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B Benacerraf

Publications and source records attributed to B Benacerraf.

At least 253 records · Page 14Linked to original sources
PubMed1977

Immunosuppressive factor(s) specific for L-glutamic acid50-L-tyrosine50 (GT). III. Generation of suppressor T cells by a suppressive extract derived from GT-primed lymphoid cells.

Injection of mice with L-glutamic acid50-L-tyrosine50 (GT)- or L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT)-specific suppressor T-cell factor (GT-TsF or GAT-TsF) up to 5 wk before antigenic challenge challenge suppresses GT-methylated bovine serum albumin (MBSA) and GAT-MBSA plaque-forming cells responses. T suppressor cells are responsible for the suppression induced by the suppressive extract as demonstrated by adoptive transfer and sensitivity to anti-Thy-1 and complement treatment. We conclude that suppressive extract induces specific suppressor T cells. The material responsible for generation of suppressor T cells is a product of the I subregion of the H-2 complex. We have excluded that suppressive quantities of antigens are present in the extract. A/J mice, which can neither be suppressed by GT nor make GT-TsF can be suppressed by BALB/c GT-tsf. Spleen cells from BALB/c GT TsF-primed A/J mice can adoptively transfer suppression to normal syngeneic recipients. A/J mice appear to be genetically defective in cells involved in factor production. These results are discussed in the light of a two-step model for induction of antigen-specific suppressor cells.

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PubMed1977

Cytotoxic T lymphocytes induced against allogeneic I-region determinants react with Ia molecules on trinitrophenyl-conjugated syngeneic target cells.

The major histocompatibility complex codes for determinants which are recognized by and serve as targets for cytolytic T lymphocytes (CTL) (1). Antigens coded for by the K and D loci of the H-2 complex can activate xenogeneic or allogeneic CTL (2,3). In addition, the H-2K or H-2D gene products function as those molecules against which syngeneic CTL responses specific for chemical, viral, and minor H antigens are directed (4-8). It has recently been shown that Ia determinants can also serve as target antigens for distinct but weaker CTL responses (9-13). Those clones which recognize Ia antigens see them independently of K- or D- coded antigens as shown in genetic studies and by antisera-blocking experiments (12,13). We have proposed that the existence of clones of CTL specific for I-region-coded determinants is not fortuitous; rather these clones specifically recognize Ia determinants and may have an immunoregulatory role. These CTL may affect those immune functions which are at least partially dependent on or controlled by I-region-coded molecules. Two predictions can be made and tested concerning the role of Ia determinants in cytolytic systems and the role, if any, of I-region- specific CTL in regulating the immune response: (a) that if as we and others have shown, certain Ia specificities can serve as a third series of major histocompatibility antigens, then Ia antigens should be susceptible to the same types of antigenic modifications as H-2K- or H-2D-coded structures and thus serve as targets for CTL directed against modified-self in selected systems; and (b) that allogeneically induced I-region-specific CTL should demonstrate cross-reactivity with targets bearing modified syngeneic I-region-coded determinants. Data will be present which demonstrates that trinitrophenyl (TNP)-modified syngeneic I-region determinants can serve as targets for CTL induced by allogeneic Ia antigens.

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PubMed1977

Immunosuppressive factor(s) specific for L-glutamic acid50-L-tyrosine50 (GT) II. Presence of I-J determinants on the GT-suppressive factor.

The responses to the synthetic antigens, L-glutamic acid(60)-L- alanine(30)-L-tyrosine(10) (GAT) and L-glutamic acid(50)-L-tyrosine(50) (GT) are controlled by genes in the I region of the mouse H-2 complex (1-3). Preimmunization of the mice bearing the H-2(p,q,s) nonresponder haplotypes with GAT stimulates the development of suppressor T cells that inhibit in vivo or in vitro antibody responses to GAT complexed to the immunogenic carrier, methylated bovine serum albumin (GAT-MBSA) (4). The copolymer GT is not immunogenic in any inbred mouse strain tested, and has a suppressive effect on the antibody responses to GT-MBSA in mouse strains bearing the H-2(d,f,k,s) haplotypes; suppressor T cells have been demonstrated to be responsible for specific GT suppression (3). We have obtained specific suppressive extracts from thymus and spleen cells of GAT-or GT-primed suppressor strains (5,6). The specific suppressive T-cell factors in the active extracts have been characterized (6,7) and appear similar to the carrier-specific suppressor factor described by Tada and Taniguchi (8). These products belong to a family of newly identified molecules coded for by the I region of the H-2 complex with affinity for antigen and helper (9,10) or suppressive (5-8) regulatory activity on the immune response. Recently, Tada et al. have reported that the keyhole limpet hemocyanin (KLH)-specific suppressor factor is coded for by the I-J subregion of the H-2 complex (11). We now demonstrate also that a GT-specific suppressor factor extracted from the spleens and thymuses of B10.BR (H-2(k)) mice bears determinants controlled by the I-J subregion of the H-2 complex.

