bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of the antigen- and mitogen-induced differentiation of B lymphocytes from asymptomatic human immunodeficiency virus-seropositive male homosexuals. Discrepancy between T cell-dependent and T cell-independent activation.
Authors: Teeuwsen V J , Logtenberg T , Siebelink K H , Lange J M , Goudsmit J , Uytdehaag F G , Osterhaus A D
Published: December 2022

Five asymptomatic human immunodeficiency virus (HIV)-seropositive male homosexuals were immunized with the recall antigens tetanus toxoid (TT) and the three types of poliovirus present in diphtheria, tetanus, and polio vaccine. Four weeks after immunization, the in vivo response to booster immunization, the in vitro pokeweed mitogen (PWM)-induced IgG secretion, and the in vitro T cell-dependent and T cell-independent antigen-induced antibody response were assayed. Increase in serum antibody titer to TT and poliovirus was low and normal, respectively. In all five subjects studied, a high rate of spontaneous IgG production, including antibodies directed toward HIV was observed. Addition of PWM to the cultures induced suppression of the spontaneous IgG secretion. Only one donor showed a slightly increased IgG production after stimulation with PWM. Peripheral blood mononuclear cells of four of the five HIV-seropositive individuals did not produce TT, or poliovirus-specific antibodies when stimulated with the respective T cell-dependent antigens. However, stimulation of these peripheral blood mononuclear cells with TT coupled to agarose beads, which was shown to be T cell-independent, resulted in the generation of IgG anti-TT antibody-forming cells.
Antigen-induced rheumatoid factors. Protein and carbohydrate antigens induce different rheumatoid factor responses.
Authors: Stanley S L , Bischoff J K , Davie J M
Published: December 2022

Rheumatoid factors, autologous IgM anti-IgG, were produced after immunization with protein or carbohydrate antigens. After immunization with either type of antigen, the kinetics of the rheumatoid factor response reflected the kinetics of the dominant IgG isotype in the anti-antigen response. Secondary immunization with protein antigens induced an IgM rheumatoid factor response which was consistently greater than that seen after carbohydrate immunization, and almost exclusively specific for the IgG1 isotype. In contrast, primary or hyperimmunization with carbohydrate antigens gave rise to a more heterogeneous response dominated by IgM anti-IgG3, with lesser amounts of IgM anti-IgG2b and anti-IgG1. Direct immunization with immune complexes gave similar results, as complexes composed of IgG1 induced exclusively IgM anti-IgG1, whereas those complexes made up of IgG3 gave rise to IgM rheumatoid factors binding IgG3 and IgG2b. Rheumatoid factor production, with isotypic specificity defined by the immunizing antigen, appears to be a natural consequence of immunization with a variety of protein and carbohydrate antigens.
Identification of an interleukin HP1-like plasmacytoma growth factor produced by L cells in response to viral infection.
Authors: Cayphas S , Van Damme J , Vink A , Simpson R J , Billiau A , Van Snick J
Published: December 2022

We have recently purified and partially sequenced a new T cell-derived lymphokine with growth factor activity for B cell hybridomas and plasmacytomas, which we named interleukin HP1 (HP1). Here we show that, in response to viral infection or after treatment with poly(rI).poly(rC), L cells produce a factor that is capable of supporting the in vitro growth and survival of HP1-dependent cell lines. Serologic and structural evidence is presented in favor of the identity between the fibroblast factor and HP1, demonstrating that non-T cells can make HP1-related molecules.
Induction of granulocyte-macrophage colony-stimulating factor by lipopolysaccharide and anti-immunoglobulin M-stimulated murine B cell lines.
Authors: Bickel M , Amstad P , Tsuda H , Sulis C , Asofsky R , Mergenhagen S E , Pluznik D H
Published: December 2022

The present study was undertaken to elucidate whether B cell lymphoma and hybridoma cell lines can be stimulated by lipopolysaccharides (LPS) or by antibodies against immunoglobulin M (IgM) to produce granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF activity was assayed on the basophil/mast cell line PT-18 which is GM-CSF- and interleukin 3-dependent. Antibodies against murine recombinant GM-CSF were used to identify the colony-stimulating factor activity present in the supernatants of the stimulated B cell lines. When these cell lines were stimulated with LPS, two of five lymphoma and five of six hybridoma lines produced GM-CSF. Two cell lines, the B cell lymphoma M12.4.1 and the hybridoma TH2.2, were analyzed more extensively under serum-free conditions. In these two cell lines, the production of GM-CSF was dependent on the dose of LPS used and time of exposure. Antibodies against IgM stimulated the TH2.2 (IgM+) but not the M12.4.1 (IgM-) cells to produce GM-CSF. Northern blot analysis of the M12.4.1 and TH2.2 cells showed that mRNA of GM-CSF can be detected in LPS-stimulated but not in unstimulated cells. Our data show that transformed B cells can be stimulated to produce GM-CSF. The present data and previous studies on GM-CSF production by normal bone marrow-derived B cells suggest a possible participation of B cells in granulopoiesis.
Characterization of a monoclonal antibody against the lymphoblast substance P receptor.
Authors: Organist M L , Harvey J , McGillis J P , Mitsuhashi M , Melera P , Payan D G
Published: December 2022

