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Biomedical subjects

B Benacerraf

Publications and source records attributed to B Benacerraf.

At least 109 records · Page 6Linked to original sources
PubMed1984

Chronic treatment with rabbit anti-mouse mu-chain antibody alters the characteristic immunoglobulin heavy-chain restriction of murine suppressor T-cell factors.

Prolonged treatment of mice, starting at birth, with rabbit anti-mouse mu-chain antibodies resulted in the elimination of immunoglobulin-bearing B cells in these animals. The ability of these animals to elicit antigen-specific delayed-type hypersensitivity or cytotoxic T-cell responses to azobenzenearsonate-coupled spleen cells was not impaired. The effect of anti-mu treatment on the restriction by immunoglobulin heavy-chain genes (Igh) of suppressor T cells was investigated. We found that first-order suppressor T-cell factor ( TsF1 ) obtained from anti-mu treated animals expresses an Igh restriction pattern distinct from that observed with TsF1 from normal untreated mice. Furthermore, TsF1 prepared from anti-mu treated animals did not express the major crossreactive idiotypic determinants normally present in TsF1 . The significance of these findings in relation to the role of immunoglobulin on the T-cell repertoire is discussed.

Animals↗
PubMed1984

Thymic T cells are driven to expand upon interaction with self-class II major histocompatibility complex gene products on accessory cells.

Murine thymocytes induce the monokine interleukin 1 upon in vitro coculture with a radioresistant Ia-bearing accessory cell [murine Ia molecule is a class II major histocompatibility complex (MHC) antigen]. The generation of interleukin 1 is critically dependent on the function of I-region gene products on accessory cells. The induced interleukin 1 appears to allow the activation and proliferation of self-MHC-specific thymocytes. Thus, in the absence of added exogenous factors, there is an Ia-dependent thymocyte proliferation. This selective activation of thymocytes is observed with both mature and immature thymic T cells. This in vitro response results in the selective amplification of developing T cells with self-MHC specificity and could be of importance to the in vivo commitment of T cells to MHC determinants that occurs in the thymus.

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PubMed1984

Suppressor cells and immunoregulation.

We have described a model system of immunoregulation in which gene products associated with both the major histocompatibility complex and the heavy-chain immunoglobulin gene complex guide a series of cellular interactions. The Igh genetic restrictions may represent the use of internal images of antigen and idiotype as suppressor-T cell receptors. The data indicate that the T-cell and B-cell Igh products are distinct. The T cell-derived idiotype-like determinants are used for suppressor-T cell communications. The MHC restrictions generally involve the I-J subregion. These restrictions are imposed by the presentation of antigen or suppressor factor by specialized populations of I-J bearing accessory cells. The role of MHC products in the induction of suppressor cells has several homologies with the mechanisms responsible for the induction of H-2-restricted helper cells. First, I-region products on specialized presenting cells determine the specificity and genetic restrictions of the T cells. Thus, recognition of antigen in the context of I-A and I-E products is required for helper-T cell induction, and similarly the various suppressor-T cell subsets recognize antigen or suppressor factor presented in the context of I-J subregion-encoded antigens. Furthermore, the data suggest that the suppressor cells bear receptors for self I-J products. As an additional analogy between suppressor and helper cells, we have shown that in H-2-heterozygous F1 animals at least two populations of suppressor cells can be induced, one specific for each parental H-2 haplotype. The NP and ABA suppressor-cell pathways consist of multiple cellular elements, including at least three and possibly four distinct T-cell populations and two or more distinctive accessory cell populations. These are summarized in Figure 1. The specific soluble suppressor factors produced by each suppressor-T cell subset are involved in cellular communication processes. The terminal phases of the suppressor-cell cascade are antigen dependent but involve nonspecific bystander effects. In this review we have indicated the numerous homologies between the data in the hapten systems studied in our laboratories and the various other suppressor-cell models previously described in the literature.

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PubMed1984

Selection of thymocyte MHC restriction specificity in vitro.