Alanine↗
PubMed1977

The I-J subregion codes for determinats on suppressor factor(s) which limit the contact sensitivity response to picryl chloride.

The cell-mediated immune reactivity (CMI) of mice to contact chemicals such as picryl chloride (PCI) is influenced by thymus-derived suppressor T lymphocytes (1,2). The development of these suppressor T lymphocytes is stimulated by the intravenous administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS). Zembala and Asherson have further demonstrated that a specific suppressor factor(s) can be detected in the supernates of cultured suppressor T cells. This factor suppresses the transfer of contact sensitivity (CS) to PCl (1,2). In experiments reported elsewhere (3), we have shown that the PCl suppressor supernates of Zembala and Asherson can also suppress the development of contact sensitivity to PCl. The immunochemical analysis of suppressor factor (SF) operative in the CS response to PCl has revealed many similar properties (3) to other suppressive moieties functioning to limit the plaque-forming cell (PFC) response to dinitrophenylated-keyhole limpet hemocyanin (DNP-KLH) as well as the strict antigen specificity of each respective suppressive factor, suggested that there might be a common origin of these substances. Indeed, in each case these respective factors were found to bear determinants controlled by the H-2 gene complex (4,5). Recently, in selected systems, the I-J subregion has been found to code for the Ia determinants present on suppressor cells (6) and suppressor factors (4,5). In accord with these findings, we report that antigen-specific SF which limit the CS response to PCl bear I-J determinants, implying that analogous suppressive regulatory mechanisms in CMI as well as antibody responses may be determined by genes of one subregion of the H-2 complex.

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PubMed1977

Restriction of primary responses to the IgG class and dependency of IgM responses on secondary immunization for the copolymers of L-glutamic acid, L-tyrosine, and L-alanine.

Primary responses to the linear polymers of L-glutamic acid, L-tyrosine, and L-alanine are restricted to the IgG class of antibodies. The appearance of specific IgM antibodies against these antigens is dependent upon secondary immunization, in contrast to many classical antigenic systems. The presence of an IgM response was verified by a direct plaque-forming cell assay, the inhibition of direct plaques by an antiserum specific for mouse micron-chain, and the physical separation of IgM and IgG GAT-specific antibodies by gel filtration. Preimmunization of the appropriate nonresponder strain with GAT or GT inhibits both the secondary IgM and IgG responses to GAT-MBSA and GT-MBSA, respectively. The tolerance observed is due to the induction of suppressor cells as demonstrated by cell transfer experiments.

Alanine↗
PubMed1977

Cytotoxic T lymphocytes specific for I region determinants do not require interactions with H-2K or D gene products.

Gene products coded for by the major hisocompatibility complex (MHC) can serve as target antigens for cytotoxic T lymphocytes (CTL) (1). A variety of test systems are available which have yielded information consistently reinforcing the importance of this complex of genes in the generation and effector phases of the cytotoxic immune response. Originally, it was shown that allogeneically-induced CTL had specificity primarily for the products of the K and D loci of the mouse H-2 complex (2). More recently this has also been found to be the case for xenogeneic immunizations (3,4). Additional examples of T cell-mediated lysis have been reported involving viral-infected or chemically- modified syngeneic stimulating and target cells in which homology at H-2K or H-2D was required between the responding and target cells for appreciable lysis to occur (5-7). Moreover, CTL specific for minor histocompatability antigens are able to lyse only target cells bearing these membrane antigens and sharing a common H-2K or H2-D gene product with the effector (8,9). Two hypotheses have been proposed to explain the requirement for H-2 identity between effector and targets in these systems. CTL may recognize new antigenic determinants created by the interaction of the modifier with syngeneic K and D gene products. Alternately, a dual recognition system my exist, requiring an antigen-specific receptor as well as a second receptor with specificity for homologous H-2K or H-2D determinants (5). Neither model can be excluded at this time. The I region also contains genes coding for histocompatibility loci since animals differing at the I-A or I-C regions of the H-2 complex reject skin grafts (10-12), though less rapidly than mice differing at the H-2K or H-2D regions, Also CTL can be generated to I region determinants but less efficiently than CTL specific for H-2K or H-2D gene products (12-14). The question can therefore be raised, whether the I region minor histocompatibility loci function independently from the H-2K or H-2D loci or whether I region-specific cytolysis requires the participation of H-2K or H-2D gene products of the target cell. This communication illustrates the generation of CTL showing specificity for I region determinants in primary mixed lymphocyte cultures. Further, we demonstrate by genetic analysis and byt eh use of speficit alloantisera that CTL directed to Ia determinants (a) do not see these antigens as modifications of H-2K or H-2D gene products but as independent gene products coded for by the I region, and (b) they do not require interaction with target cells bearing the same H-2K or H-2D gene product as the effect CTL.

