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Biomedical subjects

B Benacerraf

Publications and source records attributed to B Benacerraf.

At least 199 records · Page 11Linked to original sources
PubMed1979

Antigen- and receptor-driven regulatory mechanisms. II. Induction of suppressor T cells with idiotype-coupled syngeneic spleen cells.

Anti-p-azobenzenearsonate (ABA) antibodies, coupled covalently to normal syngeneic spleen cells and then given intravenously to normal animals, were found to be potent tolerogens for delayed-type hypersensitivity (DTH) to ABA. The ability of the antibody-coupled cells to induce tolerance was determined to be a result of the cross-reactive idiotype (CRI+) fraction of the antibodies, because anti-ABA antibodies lacking the CRI+ components when coupled to spleen cells were unable to cause any significant inhibition. Furthermore, genetic analysis revealed that the ability of CRI-coupled cells to inhibit ABA-specific DTH is linked to Igh-1 heavy chain allotype, in as much animals which possess heavy chain allotypes similar to that of A/J were sensitive to this inhibition. Adoptive transfer experiments provided evidence that CRI-coupled cells induce suppressor cells, and spleen cells or thymocytes from animals received CRI-coupled cells were able to transfer suppression to naive recipients. In addition, treatment with anti-Thy1.2 serum plus complement completely abrogated their ability to transfer suppression. Thus, this active suppression is a T-cell-dependent phenomenon. In investigating the specificity of these suppressor T cells, it was found that they functioned in an antigen-specific manner and were unable to suppress the development of DTH to an unrelated hapten 2,4-dinitro-1-fluorobenzene.

Animals↗
PubMed1979

Ir gene controlled carrier effects in the induction and elicitation of hapten-specific delayed-type hypersensitivity responses.

The genetic requirements of carrier recognition were examined in the priming and elicitation of hapten specific, T-cell mediated, delayed-type hypersensitivity (DTH) responses. It was shown that nitrophenyl acetyl-poly-(L-glu56-L-lys35-L-phe9) (NP-GLO) could prime for NP responses only in strains of mice which are Ir gene responders to GLO. In contrast to this requirement, NO-GLO could elicit an NP-specific response in NP-bovine gamma globulin primed mice, even in GLO nonresponder strains. Furthermore, the nonimmunogenic molecule, NP-GL, could elicit an NP-specific DTH response in animals primed with NP on an immunogenic carrier.

Animals↗
PubMed1979

Hapten-specific T-cell responses to 4-hydroxy-3-nitrophenyl acetyl. II. Demonstration of idiotypic determinants on suppressor T cells.

The ability of NP-coupled syngeneic spleen cells to induce antigen-specific T-suppressor cells capable of binding to NP-BSA-coated Petri dishes and mediating transfer of specific suppressive activity to NP was demonstrated. Furthermore, in strains of mice bearing the Ig-1b allotype, including SJL, and in (non-Ig-1b x Ig-1b)F1 hybrids, the NP-specific suppressor cells also interferes with expression of immunity after priming with NIP-BGG. Anti-NPb anti-idiotype antiserum plus complement treatment effectively abrogated the ability to transfer suppression. Formal genetic mapping of the fine specificity of cross-reactivity with Ig-1 allotypic congenic mice implies that expression of this trait is linked to the Ig-1b heavy chain linkage group. The sensitivity of NP-suppressor cells of appropriate strains to anti-idiotype treatment was also consistent with the formal mapping data. These experiments suggest that there are shared V-region structures on antibody and T cells that are crucial in the suppression pathway for the same antigen.

Animals↗
PubMed1979

Hapten-specific T-cell responses to 4-hydroxy-3-nitrophenyl acetyl. I. Genetic control of delayed-type hypersensitivity by VH and I-A-region genes.