The thymus is critical for the generation of mature T cells with restricted specificity for major histocompatibility complex (MHC) molecules of thymic genotype. The mechanism by which this T cell commitment to self-MHC gene products occurs in vivo prior to the exposure to foreign antigens is unknown. When thymocytes are cocultured with irradiated syngeneic accessory cells, a proliferation of cells specific for self-Class II MHC molecules is observed. This in vitro response is of interest in the context of the physiologic events that occur in the thymus. However, the functional significance of these in vitro proliferating cells, as well as their relationship to antigen-specific, MHC-restricted T cells, has not been defined. Further, whether this in vitro response is capable of influencing the MHC specificity of the thymocytes is unknown. In the work reported here, cells obtained from these cultures were tested for their ability to help a primed B cell antibody response. This approach allowed an analysis of function, antigen and MHC-restriction specificity, and the behavior of these cells upon transfer in vivo. Potent T-helper function was obtained from such cultures for an antigen-dependent, hapten-specific B cell response. When F1 thymocytes were cultured with F1 accessory cells, the T-helper cells recovered could help B cells of both parental MHC haplotypes. However, if the same F1 thymocytes were first cultured with parental accessory cells, they subsequently cooperated only with the corresponding parental or F1 B cells. This MHC restriction was determined by the MHC genotype of the accessory cell in primary culture. Monoclonal antibody blocking studies demonstrated that Ia molecules were critical to this process. Suppression did not account for the observed restrictions. The effector specificity of the T-helper cells could be mapped to the I-A subregion. On adoptive transfer to lethally irradiated hosts, the helper cells could localize to peripheral lymphoid organs. These cells retain their in vitro-imposed restriction specificity even when transferred back to and primed in an F1 environment. Using this experimental protocol, carrier antigen-specific, MHC-restricted priming of these thymic T-helper cells could be detected. These results demonstrate that one can select and amplify functional T-helper cells from cultures of thymocytes whose precise MHC-restriction specificity is determined in vitro.

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PubMed1984

Decidual cast mimicking an intrauterine gestational sac and fetal pole in a patient with ectopic pregnancy. A case report.

In a case of ectopic pregnancy, ultrasound findings showed a pseudogestational sac in the uterus containing debris that mimicked a fetal pole. Ultrasonography done one week before had revealed no intrauterine gestational sac. The progression in one week of an "empty" uterus to a seven-week-sized intrauterine gestational sac with the appearance of a fetal pole without a heartbeat should suggest to the sonographer the possibility of a pseudosac and ectopic pregnancy.

Adult↗
PubMed1984

The role of Ia molecules in the activation of T lymphocytes. IV. The basis of the thymocyte IL 1 response and its possible role in the generation of the T cell repertoire.

The activation requirements for thymocyte proliferation were investigated. Thymocytes proliferate in the presence of exogenous interleukin 1, which has been used as the classic assay for this factor. This response, however, is greatly decreased in cultures of purified thymic T cells. Purified thymic T cells will proliferate in the presence of IL 1 if accessory cells are added to culture. The requisite accessory cell is a non-T, adherent, radioresistant cell found in macrophage/dendritic cell-enriched fractions of both thymus and spleen. This cell bears Ia molecules, which are critically involved in the activation of thymocytes. This thymocyte-accessory cell interaction is not dependent on exogenous nominal antigens. Therefore, it appears that IL 1 allows the expansion of thymocytes with specificity for self-class II MHC antigens. This response was found to be unique to this stage of T cell development and can be observed with both mature and immature thymic T cell subsets. The implications of these findings for the physiologic expansion of self-restricted T cells in the thymus are discussed.

Animals↗
PubMed1983

An antigen-specific signal is required for the activation of second-order suppressor T cells in the regulation of delayed-type hypersensitivity to 2,4,6-trinitrobenzene sulfonic acid.

Suppressor T cells (Ts-1) induced with trinitrophenyl (TNP)-conjugated syngeneic spleen cells (TNP-SC) can be enriched on antigen-coated plates and are afferent suppressors. In addition, these suppressor cells produced soluble suppressor factors (TsF) that were active in vivo. Therefore, the Ts-1 cells in the TNP system are very similar to the Ts-1 cells in other systems we have studied earlier. Further characterization of these TsF-1 revealed that TsF-1 obtained from TNP-SC-induced Ts-1 is major histocompatibility complex restricted in its activity. Injection of TNP-specific TsF-1 into naive mice did not induce Ts-2 unless additional corresponding antigen was provided. Moreover, the Ts-2 cells induced by administration of both TsF-1 and trinitrobenzene sulfonic acid were antigen specific rather than antiidiotypic.