A murine monoclonal antibody to the IM-9 lymphoblast substance P (SP) receptor has been produced which recognizes the membrane-associated proteins of the SP receptor as demonstrated by immunoprecipitation of [125I]SP affinity-labeled and [35S]methionine biosynthetically labeled IM-9 soluble membranes. SP and anti-SP receptor binding to [35S]methionine-labeled IM-9 cell proteins were directly compared by attachment of each to affinity supports. Eluants from these affinity columns were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and revealed an equivalent 33-kDa protein in both cases. This protein corresponds to one of the previously described [125I]SP specifically affinity-labeled membrane-associated proteins. In addition, two-color fluorescence-activated cell sorter analysis with human peripheral blood T lymphocytes with fluorescein-SP and rhodamine-labeled antireceptor antibody revealed a distinct population of cells (20 to 30%) that were equally labeled by both the fluorescent peptide and antibody. This result indicates that the anti-SP receptor antibody recognizes an epitope of the receptor that is common to both human peripheral blood T lymphocytes and IM-9 lymphoblast cells.
The generation of infective stage Leishmania major promastigotes is associated with the cell-surface expression and release of a developmentally regulated glycolipid.
Authors: Sacks D L , da Silva R P
Published: December 2022

A monoclonal antibody, 3F12, was generated which reacted specifically against infective or metacyclic stage Leishmania major promastigotes, but not with noninfective promastigotes obtained from log phase cultures. The antibody recognized a cell surface and released molecule that could be metabolically labeled with [14C]glucose, [3H]mannose, [3H]galactose, and [3H]palmitic acid, but not with [35S]methionine or [3H]leucine. The molecule was the major species surface-labeled by [3H]sodium borohydride after periodate treatment. The glycolipid appeared to be shed primarily as free carbohydrate because 70% of the released material partitioned in the aqueous fraction after phase separation in TX-114. The molecule could be distinguished from the L. major glycolipid which has already been extensively described because its migration on sodium dodecyl sulfate-polyacrylamide gel electrophoresis was of higher relative m.w. However, a close relationship between the two molecules was indicated by the finding that another monoclonal antibody, WIC-79.3, recognized both forms of the glycolipid; one produced and released only by log phase promastigotes, and one produced and released only by metacyclic promastigotes. The loss of agglutination with peanut agglutinin which has been shown to accompany metacyclogenesis was found to be caused by the loss of expression of the log form of the glycolipid which in most cases appeared to be the result of the developmental modification of this molecule. A survey of a number of virulent and avirulent. L. major strains and clones reinforced an absolute association between the ability of these promastigotes to initiate infection in BALB/c mice and their expression and release of the 3F12-binding, developmentally regulated form of the glycolipid. Not only does this glycolipid serve as the first well defined molecular marker for infective stage metacyclic promastigotes, but its unique structure is very likely to contribute to the adaptive changes that allow these parasites to survive within the vertebrate host.
Prophylactic immunization against experimental leishmaniasis. VI. Comparison of protective and disease-promoting T cells.
Authors: Liew F Y , Hodson K , Lelchuk R
Published: December 2022

In previous studies, we reported that mice immunized i.v. with lethally irradiated Leishmania major promastigotes developed substantial resistance to a subsequent L. major infection. However, such protection could be totally suppressed by prior s.c. injection with the same antigens. Both the protective immunity and the inhibition of its induction could be adoptively transferred with specific Lyt-2- T cells. Here, we present evidence showing that protection and disease promotion resulting from i.v. or s.c. immunization, respectively, are mediated by functionally distinct subsets of T cells. In a series of titration experiments, it was found that freshly isolated T cells derived from prophylactically i.v. immunized BALB/c mice were either protective (greater than 10(7) cells/recipient) or ineffective (less than 10(7) cells/recipient). No exacerbation of disease was observed at any dose. Conversely, T cells from mice immunized s.c. either accelerated disease development and inhibited protective immunization (greater than 10(7) cells/recipient) or had no effect (less than 10(7) cells/recipient). No protection was observed at any dose tested. In mixed transfer experiments, increasing numbers of T cells from s.c. immunized donors progressively inhibited the protective effect of T cells from i.v. immunized donors. Supernatant of T cell cultures from protectively immunized donors contained substantial macrophage-activating factor whereas such activity was not detectable in the supernatant of T cell culture from s.c. immunized donors. Analysis by flow cytometry showed that the spleen and lymph nodes of normal, i.v., or s.c. immunized BALB/c mice contained similar ratios of L3T4+ cells and Lyt-2+ cells.
Cloning and characterization of a novel T cell activation gene.
Authors: Burd P R , Freeman G J , Wilson S D , Berman M , DeKruyff R , Billings P R , Dorf M E
Published: December 2022

We have used the technique of subtractive hybridization to identify a T cell gene selectively expressed during activation via the antigen-receptor pathway. This gene, termed TCA3 (for T cell activation) encodes a mRNA which is expressed following concanavalin A (Con A) activation of T cell clones at levels of approximately 1% total poly(A)-containing mRNA. The cDNA isolate, termed TCA3.0, is 512 bases in length excluding poly(A) and encodes a predicted 92-amino acid protein having the characteristics of a secreted polypeptide of approximately 69 amino acids. The genomic organizations of TCA3 was determined for two lambda phage clones and was found to be a single copy gene containing at least three exons dispersed over less than 4.7 kb. The temporal appearance of TCA3 mRNA in response to several activating agents was examined. It is not transcribed in response to interleukin 2 stimulation, but is transcribed in response to either antigen or Con A stimulation and can be detected as early as 1 hr poststimulation. Expression TCA3 in response to Con A is blocked by cyclosporin A treatment. The combined data suggest that TCA3 may represent a new lymphokine.
Immune regulation of the L5178Y murine tumor-dormant state. II. Interferon-gamma requires tumor necrosis factor to restrain tumor cell growth in peritoneal cell cultures from tumor-dormant mice.
Authors: Suzuki Y , Liu C M , Chen L P , Ben-Nathan D , Wheelock E F
Published: December 2022