Hapten-specific delayed-type hypersensitivity (DTH) was induced in several strains of mice. (4-hydroxy-3-nitrophenyl)acetyl-bovine gamma globulin (NP-BGG)-primed mice which did not bear the Ig1b heavy-chain linkage group made a NP-specific DTH response when challenged with NP bovine serum albumin (BSA) and failed to respond to challenge with (4-hydroxy-5-iodo-3-nitrophenyl)acetyl-bovine serum albumin (NIP-BSA). Strains of NP-BGG-primed mice bearing the Ig1b allotype, including SJL, responded to challenges of either NP-BSA or NIP-BSA. F1 hybrids between a cross-reactive strain, C57BL/6, and two other noncross-reactive strains were cross-reactive. Genetic mapping of the NIP-cross-reactive DTH response localized the trait to the VH-region of the Ig1b heavy-chain linkage group. The fine-specificity pattern of the T-cell anti-NP response, and the genetic mapping of this trait, were analogous to the reported fine specificity and mapping data of the humoral heteroclitic anti-NP response. Adoptive transfer studies on the ability to transfer NP-specific DTH between various strain combinations showed that the T-cell donors and the recipient must have homology for at least the I-A subregion. Whenever NP-specific reactivity was transferred from a strain which cross-reactively responded to NIP, the recipient also responded to both NP and NIP. The implications of the control of NP-primed DTH-reactive populations of T cells by two distinct genetic regions, VH and H-2, were discussed.

Animals↗
PubMed1979

Mechanisms of regulation of cell-mediated immunity. III. The characterization of azobenzenearsonate-specific suppressor T-cell-derived-suppressor factors.

Delayed type hypersensitivity to the hapten azobenzenearsonate (ABA) can be induced and suppressed by the administration of hapten-coupled syngeneic spleen cells by the appropriate route. Suppressor T cells stimulated by the intravenous administration of ABA-coupled spleen cells have been shown to produce a discrete subcellular factor(s) which is capable of suppressing delayed type hypersensitivity to azobenzenearsonate in the mouse. Such suppressor factors may be produced by the mechanical disruption of suppressor cells or by placing such suppressor cells in culture for 24 h. The suppressor factor(s) (SF) derived from ABA-specific suppressor cells exhibit biological specificity for the suppression of ABA delayed type hypersensitivity (DTH), but not trinitro-phenyl DTH, as well as the capacity to bind to ABA immunoadsorbents. Passage of suppressor factor(s) over reverse immunoadsorbents utilizing a rabbit anti-mouse F(ab')2 antiserum demonstrated that the antigen-specific T-cell derived SF does not bear conventional immunoglobulin markers. The suppressor factor(s) are not immunoglobulin molecules was further demonstrated by the inability of anti-ABA antibodies to suppress ABA DTH. Gel filtration of ABA suppressor factor(s) showed that the majority of the suppressive activity was present in a fraction with molecular weight ranging between 6.8 x 10(4) and 3.3 x 10(4) daltons. We also analyzed for the presence of determinants encoded by the H-2 major histocompatibility complex (MHC) and found that immunoadsorbents prepared utilizing antisera capable of interacting with gene products of the whole or selected gene regions of H-2 MHC, i.e., B10.D2 anti-B10.A and B10 anti-B10.A immunoadsorbents, retained the suppressive activity of ABA-SF. Elution of such columns with glycine HCl buffers (pH 2.8) permitted recovery of specific suppressive activity. Taken collectively such data supports the notion that suppressor T-cell-derived ABA suppressor factors have antigen-binding specificity as well as determinants controlled by the K end of the H-2 MHC. The distribution of strains capable of making SF has also been analyzed. The relationship of the antigen-binding specificity to VH gene products is discussed in this and the companion paper.

Animals↗
PubMed1979

Mechanisms of regulation of cell-mediated immunity. IV. Azobenzenearsonate-specific suppressor factor(s) bear cross-reactive idiotypic determinants the expression of which is linked to the heavy-chain allotype linkage group of genes.