Animals↗
PubMed1983

Inhibition of antigen-specific T lymphocyte activation by structurally related Ir gene-controlled polymers. Evidence of specific competition for accessory cell antigen presentation.

The interaction of nominal Ag with major histocompatibility complex (MHC)-restricted T cells and accessory cells was studied by analyzing the effect of structurally related antigens on the response of antigen-specific MHC-restricted T cell hybridomas. The copolymer L-glutamic acid50-L-tyrosine50 (GT) completely inhibits the response of L-glutamic acid60-L-alanine40-L-tyrosine10 (GAT)-specific, I-Ad-restricted T cell hybridomas to GAT plus accessory cells. This inhibition is specific, as hybridomas of other specificities are not inhibited under identical conditions, and is unique to the GT antigen, as other similar copolymers are not inhibitory. The inhibitory effect is reversible by adding increasing amounts of GAT. Antigen-pulsing experiments localized the inhibition to the level of antigen-presenting cell (APC). GT-prepulsed APC are not inhibitory in cell-mixing experiments and can present other antigens. GT only inhibits the nominal antigen-directed component of a GAT-specific, autoreactive hybrid's response. Together these findings suggest that GT causes inhibition by competing for GAT association at the accessory cell. GT interferes with GAT presentation by an I-Adxb F1 APC to a BALB/c, I-Ad-restricted, but not B10, I-Ab-restricted, T cell hybridoma, and GT inhibits presentation by GAT-prepulsed APC. The implications of these findings for MHC-restricted presentation of antigen are discussed.

Animals↗
PubMed1983

Identification of an I-J+ antigen-presenting cell required for third order suppressor cell activation.

We have found that an I-J+ I-A- antigen-presenting cell (APC) is required for Ts3 activation in vivo. Together with the I-J restriction previously reported for Ts3 induction (Takaoki, M., M.-S. Sy, A. Tominaga, A. Lowy, M. Tsurifiji, B. Benacerraf, R. Finberg, and M. I. Greene, 1982, J. Exp. Med., 156:1325), it appears that this I-J+ APC is responsible for I-J restriction in the triggering of Ts3. This restriction may be exerted via a pre-Ts3 associative recognition of antigen and I-J encoded determinants, analogous to the T helper recognition of antigen in the context of I-A and I-E determinants.

Animals↗
PubMed1983

The role of Ia molecules in the activation of T lymphocytes. III. Antigen-specific, Ia-restricted, interleukin 2-producing T cell hybridomas with detectable affinity for the restricting I-A molecule.

Antigen-specific I region-restricted, interleukin 2-producing T cell hybridomas were produced by fusing GAT-specific T cell blasts with BW5147. Two antigen-specific phenotypes were identified, one autoreactive and one nonautoreactive. All of the antigen-specific and autoreactive clones were H-2 restricted, mapping to the IA subregion by genetic analysis and monoclonal antibody inhibition. Both the antigen-specific and autoreactive stimulation are the property of a single cell and required no known exogenous antigens.

Animals↗
PubMed1983

Inhibition of delayed-type hypersensitivity by heparin depleted of anticoagulant activity.

The intravenous or intraperitoneal injection of heparin fractions depleted of anticoagulant activity (HFDA) into mice, either at the time of immunization or challenge, inhibited hapten-specific delayed-type hypersensitivity (DTH) reactions. The loss was not due to functional elimination of sensitized lymphocytes, since mice sensitized with the contactant and then treated with HFDA retained their ability to transfer reactivity into normal syngeneic recipients. In contrast, lymphocytes from sensitized mice were unable to produce DTH reactivity in recipient mice pretreated with HFDA. The intravenous injection of HFDA resulted in a rapid, but transient increase in the number of circulating leukocytes. The intravenous injection of HFDA also reduced the footpad swelling that resulted from a local injection of concanavalin A. It is postulated that HFDA exercise their inhibitory effects on the DTH response by interfering with the migration of cells into the challenge site.

Animals↗
PubMed1983

Molecular signals in antigen presentation. I. Effects of interleukin 1 and 2 on radiation-treated antigen-presenting cells in vivo and in vitro.

