLOMERULAR MESANGIUM
Authors: Mauer S. Michael , Sutherland David E. R. , Howard Richard J. , Fish Alfred J. , Najarian John S. , Michael Alfred F.
Published: June 2004

A mechanism of immune glomerular injury is described based on the fixation of antibody (Ab) to an antigen (Ag) that has localized in the glomerular mesangium. Rabbits were given, intravenously (i.v.), aggregated human IgG (AHIgG) or albumin (AHSA) and 10 h later, when the Ag by immunofluorescent microscopy was present in the mesangium, a kidney was removed and transplanted into a normal rabbit. The recipient then received, i.v., rabbit anti-HIgG or anti-HSA.

Within minutes of Ab infusion, glomeruli of the donor kidney had polymorphonuclear (PMN) infiltration that over the next few hours became marked and was associated with glomerular cell swelling. At 24 h a decrease in PMN's and early mesangial proliferation was seen. By 3 days there was marked mesangial hypercellularity and increased mesangial matrix. Within minutes after Ab administration rabbit IgG, C3, and fibrin were seen in the glomerular mesangium. There was a fall in complement titer by 1 min after Ab infusion that was due to complement consumption by the donor kidney. Complement then returned to normal levels by 48 h.

Significant glomerular injury did not occur (a) in the recipient's own kidney, (b) from Ag administration and transplantation without recipient Ab administration, or (c) from transplantation and Ab administration without prior Ag administration.

These studies demonstrated that Ag localized in the glomerular mesangium can react with circulating Ab and complement resulting in severe glomerular injury.
STUDIES ON GONOCOCCUS INFECTION
Authors: Swanson John
Published: June 2004

Attachment of Neisseria gonorrhoeae to amnion cells in tissue culture is facilitated if the gonococci bear pili. This has been determined by studying the number of pilated, colony type 2 gonococci associated with amnion cells after incubation in vitro as compared with the number of nonpilated, colony type 4 gonococci present with amnion cells under the same conditions. These data are supported by light microscope findings. Electron microscope studies provide visualization of fine structure of gonococcal attachment. Gonococci are also found within amnion cells in this in vitro system.
RADIOIMMUNOASSAY OF MAMMALIAN TYPE C VIRAL PROTEINS
Authors: Parks Wade P. , Livingston David M. , Todaro George J. , Benveniste Raoul E. , Scolnick Edward M.
Published: June 2004

A radioimmunoassay specific for a murine leukemia virus structural protein, the gs antigen, detects an antigenic reactivity in normal murine cells in culture and natural tissues. The assay was shown to measure an antigen that is highly related to the virion protein as shown by absorption tests, immunoadsorbent chromatography, and by analysis of linearized dose-response curves. These findings combined with the finding of viral-specific RNA indicate that portions of the viral genome are being expressed with a much greater frequency than previously appreciated.
BIOLOGICAL EXPRESSIONS OF LYMPHOCYTE ACTIVATION
Authors: Rich Robert R. , Pierce Carl W.
Published: June 2004

A population of thymus-derived lymphocytes has been identified that, upon activation by the nonspecific plant mitogen concanavalin A, suppresses the development of plaque-forming cell responses in fresh or 48-h antigen-stimulated cultures of mouse spleen cells. Suppressor cells can inhibit both primary and secondary IgM and IgG responses in vitro. X-irradiation before activation of peripheral thymus-derived cells by concanavalin A abrogates generation of suppressor cells. After a 48 h activation period, however, the function of concanavalin A-activated suppressor cells is radioresistant. As yet uncertain is whether these suppressor cells are a population of cells distinct from thymus-derived "helper" cells. In certain important regards, the cells mediating these two opposing functions share similar characteristics; the effect observed may be determined by the circumstances of activation or the numbers of activated cells, and may consequently represent different functions of a single thymus-derived regulator cell population.
A STUDY OF ALLOGRAFT KIDNEY REJECTION OCCURRING SIMULTANEOUSLY IN WHOLE ORGAN AND EAR CHAMBER GRAFTS IN THE RABBIT
Authors: Hobbs J. B. , Cliff W. J.
Published: June 2004

When portions of adult renal tissue are allografted into the rabbit ear chamber, they usually survive for periods of up to several months (6). When a kidney from the same donor is grafted as a whole organ, the ear chamber grafts then reject with the whole organ in 7 days. During that time serial needle biopsies of the whole organ are compared with the in vivo appearance of the ear chamber grafts. This establishes that the changes occurring in the ear chamber grafts are monitoring the rejection process proceeding in the whole organ grafts.

Dramatic vascular changes herald the earliest stages of unmodified rejection. A highly characteristic form of individual discrete platelet adhesion to both endothelium and adherent leukocytes is observed which is associated with the release reaction. At times as many as 20 such discrete platelets are clearly visible in profile in one high-power field. This demonstrates in vivo a mechanism whereby vascular and parenchymal damage may be produced by platelet contents, without previous aggregation or thrombus formation being necessary.
A MAJOR GENETIC LOCUS AFFECTING RESISTANCE TO INFECTION WITH MURINE LEUKEMIA VIRUSES
Authors: Rowe Wallace P. , Humphrey James B. , Lilly Frank
Published: June 2004

The Fv-1 gene, which regulates sensitivity of mouse cells to infection by naturally occurring host-range types of murine leukemia virus, was shown to be located on linkage group VIII (chromosome 4), 39 map units from b.
DISTRIBUTION OF A CROSS-REACTIVE IDIOTYPIC SPECIFICITY IN INBRED STRAINS OF MICE
Authors: Pawlak Laura L. , Nisonoff Alfred
Published: June 2004

The expression of an idiotype characteristic of anti-p-azophenylarsonate antibodies of all A/J mice was explored in F1 progeny, in other inbred strains, and in congenic mice. Of the strains tested only those closely related to A/J produced antibodies with the cross-reactive idiotype (CRI). None of the mice synthesized intermediate levels of CRI. No relationship between H-2 type and idiotype was noted. Congenic mice with a strain A background but a different H-2 type produced CRI in amounts quantitatively equivalent to those of strain A mice. Conversely, the presence of the H-2 genotype of strain A on an unrelated background was not associated with the formation of CRI. Nearly all F1 progeny of strain A mice formed CRI, indicating that failure of the other (non-A) parental strain to produce CRI is not attributable to the presence of a gene controlling the synthesis of a suppressor of CRI. NZB mice, which have the same heavy chain allotype as strain A, but are unrelated in origin, failed to produce CRI, although allotype has been shown to be linked to idiotype in congenic strains.