T-cell derived suppressor factor(s) (SF) specific for azobenzenearsonate (ABA) were prepared by the mechanical disruption of suppressor cells. Such suppressor factors were adsorbed to and recovered from immunoadsorbents prepared from the F(ab')2 fragments of rabbit immunoglobulin directed against the cross-reactive idiotype of A/J anti-ABA antibodies. These ABA-suppressor factors were not retained on Sepharose 4B immunoadsorbent columns which had been coupled with F(ab')2 fragments or normal rabbit immunoglobulins prepared from prebleeds of rabbits used to make anti-idiotypic antiserum. The specificity of the F(ab')2 rabbit anti-idiotypic serum was established by direct idiotypic-binding assays and by affinity purification over an immunoadsorbent consisting of CRI+ anti-ABA immunoglobulin from A/J mice. ABA-suppressor factors were shown to be specifically absorbed and eluted from F(ab')2 anti-idiotypic columns. Futhermore, the eluted suppressor factor can be specifically reabsorbed and recovered from a second anti-idiotypic immunoadsorbent. The concordance between antigen-binding specificity and the presence of idiotypic determinants was demonstrated by adsorbing ABA SF to antigen columns and then fractionating the ABA-specific factor on anti-idiotypic immunoadsorbents. ABA-suppressor factors were shown to be specifically retained on immunoadsorbents directed against major histocompatibility complex (MHC) determinants. Factor eluted from anti-MHC columns could then be specifically adsorbed to anti-idiotypic immunoadsorbents. This suggests that the same molecular complex that is recognized by the H-2 alloantiserum is specifically adsorbed to an anti-idiotypic immunoadsorbent. Genetic analysis of the expression of CRI+ suppressor factor was performed using the C.AL-20 mouse strain which has the AL/N allotype and produces CRI+ anti-ABA immunoglobulins. The implication of these findings to the nature of T-cell-derived regulatory molecules is discussed.

Animals↗
PubMed1979

Shared idiotypic determinants on antibodies and T-cell-derived suppressor factor specific for the random terpolymer L-glutamic acid60-L-alanine30-L-tyrosine10.

T-cell derived suppressor factors (TsF) specific for the random copolymers L-glutamic acid60-L-alanine30-Ltyrosine10 and L-glutamic acid60-L-alanine40, referred to as GAT and GA, respectively, were prepared and partially purified on the approprate antigen immunoadsorbents. GAT-TsF obtained from nonresponder DBA/1 (H-2q) and SJL (H-2s) mice were passed over immunoadsorbents prepared from normal guinea pig serum (NGPS) or guinea pig anti-idiotype antiserum (anti-CGAT) specific for a common cross-reactive idiotype found on most anti-GAT antibodies in all mouse strains tested. Both the directly suppressive activity of the GAT-TsF and the ability of GAT-TsF to induce new suppressor T cells (Ts2) in vitro were adsorbed to and fully recoverable from the guinea pig anti-CGAT-Sepharose immunoadsorbent, while the TsF passed through the control NGPS-Sepharose without appreciable binding. The SJL GAT-TsF specifically eluted from anti-CGAT-immunoadsrobents was shown to still posses I-J determinants. These data provide evidence suggesting a sharing of V region structures between B-cell antibody and T-cell suppressor factor specific for an antigen (GAT) under Ir gene control, in agreement with earlier studies on T and B-cell alloreceptors, T-cell helper factors, and T and B-cell receptors for conventional antigens.

Alanine↗
PubMed1979

Generation of cytolytic T lymphocytes after reovirus infection: role of S1 gene.

Cytotoxic T lymphocytes (CTLs) can be generated if spleen cells from reovirus-infected mice are stimulated in vitro with syngeneic reovirus-infected cells. These cytolytic effector cells demonstrate: (i) serotype specificity (i.e., maximal cytolytic activity is observed on target cells infected with the serotype used to induce the CTLs) and (ii) H-2 restriction. The SI gene was shown to be the predominant viral gene determining the specificity of the cytotoxic T cells. This genome segment has previously been demonstrated to encode the viral hemagglutinin and determines reovirus cell tropism in the nervous system.

Animals↗
PubMed1979

Impairment of antigen-presenting cell function by ultraviolet radiation.

UV light irradiation of BALB/c mice was found to result in impairment of antigen-presenting cell function. Adherent trinitrophenyl-derivatized cells from the peritoneal exudate cell population or the spleen of UV-treated donors could not induce hapten-specific delayed hypersensitivity responses in UV-irradiated syngeneic mice, whereas adherent trinitrophenyl-derivatized cells from normal mice were able to do so. The failure to induce immunity in UV-treated mice by utilizing UV-treated adherent antigen-presenting cells was associated with the development of antigen-specific suppressor T cells. The implication of these results for UV-induced carcinogenesis is discussed.

Animals↗
PubMed1979

Regulation of immune response to tumor antigen: interference with syngeneic tumor immunity by anti-IA alloantisera.