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PubMed1977

Immunosuppressive factor(s) extracted from lymphoid cells of nonresponder mice primed with L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT) II. Cellular source and effect on responder and nonresponder mice.

The synthetic terpolymer of L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT) fails to stimulate development of GAT-specific antibody responses in nonresponder strains of mice, but does stimulate the development of GAT-specific suppressor T cells that inhibit the development of normal anti-GAT antibody responses to GAT complexed to methylated bovine serum albumin (GAT-MBSA). Furthermore, extracts prepared from lymphoid cells of GAT-primed, but not control, nonresponder mice inhibit the development of antibody responses to GAT-MBSA by normal nonresponder mice. This suppression is specific, dose-dependent, and can be readily analyzed in vitro. The suppressive factor is a T-cell product. An extract from GAT-primed DBA/1 mice inhibits the response to GAT-MBSA by spleen cells from histoincompatible strains of mice that are nonresponders to GAT, but not strains that are responders to GAT.

Animals↗
PubMed1977

Immunosuppressive factor(s) extracted from lymphoid cells of nonresponder mice primed with L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT) III. Immunochemical properties of the GAT-specific suppressive factor.

The GAT-specific suppressor T-cell factor (GAT-TsF) extracted from lymphoid cells from GAT-primed, nonresponder DBA/1 mice has been partially characterized. It is a protein that has affinity for GAT and determinants encoded by the I region of the H-2 complex. On the basis of specificity and avidity, GAT-TsF resembles anti-GAT-MBSA antibodies produced by DBA/1 mice in spite of the fact that it is too small to be classical antibody and has no constant-region determinants of heavy or light chains. Further, GAT or a fragment of GAT is associated with the GAT-TsF. GAT-TsF has been partially purified from the crude extract by absorption to GAT-Sepharose and elution with 0.4 to 0.6 KCl. GAT-TsF purified on the basis of its affinity for GAT bears I-region determinants but not detectable GAT or GAT fragment.

Animals↗
PubMed1977

Functional specificity of thymus- dependent lymphocytes.

Thymus-dependent lymphocytes display a restricted range of specificity when compared to thymus-independent (B) lymphocytes. They react particularly to thymus-dependent protein and cell surface antigens and to products of genes encoded in the MHC. In addition, T lymphocytes have important functions in regulating the immune response and in discriminating of self from nonself. Recent work indicates that individual T lymphocytes possess receptors that interact with both thymus-dependent antigens and MHC gene products, either independently or as associated structures. We attempt to relate this complex specificity pattern to the regulatory and surveillance functions of T lymphocytes.

Animals↗
PubMed1977

Immunosuppressive factor(s) specific for L-glutamic acid50-L-tyosine50. IV. In vitro activity and immunochemical properties.

The responsiveness of BALB/c spleen cells to the terpolymer L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT), the copolymer of L-glutamic acid50-L-tyrosine50 (GT) and the corresponding complexes with methylated bovine serum albumin (MBSA) has been studied in vitro in a modified Mishell-Dutton culture system. Cultures of BALB/c spleen cells respond to GAT, GAT-MBSA and GT-MBSA over a wide dose range. Contrary to in vivo findings BALB/c spleen cell cultures respond to GT in vitro although in a much narrower dose range. Lymphoid extracts from GT-primed BALB/c or B10.BR mice (GT-TSF) specifically suppress the GT-MBSA response in vitro. This culture system has allowed us to further investigate immunochemical properties of both BALB/c and B10.BR GT-TSF-GT-TSF from both strains display affinity for GT-Sepharose and bear determinants encoded by the I region of the H-2 complex. Moreover, we demonstrate that the suppressive activity from B10.BR mice is a molecule or a molecular complex which displays affinity for GT and bears determinants of the I-J subregion of the H-2k haplotype.

Animals↗
PubMed1977

Presence of common idiotypes on antibodies induced by glutamic acid-lysine-containing terpolymers in responder and nonresponder mice with the Ig-1b heavy chain allotype.