L5178Y lymphoma cells are restrained from progressive growth in peritoneal cell ("in vitro tumor-regressor" PC) cultures prepared from many DBA/2 mice which harbor the tumor cells in the peritoneal cavity in a tumor-dormant state. Treatment of these PC cultures with 'antibodies to murine interferon-gamma (MuIFN-gamma) and murine tumor necrosis factor (MuTNF) but not with antibody to interleukin 2 (IL-2) receptors eliminated the restraint on tumor cell growth and permitted their progressive proliferation. L5178Y cells were found to be resistant to the direct toxic effects of large concentrations (3,000 U/ml) of MuIFN-gamma and of MuTNF, either alone or in combination. Treatment of PC cultures from tumor-dormant mice, in which tumor cells grew progressively ("in vitro tumor-progressor"), but not PC cultures from normal mice, with exogenous MuIFN-gamma resulted in a marked inhibition of tumor cell growth. The MuIFN-gamma-induced cytotoxic activity was cell-mediated since no soluble tumor-cytotoxic factors could be detected in the cultures. MuIFN-gamma induced cytotoxic activity in plastic-adherent peritoneal cell (AD-PC) cultures, but induced no cytotoxic activity in nonadherent-PC cultures unless small numbers (2%) of AD-PC were present, and inclusion of antibody to MuTNF in these mixed PC cultures blocked the development of cytotoxic activity. Antibody to MuTNF also blocked the development of cytotoxic activity in cultures of MuIFN-gamma-treated whole PC and AD-PC from tumor-dormant mice. These results indicate that MuIFN-gamma and MuTNF are both important in restraining tumor cell growth in PC cultures from tumor-dormant mice, and that MuIFN-gamma requires the presence of MuTNF to induce cytotoxic activity in these cultures.
Human K/natural killer cells targeted with hetero-cross-linked antibodies specifically lyse tumor cells in vitro and prevent tumor growth in vivo.
Authors: Titus J A , Perez P , Kaubisch A , Garrido M A , Segal D M
Published: December 2022

We have induced fresh peripheral blood K/natural killer cells to lyse a variety of target cells by coating them with anti-Fc gamma receptor (anti-Fc gamma R) (CD16) antibody hetero-cross-linked with anti-target cell antibody. The cytotoxic cell mediating this activity is different, as judged by depletion studies, from the CD3+, CD8+ T cell which is targeted by anti-CD3 cross-linked to anti-target cell antibody. Targeted K cell activity from some donors is enhanced by exposure to interleukin 2 but not interferon-gamma; other donors exhibit high amounts of this activity without stimulation. Specificity of lysis mediated by targeted K cells is dictated by the specificity of the anti-target cell antibody within the heteroconjugate, and bystander cells are not lysed by targeted K cells. Hetero-cross-linked antibodies containing anti-histocompatibility leukocyte antigen class I instead of anti-Fc gamma R (CD16) do not promote lysis, suggesting that the bridging of the target cell to Fc gamma R on the K cell is required to activate the lytic process. Lysis mediated by targeted K cells is much less inhibitable by polymerized IgG than is classical antibody-dependent cellular cytotoxicity. Fresh human melanoma cells are lysed specifically by K cells coated with anti-Fc gamma R (CD16) cross-linked to the 96.5 anti-melanoma antibody. In vivo, targeted K cells prevent tumor growth at low effector to target ratios in Winn-type tumor neutralization assays. Targeted K cells may therefore provide a new immunotherapeutic approach for the destruction of detrimental cells, such as tumor and virally infected cells.
Observations with the Precipitin Reaction
Authors: Hektoen Ludvig
Published: December 2022

The results of the simple experiments that I have summarized emphasize the value of the precipitin reaction in studying certain constituents of the body for various purposes. The reaction may be of service to physiological, chemical and immunological research as well as for diagnosis. Of the substances that have been considered in the foregoing, the serum proteins, hemoglobin, and the specific precipitinogen in semen appear to be distinctive or specific for the species, and consequently presumably different chemically in each species, while the lens proteins, fibrinogen and thyroglobulin appear to be more or less closely related in many distinct species. Of this latter group, the lens and casein2 have been the standard illustrations to which we now can add fibrinogen and thyroglobulin. That fibrinogen should disregard so completely the species limitations of the immune reactions of serum and its constituents as well as of hemoglobin is both surprising and interesting. In fibrinogen the blood reveals a much wider antigenic relationship than is ordinarily assumed to be the case. It is of special interest that in connection with the fundamental problems of immune specificness and the production of antibodies these nonspecies-specific antigens can evoke the formation of corresponding antibodies in the homologous species, at least under certain conditions. In view of this circumstance may it not be well to subject to renewed experimental scrutiny the old assumption that species-specific antigens are incapable of provoking any antibody response in their own species?
Local Hypersensitiveness
Authors: Dienes L.
Published: December 2022