We present evidence for a role of I-A subregion-encoded determinants in syngeneic tumor immunity. In animals rendered immune to the S1509a fibrosarcoma, daily treatment with microliter quantities of antisera directed against Kk and I-Ak determinants expressed on lymphoid cells of host origin decreased the capacity for immune tumor rejection. Absorption studies revealed that anti-I-Ak antibody activity alone was sufficient for the manifestation of this effect. Furthermore, experiments utilizing F1 hybrids showed that an antiserum that was genetically unable to interact with H-2 determinants expressed on the tumor was equally effective in inhibiting tumor immunity. Suggestive evidence that the activity of this antiserum is related to interference with the generation of effector T cell function was provided by the observation that hyperimmune animals pretreated with an anti-Kk,I-Ak antiserum were no longer capable of adoptively transferring tumor immunity to naive recipients. Thus, it is possible to regulate the secondary immune response to tumor antigens by using antisera with specificity for I-A determinants expressed on cells or possibly on factors of the host lymphoid system.

Animals↗
PubMed1979

Fine specificity of antibodies to poly(Glu60Ala30Tyr10) produced by hybrid cell lines.

The polyethylene glycol-mediated cell fusion technique has been used to analyze the diversity of the antibody response to the terpolymer poly(Glu60Ala30Tyr10)(GAT). Nine stable clones (all producing IgM K anti-GAT antibodies) were isolated from a fusion between P3-X63-Ag8 myeloma cells and spleen cells from a DBA/2 mouse sensitized to GAT 5 days earlier. Seven other clones (producing IgG K anti-GAT antibodies) were derived from another fusion between NSI myeloma cells and spleen cells of (C57BL/6 X DBA/2)F1 hybrid mice hyperimmunized with GAT. These 16 anti-GAT antibodies were grouped according to their pattern of reactivity with GAT and the two related polymers of poly(Glu60Ala40) (GA) and poly(GLU50Tyr50) (GT). Two monoclonal anti-GAT antibodies (IgM F9-102.2 and IgG F17-148.3) demonstrated crossreactivity with GA but failed to crossreact with GT determinants. In contrast, the remaining 14 hybridoma antibodies demonstrated preferential reactivity with GAT but also exhibited crossreactive binding to GT and in some cases GA. There was a correlation between the fine specificity pattern and the presence of a common anti-GAT idiotype on these antibodies. Thus, the hybridoma anti-GAT antibodies which reacted with GT shared crossreactive idiotypic determinants (CGAT) present in mouse anti-GAT immune sera. In contrast, the monoclonal F9-102.2 and F17-148.3 antibodies that failed to bind to GT lacked the major CGAT idiotypic determinants.

Alanine↗
PubMed1979

Idiotypic analysis of monoclonal antibodies to poly(Glu60Ala30Tyr10).

Fifteen hybridoma anti-poly(Glu60Ala30Tyr10) (anti-GAT) antibodies were analyzed for the presence of a common set of idiotypic specificities associated with murine anti-GAT antibodies, termed CGAT idiotype, which are present on the anti-GAT antibodies of all mouse strains. Thirteen of these monoclonal anti-GAT antibodies expressed a major fraction of CGAT idiotypic specificities. However, the remaining fraction of CGAT idiotypic specificities were not detected in individual or pooled hybridoma anti-GAT antibodies. Anti-idiotypic antisera made against each of the 15 hybridoma anti-GAT antibodies preferentially bound homologous ligand and showed minimal binding activity to specifically purified serum anti-GAT antibodies. Furthermore, the diversity of the hybridoma anti-GAT antibodies was demonstrated by the presence of individual idiotypic specificities on each of the hybridoma anti-GAT antibodies. However, relatedness among some of the hybridoma antibodies was also apparent since idiotypic analysis revealed that some hybridoma anti-GAT antibodies shared cross-reactive idiotypic specificities not associated with CGAT idiotype. The genetic mechanisms which could account for the generation of such antibody diversity are discussed.

Alanine↗
PubMed1979

Gene dose effects in Ir gene-controlled systems.