A B10.A (5R) responder mouse to the random linear terpolymer, poly--(Glu, Lys, Phe), GLphi, can produce immunoglobulins which bind poly-L (Glu, Lys), GL, that share idiotypic determinants with GL-binding antibodies produced by other members of the same strain. Expression of these common idiotypic determinants, termed BGL, is independent of the H-2 halotype and closely linked to the Ig-lb heavy chain allotype. Moreover, nonresponder mice with the Ig-lb heavy chain allotype, when immunized with GLphi that has been chemically coupled to an immunogenic carrier, chicken IgG, can produce GL-binding antibodies that share BGL idiotypic specificities with anti-GLphi antibodies produced by responder animals. Also, the responses to other GL-containing polymers, such as poly-L (Glu, Lys, Ala) and poly-L (Glu, Lys, Pro), which are under the control of distinct Ir genes, can stimulate the production of GL-binding antibodies that share common BGL idiotypic determinants with antibodies induced with GLphi. These findings are discussed with respect to their implications concerning the mechanism(s) of Ir gene control.

Animals↗
PubMed1977

Mouse cytolytic T lymphocytes induced by xenogeneic rat stimulator cells exhibit specificity for H-2 complex alloantigens.

When mouse spleen cells were stimulated with irradiated xenogeneic, allogeneic, or trinitrophenyl-modified syngeneic lymphoid cells, the strongest cytolytic response was induced by alloantigens. Mouse cytolytic T lymphocytes generated to rat lymphoid cells demonstrated specificity for the immunizing rat strain, but extensive lysis of allogeneic target cells from certain mouse strains was also observed. Cold target inhibition studies indicated that separate clones of xenoantigen-induced cytolytic T lymphocytes lysed each of the allogeneic murine targets. [3H]Thymidine suicide of the effector cells generated to the rat stimulators revealed that only some of all potentially reactive mouse cytolytic T lymphocyte precursors with specificity for a given allogeneic target are activated by the stimulation with rat cells. This evidence that xenoantigens induce alloreactive cytolytic T lymphocyte receptor repertoire is directed at variants of autologous major histocompatibility complex antigens.

Animals↗
PubMed1977

Reduction of syngeneic tumor growth by an anti-I-J-alloantiserum.

Highly significant suppression of the growth of S1509a and Sa-I syngeneic sarcomas was observed in A/J mice following daily intravenous injections of 2 microliter of anti-I-Jk alloantiserum. This effect persisted as long as the anti-I-Jk serum was administered (day 15), In contrast, a control anti-I-Js serum had no discernible effect on the growth of the S1509a tumor. The inhibitory activity of the anti-I-Jk serum on the growth of the tumor was absorbed specifically by B10-BR spleen cells bearing I-Jk determinants. In other experiments, we established that A/J mice treated with anti-I-Jk serum, according to the protocol described above, are no longer a source of tumor-specific suppressor cells for adoptive transfer into immune tumor-bearing recipient mice. We conclude that anti-I-Jk serum inhibits tumor growth in A/J mice by abolishing tumor-specific suppressor activity.

Animals↗
PubMed1977

Potentiation of a primary in vivo antibody response by alloantisera against gene products of the I region of the H-2 complex.

Mice were immunized intravenously with suboptimal numbers (3.5-5 X 10(5)) of sheep erythrocytes together with various anti-Ia antisera or with sheep erythrocytes alone, and the primary IgM and IgG plaque-forming cell responses were assayed 6 days later9 A/J (H-2a) mice given 5 X 10(5) sheep erythrocytes together with as little as 0.4 mul of a (129 X A.TH)F1 anti-A.TL (anti-Iak) antiserum developed 2-3 times as many IgM and IGG plaque-forming cells as mice injected with antigen alone or together with various antisera not containing anti-Ia antibodies. Similar results were obtained with BALB/c (H-2d) mice and a (C3H X LG/Ckc)F1 anti-C3H. OH (anti-Iad) antiserum plus sheep erythrocytes. In the case of the anti-Iad antiserum, the potentiating activity could be absorbed with C3H. OH (Id) but not C3H(Ik) spleen cells, demonstrating that the active antibodies were specific for the Id region. Antiserum to I-Jk subregion-coded determinants was tested in A/J (I-Jk) mice and found to also potentiate 2- to 3-fold the plaque-forming cell response to suboptimal erythrocyte immunization. This antiserum [(BIO.A(3R) X DBA/2)F1 anti-B10.(5R)] failed to potentiate responses in BALB/c (I-Jd) mice, as expected on a genetic basis. The potentiating antibodies could be removed by absorption with B10.BR (I-Jk) but not B10 (I-Jb) spleen cells, also confirming the I-J specificity of the activity. The interference of anti-I-J antibodies with T lymphocyte suppressor mechanisms is prposed as a possible explanation for this phenomenon.

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