General Summary

As we stated at the beginning of this paper our observations add to the observations of Lewis and Loomis concerning the increased antigenic response of the guinea pig during the tuberculous infection that beside the increased antibody production strong hypersensitiveness can develop and only small amounts of eggwhite are necessary for a strong response. It could not be decided whether the strong necrotic local reactions observed in the tuberculous animals are essentially similar to the evanescent reaction observed in the non-tuberculous animals or with the tuberculin reaction, and the connection between the sensitiveness and serum antibodies remained undecided. If a similar increase of the response, as it can be observed in the tuberculous animal, is present in the course, or in certain phases of the course, of other infectious diseases the importance of it for the development of immunity and the symptoms of the diseases is evident. We have only little information as to whether or not such influence in other cases is present.
Local Hypersensitiveness
Authors: Dienes L. , Schoenheit E. W.
Published: December 2022

Non-tuberculous guinea pigs after treatment with eggwhite react to the intracutaneous injection of varying amounts of egg-white with a quickly developing large swelling, which disappears in twenty-four to forty-eight hours. This reaction corresponds to the reaction called “immediate” by Zinsser.

In tuberculous guinea pigs after treatment with eggwhite there appears first a sensitiveness similar to that of the non-tuberculous guinea pigs, but usually in a few days it gives place to a persistent necrotic reaction. After a shorter or longer period the evanescent reaction may reappear.

The hypersensitiveness of tuberculous guinea pigs demonstrated with the necrotic skin reaction is similar to the Arthus phenomenon of rabbits. Subcutaneous injections cause very extensive necrosis, but do not kill the animal. Precipitins are present in large amount in the blood serum. Anaphylaxis against eggwhite is also present.

In general there seems to be a parallelism between the precipitin content of the blood serum and the sensitiveness. But in four tuberculous guinea pigs of the two first series which produced precipitins only slightly, two were very sensitive, and several with strong precipitin production were only slightly sensitive.

Sensitiveness and precipitins appear about the same time—around the seventh day after treatment. Very small amounts of eggwhite are needed for the production of both.

The complement fixation has no direct connection either with the sensitiveness or precipitation. In no case did we observe complement fixation with crystalline egg albumin.

Desensitization is possible with larger doses of eggwhite given subcutaneously. The tuberculin reaction is only slightly affected.

The sensitization with the eggwhite is mainly against the egg globulin. With egg globulin the sensitization is as successful as with the eggwhite. With egg albumin we obtained necrotic skin reaction only after more prolonged treatment.

After treatment with timothy pollen we obtained in two animals a strong necrotic skin reaction, and in two others a moderately strong reaction. The formation of precipitins and complement fixation antibodies were observed only in the tuberculous animals. With typhoid bacilli we obtained in the tuberculous animals neither sensitiveness nor increased agglutinin formation.
The Intradermal Test for the Virulence of Diphtheria Cultures
Authors: Gibbs Charles S. , Ken Chen
Published: December 2022

The intracutaneous test for the preliminary standardizing of diphtheria toxin was found to give satisfactory results. Also the intracutaneous test for determining the virulence of diphtheria cultures was found economical and efficient in experienced hands. The cutaneous lesions associated with mixed throat infections furnished valuable aid in determining whether virulent or avirulent diphtheria bacilli were present or not. When the cutaneous lesions were marked by rapid necrosis and abscess formation an examination of the subcutaneous tissues was helpful in deciding whether diphtheria toxins had been formed or not.
The Preparation and Purification of Pollen Extracts
Authors: Alles Gordon A. , Lamson Robert W.
Published: December 2022

At least one-half of the N present in pollen extracts is contained by substances that are not immunologically important. The presence of whole protein is difficult to show even in concentrated unpurified pollen extracts, though undoubtedly present. Washing the pollen grains with 80 volume per cent alcohol removes a considerable amount of inactive substances. This treatment, followed by the usual extraction of the active substances, yields extracts that are clinically somewhat less active than standard extracts.
Transmission of Protein Hypersensitiveness from Mother to Offspring
Authors: Ratner Bret , Jackson Holmes C. , Gruehl Helen Lee
Published: December 2022

Rosenau and Anderson (1) were the first to record instances of the transmission of hypersensitiveness or anaphylaxis; this hypersusceptibility was transmitted to young guinea pigs whose mothers had been given diphtheria toxin-antitoxin mixture or normal horse serum two or three months before parturition.

The diphtheria toxin immunity transferred from mother to offspring, demonstrated by Wernicke (2) in 1895, Smith (3) in 1905, Anderson (4) in 1906 and the transmission of hypersusceptibility first shown by Rosenau and Anderson (1) in 1906, led Anderson (5) to question whether female guinea pigs that received toxin-antitoxin, either before or during pregnancy, could give birth to offspring that were both immune to diphtheria toxin and hypersusceptible to horse serum. He readily found that a mother can simultaneously transmit to her young these two properties—the immunity to diphtheria toxin and the hypersusceptibility to horse serum.
Transmission of Protein Hypersensitiveness from Mother to Offspring
Authors: Ratner Bret , Jackson Holmes C. , Gruehl Helen Lee
Published: December 2022