(B10.A x B10.S)F1 hybrid mice produce lower levels of anti-GL phi antibody than B10.S(9R) and B10.HTT mice. To determine whether this difference is due to a gene dose or a cis-trans effect, [B10.S(9R) x B10.S(8R)]F1 mice were immunized with GL phi. These mice carry one dose of the responder Ir gene alleles in the cis position whereas the recombinant B10.S(9R) and B10.HTT mice carry two doses of the relevant genes. Both (B10.A x B10.S) and [B10.S(9R) x B10.S(8R)] F1 mice produced comparably lower amounts of antibodies as compared to the recombinant strains. The data therefore demonstrate that gene dose and not cis-trans effect accounts for the differences between F1 and recombinant strains in their antibody response to GL phi controlled by complementary Ir genes.

Animals↗
PubMed1979

Regulation of the immune response to tumor antigen.

Reduction of syngeneic tumor growth in primary tumor-bearing murine hosts has been accomplished using a variety of treatments designed to decrease endogenous suppressor cell activity or augment host effector responses. Selective interference with suppressor cell function can be achieved by in vivo administration of anti-thymocyte serums at critical times during the early stages of tumor development or by continuous treatment with antiserums directed to interact with I-J determinants on suppressor cells or suppressor factors. This later mode of therapy also results in a delay in tumor appearance when suboptimal doses of tumor are given. Preferential diminution of suppressor cell precursor activity has also been observed by pretreatment of tumor recipients with low doses of cyclophosphamide. Normal animals so treated are capable of adoptively transferring primarily helper-type activity to tumor-bearing recipients. Decreased tumor growth and prolonged host survival have also been achieved using BCG as a means of augmenting host effector potential. Thus, it is possible to inhibit tumor development in a murine model by modes of immunotherapy which may be relevant to the early treatment of certain human neoplasms.

Animals↗
PubMed1979

Characterization of the primary IgM response to GAT and GT: conditions required for the detection of IgM antibodies.

Primary IgM antibody responses to synthetic linear copolymers of L-glutamic acid, L-tyrosine, and L-alanine were investigated. The appearance of primary IgM anti-GAT antibodies was detected in BALB/c mice by using a solid phase radioimmunoassay (SPRIA) procedure. The finding was verified for GAT in responder mice and GAT-MBSA and GT-MBSA in nonresponder mice in an indirect plaque forming cell (PFC) assay by using a rabbit antiserum directed against the mulambda myeloma protein, MOPC 104E. Facilitated IgM PFC could be inhibited by a purified muK myeloma protein, TEPC 183. Maximal facilitated IgM plaque response was found to precede the IgG response by several days. A direct plaque assay was developed for the detection of IgM anti-GAT plaques using poly-L-lysine (PLL) to couple GAT to sheep erythrocytes (SRBC). GAT-SRBC coupled by the PLL method optimally couple 4 to 5 times less antigen to the indicator cell surface than does the CrCl3-coupling method routinely employed in our laboratory. These findings were extended to a conventional antigen, chicken gamma globulin (CgammaG). We found that a less dense epitope coat on the indicator cell surface favors detection of direct IgM PFC, whereas a more densely coated indicator cell favors the detection of facilitated IgM and IgG PFC responses.

Alanine↗
PubMed1979

Idiotypic analysis of anti-GAT antibodies. III. Determinant specificity and immunoglobulin class distribution of CGAT idiotype.

The humoral response to poly-(L-glutamic acid60, L-alanine 30, L-tyrosine10), GAT, in mice is further characterized by both idiotype and fine specificity analyses. The common idiotype on murine anti-GAT antibodies (CGAT) was identified in anti-GAT antisera from seven additional strains of mice. These data confirm that the CGAT idiotype can be induced in all inbred strains of mice. Using a partially inbred strain of mice selected for their ability to respond to poly-(L-glutamic acid50, L-tyrosine50), GT, we demonstrated that the GT copolymer is capable of inducing antibodies that express the CGAT idiotype. In contrast, antisera directed against poly-(L-glutamic acid60, L-alanine40), GA, bind GAT but lack CGAT idiotype. These results indicate that GAT molecules contain determinants either similar or identical to those on GT molecules, which are responsible for the induction of CGAT idiotypic antibodies. We also demonstrated that both GAT responder and nonresponder strains of mice can produce anti-GAT antibodies with similar fine specificity patterns and CGAT idiotype. In addition, we demonstrate that antibodies of the IgM, IgG1, and IgG2 immunoglobulin classes express the CGAT idiotype.

Alanine↗