There are certain clinical indications which have suggested the possibility that the breast milk of mothers may transmit foreign food proteins and thus produce nutritional and allergic disturbances in the nursling. This is shown in the case reports of Talbot (1), O'Keefe (2), and Ratner (3). As a result of O'Keefe's work which first demonstrated positive allergic skin reactions in nursing infants to foods of which they had never partaken, Shannon (4), in 1921, attempted to demonstrate experimentally the actual presence of foreign food proteins in the milk of certain nursing mothers. He believes that he has proved the presence of egg protein in breast milk and concludes that the passage of this egg protein was responsible for the eczema and nutritional disturbances of these infants. The following year, in a clinical paper (5), he states that he has also shown the passage of veal protein and believes that any foreign protein may be demonstrated in the breast milk.
Effect of Histamine on the Parenteral Denaturization of Foreign Protein
Authors: Manwaring W. H. , Marino D. H. , Boone T. H.
Published: December 2022

Histamine injected intravenously into normal dogs has the effect of delaying the normal parenteral denaturization of foreign protein. This is shown: (a) by a prolongation of the initial period of increased anaphylactic toxicity, and (b) by a marked delay in the development of complete anaphylactic detoxication.

Since histamine is known to inhibit the action of certain tissue enzymes, this finding is not inconsistent with the hypothesis that the initial increased toxicity and the subsequent complete detoxication of parentically introduced foreign proteins are due to enzyme action (2).
Skin Reactions in the Normal and Hypersensitive Guinea Pig
Authors: Lamson R. W. , Pope Maxy Alice
Published: December 2022

In an attempt to study the mechanism governing skin hypersensitivity in man we turned our attention to similar phenomena in the common laboratory animal. First of all it seemed desirable to standardize the skin reaction, if one could be produced, in these animals by the use of an antigen that was relatively simple in composition. For this reason we selected crystalline egg albumin in preference to horse serum or whole egg white which are perhaps more commonly used. We hoped to determine the size and character of the wheal produced in the skin of the sensitized animal, the time factors concerned, and the frequency with which the results could be duplicated at two or more sites on the same animal. The antigen we selected did not fulfill the purpose intended of it, but it did furnish us with certain interesting results. These data and those additional ones obtained in an attempt to explain our first observations are presented herein.
Sequential events in thymocyte differentiation and thymus regeneration revealed by a combination of bromodeoxyuridine DNA labeling and antimitotic drug treatment.
Authors: Penit C , Vasseur F
Published: December 2022

The proliferative status of thymocyte cell subsets in vivo was assessed by observing the effect of two antimitotic drugs, hydroxyurea (HU) and demecolcine. Both drugs had the greatest effect on the double-positive (DP) subset followed by the L3T4+ single-positive (SP) subset. However, the decrease in the latter type was delayed by several days, showing that their precursors rather than the cells themselves were killed by HU. Double-negative (DN) cells were less affected, indicating that they contain a resting subset and that they are renewed by emigration rather than by autonomous in situ proliferation. After drug treatment all cycling cells were eliminated from the thymus but, as shown by in vivo and in vitro bromodeoxyuridine incorporation, new cells rapidly reentered in cycle, starting from DN cells and Lyt-2+ SP cells and followed by DP cells. Lyt-2+ SP cycling cells represent an intermediary stage between DN and DP cells, and they are very transient. Injection of HU 24 h after in vivo BrdUrd labeling eliminated most labeled DN cells, but did not prevent the emergence of L3T4+ SP-labeled cells on day 3 as observed in control thymuses. These results suggest that these L3T4+ SP cells are generated from DP cells in the absence of proliferation. Cycling cells in the regenerating thymus were first located at the corticomedullary junction and then in the subcapsular region, suggesting a reverse migration process to that observed after cessation of proliferation. A model is proposed to summarize these sequential events.
Allogeneic non-T spleen cells restore the responsiveness of normal T cell clones stimulated with antigen and chemically modified antigen-presenting cells.
Authors: Jenkins M K , Ashwell J D , Schwartz R H
Published: December 2022

Stimulation of IL-2-producing T cell clones with chemically modified APC and Ag induces a state of proliferative unresponsiveness, i.e., subsequent stimulation with normal APC and Ag fails to elicit IL-2 production. One possible effect of chemical modification on the APC is the destruction of its ability to provide costimulatory signals. To test this, various potential costimulators were added to T cells at the time of exposure to Ag and chemically modified APC. None of the cytokines tested, including IL-1, had a positive effect; however, addition of allogeneic spleen cells allowed a T cell proliferative response and prevented the induction of subsequent unresponsiveness. Fractionation of the spleen cells showed that low density B cells and macrophages were the best source of costimulatory activity. Allogeneic resting B cells provided some costimulatory activity and resting T cells, none at all. Attempts to mimic costimulatory signals with the phorbol ester PMA were only partially successful. PMA prevented the induction of T cell unresponsiveness but failed to allow T cell proliferation in response to Ag plus chemically modified APC. Our results suggest that IL-2 production by normal T cell clones is dependent not only on T cell receptor occupancy, but also on short range costimulatory signals that are provided to different degrees by various non-T accessory cells.
Frequencies of IL-2- and IL-4-secreting T cells in naive and antigen-stimulated lymphocyte populations.
Authors: Powers G D , Abbas A K , Miller R A
Published: December 2022

The relative frequencies of IL-2-and IL-4-secreting precursors in naive and Ag-primed populations were investigated by using limiting dilution analysis. Cells capable of IL-4 production in lymphoid populations freshly isolated from mice were rare in comparison with those producing IL-2 when the cells were stimulated by nominal Ag, by alloantigens, or by mitogens. One cycle of in vitro Ag restimulation and rest, however, enabled us to detect high proportions of IL-4-secreting cells among keyhole limpet hemocyanin-primed lymph node cells. With cultures set up at monoclonal cell doses, it was shown that IL-2 and IL-4 are secreted by separate precursor populations at this stage of their development. The IL-4-secreting cells were further shown to be dependent upon the presence of IL-2, either secreted by separate precursors or exogenously added, for the production of detectable amounts of IL-4. Analysis of the frequencies of helper cells producing both IL-2 and IL-4 at various stages of the in vivo immune response and the requirements for their growth and differentiation should give a better understanding of the relative contributions of each cell type.
Picogram quantities of anti-Ig antibodies coupled to dextran induce B cell proliferation.
Authors: Brunswick M , Finkelman F D , Highet P F , Inman J K , Dintzis H M , Mond J J
Published: December 2022

To investigate the properties which enable type 2 Ag, as exemplified by dextran and Ficoll, to stimulate high levels of antibody responses in the relative absence of T cells, we conjugated anti-IgD and anti-IgM mAb to both dextran and Ficoll and examined their B cell-activating properties. Such conjugated anti-Ig antibodies stimulated both early and later stages of B cell activation at picogram concentrations, which are at least 1000-fold lower than that required for B cell stimulation by unconjugated anti-Ig antibodies, and the level of proliferation they stimulated was on average 10-fold greater. Furthermore, concentrations of anti-Ig dextran (100 pg/ml) which modulated little sIgD from the B cell surface were strong inducers of enhanced B cell expression of MHC class II molecules. Conjugation of Fab fragments of anti-IgD or nonmitogenic anti-IgM mAb to dextran rendered them as mitogenic as dextran conjugated to strongly stimulatory anti-IgD or anti-IgM antibodies. The ability of dextran and Ficoll to serve as effective carrier molecules for anti-IgD was not related solely to their large m.w., because anti-IgD coupled to polymerized BSA (m.w. 1.5 X 10(6), was only 10- to 50-fold more potent than unconjugated anti-IgD antibodies at stimulating B cell DNA synthesis. These results suggest, therefore, that the unique ability of picogram concentrations of haptenated type 2 Ag to stimulate Ig secretion in the absence of T cells may be a function of their ability to promote effective cross-linking without resulting in the modulation of sIg. This would enable such Ag to mediate repetitive B cell signaling, a situation that cannot be achieved by unconjugated anti-Ig antibodies which result in modulation of sIg at their mitogenic concentrations. These compounds therefore may be employed to study B cell activation stimulated by sIg cross-linking at concentrations that may more closely reflect those which are achieved under physiologic conditions by type 2 Ag.
Total lymphoid irradiation leads to transient depletion of the mouse thymic medulla and persistent abnormalities among medullary stromal cells.
Authors: Adkins B , Gandour D , Strober S , Weissman I
Published: December 2022

Mice given multiple doses of sublethal irradiation to both the thymus and the peripheral lymphoid tissues showed major transient, and some persistent disruptions in general thymic architecture and in thymic stromal components. At 2 wk after total lymphoid irradiation (TLI), the thymus lacked identifiable medullary regions by immunohistochemical analyses. Medullary stromal cells expression MHC Ag or a medullary epithelial cell Ag, as well as medullary macrophages, were undetectable. Instead, the processes of cortical epithelial cells were observed throughout the entire thymus. Strikingly, thymocyte subsets with mature phenotypes (CD4+CD8- and CD4-CD8+) were present in the apparent absence of a medulla. This early, gross effect was rapidly reversed such that by 1 to 2 mo after TLI, medullary areas with MHC Ag-positive cells were evident. However, abnormalities in a subset of medullary stromal cells appeared to be more persistent. Medullary epithelial cells, identified by the MD1 mAb, were greatly reduced in number and abnormally organized for at least 4 mo after TLI. In addition, macrophages containing endogenous peroxidase activity, normally abundant in medullary regions, were undetectable at all times examined after TLI. Therefore, this irradiation regimen induced both transient and long term effects in the thymus, primarily in medullary regions. These results suggest that TLI may be used as an experimental tool for studying the impact of selective depletion of medullary stromal cells on the development of specific T cell functions.
Resistance to experimental autoimmune myasthenia gravis in genetically inbred rats. Association with decreased amounts of in situ acetylcholine receptor-antibody complexes.
Authors: Biesecker G , Koffler D
Published: December 2022

Genetically related susceptibility for experimental autoimmune myasthenia gravis was investigated in nine inbred strains of rats immunized with heterologous acetylcholine (AChR) from Torpedo californica. Wistar Munich and Fischer strain animals consistently developed severe, fatal disease associated with impaired neuromuscular transmission and increased sensitivity to low doses of curare. A lower incidence of disease was induced in Wistar Kyoto, ACI, Brown Norway, Buffalo, and Lewis strain animals. In contrast, Wistar Furth and Copenhagen strain animals were resistant to experimental autoimmune myasthenia gravis, electrophysiologic responses were normal, and animals were insensitive to curare. All strains of animals manifested equivalent amounts of serum antibody to AChR and total muscle AChR was reduced to the same extent in both resistant and susceptible animals. In contrast, the amount of antibody-bound AChR was greater in susceptible Wistar Munich animals than the amount observed in resistant Wistar Furth animals. These data suggest that impaired neurotransmission is correlated with the extent of antibody binding to the AChR. The discordance in the amount of antibody bound to the AChR of resistant and susceptible animals may result from heritable differences in antibody properties. Cross-breeding experiments with Wistar Munich and Wistar Furth animals show that resistance for development of experimental autoimmune myasthenia gravis is recessive and indicate that disease susceptibility is linked to one or two genetic loci.
Incidence of three cross-reactive idiotypes on human rheumatoid factor paraproteins.
Authors: Crowley J J , Goldfien R D , Schrohenloher R E , Spiegelberg H L , Silverman G J , Mageed R A , Jefferis R , Koopman W J , Carson D A , Fong S
Published: December 2022

The basis for rheumatoid factor (RF) production in autoimmune or lymphoproliferative diseases cannot be understood without defining the molecular factors that dictate RF structure and specificity. Recently three different mAb (6B6.6, 17.109, and G6) have been developed that define cross-reactive idiotypes (CRI) on intact L or H chains of human monoclonal RF cryoglobulins. However, the true incidence of these CRI among RF and their relationship to each other have not been delineated. In the present experiments, a panel of 163 randomly selected IgM paraproteins was evaluated for the expression of the two kappa L chain CRI, 6B6.6 and 17.109, and the H chain CRI, G6. Among the paraproteins with kappa L chains, 14% expressed the 17.109 CRI, and 9% expressed the 6B6.6 CRI. Both ELISA and Western immunoblotting experiments showed that the two L chain CRI were mutually exclusive. Anti-IgG activity was documented in 22 of the IgM-kappa paraproteins, among which mAb 6B6.6 reacted with 7 (32%) and mAb 17.109 with 6 (27%). Both CRI were expressed exclusively by L chains within the kappaIII variable gene subgroup. Although 17.109 CRI+ paraproteins had kappaIIIb L chains, none of the 6B6.6 CRI+ paraproteins possessed L chains with this kappa sub-subgroup specific Ag. The G6 CRI was found predominantly among RF paraproteins and was frequently yet not exclusively associated with the 17.109 CRI+ L chains. Additional experiments were performed on a panel of normal adult human sera and documented the presence of 6B6.6 and 17.109 CRI on a small percentage (0.1 to 2.0%) of IgM from most individuals. These data indicate that 1) the mAb 6B6.6 and 17.109 identify two major and distinct CRI among IgM-RF paraproteins, 2) both CRI are associated exclusively with kappaIII L chains, 3) kappaIIIb and kappaIII non-b L chains are equally prevalent among IgM-RF, 4) the G6 H chain CRI is frequently associated with 17.109 CRI+ L chains, but not with 6B6.6 CRI+ L chains, and 5) although the ability to make 6B6.6 and 17.109 CRI+ kappa L chains is common in humans, these CRI are present in low concentrations in normal IgM.
Defective primary and secondary IgG responses to thymic-dependent antigens in autoimmune PN mice.
Authors: Walker S E
Published: December 2022

Palmerston North (PN) mice spontaneously develop autoimmune disease resembling SLE. Because immune responsiveness has not been defined in this strain, a study was designed to assay primary splenic plaque-forming cell (PFC) responses to thymus-dependent (TD) and thymus-independent (TI) Ag. Initial surveys of PN mice inoculated with the TD Ag SRBC showed adequate production of IgM PFC, but small numbers of IgG PFC were developed with polyspecific antiserum. In contrast, H-2-compatible DBA/1 control mice gave the expected responses to SRBC (IgG plaques elevated twofold compared with IgM plaques). PN mice had the usual responses to Ag that are largely TI; both PN and DBA/1 mice had active IgM and modest IgG responses to TNP-LPS and TNP-Ficoll. Additional experiments determined that PN mice had similar patterns of defective IgG responses to several different TD Ag (SRBC, horse RBC, and DNP-keyhole limpet hemocyanin). In each instance, the usual predominance of IgG1 plaques was absent, and total numbers of plaques developed with antisera specific for IgG isotypes were suppressed. Defective PN IgG production was evident as early as 3 wk of age, was not influenced by aging to 43 wk, and was not corrected by increasing the antigenic challenge 10-fold. PN spleen cells treated with monoclonal anti-Thy-1.2 and C were injected with pools of DBA/1 T cells into 850-rad irradiated (DBA/1 x PN)F1 hybrids. These recipients expressed low IgG1 responses to SRBC, suggesting that the B cell-containing fraction that was not lysed by anti-Thy-1.2 transferred the PN defect. PN mice, which do not respond to TD Ag with active IgG production, contradict the proposal that autoimmunity is associated with hyper-responsiveness to TD and TI Ag.
Immune studies in the depigmenting C57BL/Ler-vit/vit mice. An apparent isolated loss of contact hypersensitivity.
Authors: Amornsiripanitch S , Barnes L M , Nordlund J J , Trinkle L S , Rheins L A
Published: December 2022

Vitiligo is a human disorder which destroys pigment cells in the skin, ears, eyes, and meningeal tissues and has often been associated with a variety of autoimmune disorders. The C57BL/Ler-vit/vit mouse is a mutant strain that exhibits a loss of epidermal pigment cells and a selective cell-mediated immune deficiency to epicutaneous-administered allergens. This observation is consistent with that observed in humans with vitiligo, who also exhibit loss of contact hypersensitivity (CHS), that appears to be associated with loss of pigment cells from the epidermis. Other cellular immune parameters such as delayed type hypersensitivity and antibody generation to both particulate and soluble Ag are normal or even hyperimmune in the vit/vit mice compared with congenic C57BL/6 controls. Cyclophosphamide treatment could reconstitute CHS responsiveness of the vit/vit mice to the allergen dinitrofluorobenzene. Further, this loss of CHS responsiveness to dinitrofluorobenzene could be restored with skin transplants from normal pigmented C57BL/6 mice to vit/vit mice. Normal C57BL/6 mice bearing white skin grafts from vit/vit mice did not contact sensitize. We suggest that this vit/vit mouse strain may serve as an excellent system to investigate various aspects of other contact hypersensitivity reactions as well as vitiligo.
Dominance of resistance to the cytocidal effect of tumor necrosis factor in heterokaryons formed by fusion of resistant and sensitive cells.
Authors: Nophar Y , Holtmann H , Ber R , Wallach D
Published: December 2022

The mechanisms underlying differences in vulnerability to the cytocidal effect of TNF, among various cell lines and strains, were explored by examining the response to TNF of heterokaryons formed by fusing TNF-resistant and -sensitive cells. Several combination pairs of human and murine cells, differing significantly in response to TNF toxicity, yet expressing a similar level of TNF receptors, were examined. In all combinations tested, the heterokaryons exhibited resistance to TNF toxicity, comparable, in extent, to that of the more resistant of the two parental cell lines. This dominance of resistance suggests that differences in vulnerability to TNF toxicity reflect activities which are expressed by resistant cells and are deficient in vulnerable ones, activities which perhaps protect the cell against the cytocidal effect of TNF.
Modulation of human polymorphonuclear leukocyte IgG Fc receptors and Fc receptor-mediated functions by IFN-gamma and glucocorticoids.
Authors: Petroni K C , Shen L , Guyre P M
Published: December 2022

Human polymorphonuclear neutrophils (PMN) normally express two distinct types of IgG Fc gamma R, the 40-kDa Fc gamma R referred to as Fc gamma RII and the low affinity 50- to 70-kDa Fc gamma R designated Fc gamma RIII. A third type of Fc gamma R, the 72-kDa high affinity receptor known as Fc gamma RI, is also detectable on PMN that have been activated by IFN-gamma. Using mAb that discriminate among the three known types of Fc gamma R, we examined the effects of IFN-gamma and glucocorticoids on human PMN Fc gamma R expression. We also studied effects of IFN-gamma and the synthetic glucocorticoid dexamethasone (DEX) on antibody-dependent cytotoxicity (ADCC) of chicken erythrocytes and phagocytosis of IgG-coated ox RBC by human PMN. In 20 donors studied, we found that treatment of PMN with 400 U/ml IFN-gamma induced a 9- to 20-fold increase in the number of Fc gamma RI sites per cell, and DEX inhibited this induction of Fc gamma RI by 39 to 73%. Similarly, DEX significantly reduced the IFN-gamma stimulation of ADCC and phagocytosis. IFN-gamma had no effect on expression of Fc gamma RII or Fc gamma RIII. Fc gamma RI and Fc gamma RII expression was unaltered by 24 h of treatment with DEX alone, but Fc gamma RIII expression was sometimes increased by about 20% on PMN cultured with DEX. Nevertheless, we found a small but significant inhibition of ADCC and phagocytosis by 200 nM DEX. Our results indicate that Fc gamma RI plays a major but not exclusive role in the regulation of ADCC and phagocytosis by IFN-gamma and DEX.
Shared idiotypes on anti-DNA and anti-poly (ADP-ribose) antibodies.
Authors: Sibley J T , Latimer L J , Lee J S
Published: December 2022

Hed 10 is a ssDNA-specific mAb derived from an NZB/W autoimmune mouse. ADP 1 is a poly(ADP-ribose)-specific mAb derived from a C57BL/6 mouse. Rabbit anti-idiotypic sera were raised against Hed 10 and ADP 1. By affinity chromatography it was shown that at least 20 to 30% of DNA-binding antibodies contained these idiotypes. The sera were also used to evaluate idiotypic cross-reactivity among 26 diverse, predominantly anti-nucleic acid, murine mAb. Each serum bound directly to several mAb and in addition inhibited the binding of several antibodies to their appropriate Ag. The anti-Hed 10 serum detected an idiotype which was restricted to antibodies that bound to poly(dT) and/or poly(ADP-ribose). The anti-ADP 1 serum detected a more widely distributed idiotype contained in antibodies which bound to a variety of nucleic acids. Although both sera bound directly to Hed 10, only the anti-Hed 10 serum could compete for the binding of Hed 10 to poly(dT). On the other hand, both sera could compete for the binding of ADP 1 to poly(ADP-ribose) as well as bind directly to ADP 1. In addition anti-ADP 1 serum appeared to enhance, rather than inhibit, the binding of one mAb to native calf thymus DNA and poly[d(AT)] but had no effect on the binding to several ssDNA. These results demonstrate that many antibodies which recognize DNA and poly(ADP-ribose) have shared idiotypes. This may be of relevance to the development of autoimmunity because poly(ADP-ribose) is ubiquitous and immunogenic.