In order to clarify the nature of the defect in the process of antigen presentation caused by uv radiation, low-density spleen cells were used as a potent APC source in a hapten-specific cytolytic T-cell (Tc) system. It was demonstrated that IA+ weakly adherent low-density spleen cells, when directly coupled with azobenzene arsonate (ABA), led to the activation ABA-specific Tc. When these APC were exposed to uv radiation (12 J/m2/sec) for 30 sec, their ability to lead to Tc activation was markedly inhibited. The defect imposed by uv radiation could be specifically bypassed by the addition of small amounts of homogeneous IL-1 or IL-2. This led to the specific activation of ABA-reactive H-2-restricted Tc. The purified IL-1 was also found to bypass the systemic defect imposed in vivo by external uv radiation of mice. This may indicate a potential therapeutic role for IL-1.

Animals↗
PubMed1983

Effect of vesicular stomatitis virus (VSV) infection on the development and regulation of T cell-mediated immune responses.

Infection of mice with vesicular stomatitis virus (VSV) at the time of immunization failed to enhance T cell-mediated immune response to azobenzenearsonate-(ABA) conjugated spleen cells as measured by delayed-type hypersensitivity and by in vitro proliferation and in vitro generation of ABA-specific cytotoxic T cells. However, mice infected with VSV are incapable of responding to signals from suppressor T cells or their soluble factors. Further analysis revealed that VSV infection does not interfere with the induction of Ts-1 or Ts-2 cells. Because infection of Ts-1 or Ts-2 donors had no effect on the subsequent response seen in the recipients of antigen and suppressor T cells, the most likely candidate for the target of VSV infection is therefore the Ts-3 cell or another T cell interacting with Ts-3. This is supported by our observation that it is possible to bypass the VSV effect by providing the recipients of VSV with normal Lyt-2+-bearing T cells.

Animals↗
PubMed1983

Regulation of the hapten-specific T cell response. I. Preferential induction of hyporesponsiveness to the D-end of the major histocompatibility complex in the hapten-specific cytotoxic T cell response.

In this paper we have examined the phenomenon of hapten-specific tolerance in the cytolytic T lymphocyte (CTL), using the trinitrophenyl (TNP) and azobenzenearsonate haptens. We found that the H-2 K and H-2 D-end restricted CTL in H-2a mice are differentiable in the ease with which they are tolerized to the TNP hapten. With TNP modified syngeneic spleen cells (TNP-SC), or low amounts of trinitrobenzylsulfonic acid as tolerogen, preferential hyporesponsiveness of D-end restricted CTL can be observed. Larger doses of hapten, e.g. a higher amount of trinitrobenzylsulfonic acid, will tolerize both K- and D-end restricted TNP-specific CTL in H-2a mice. The phenomenon of preferential D-end restricted CTL hyporesponsiveness is not observed in H-2d, H-2k, or H-2b mice, nor is it observed in H-2a mice with respect to the azobenzenearsonate hapten. We have also shown that the clones of CTL responsible for lysis of TNP-modified allogeneic targets (cross-reactive lysis) in H-2a mice probably overlap with the D-end restricted TNP-specific CTL since D-end restricted hyporesponsiveness induced by intravenous injection of TNP spleen cells also results in the elimination of cross-reactive lysis of TNP-modified allogeneic targets. The possible mechanisms of preferential D-end hyporesponsiveness to the TNP hapten in the H-2a mice as well as its significance and relationship to previous work in this area are discussed in this paper.

Animals↗
PubMed1983

Inhibition of tumor growth by monoclonal anti-I-J antibodies.

In this paper we have examined the effects of i.v. administered monoclonal anti-I-J antibodies on tumor growth in syngeneic and semi-syngeneic hosts. These antibodies inhibit tumor growth in mice bearing the appropriate I-J-encoded gene product on their lymphoid cells at nanogram dosages. The spleens of monoclonal anti-I-J-treated primary tumor-bearing mice do not contain transferable tumor-specific cells. These findings suggest that inhibition of suppressor cell function may be the mechanism by which anti-I-J antibodies inhibit tumor growth. We have also demonstrated that tumors growing in F1 hybrid mice are inhibited by monoclonal anti-I-J antibodies reactive with either parental haplotype and that there is no evidence of synergy when both antibodies are administered simultaneously. This may indicate that I-J molecules are codominantly expressed on a critical component of the F1 suppressor pathway.

Animals↗
PubMed1983

The role of Ia molecules in the activation of T lymphocytes. II. Ia-restricted recognition of allo K/D antigens is required for class I MHC-stimulated mixed lymphocyte responses.

The role of Ia molecules in the T cell proliferative response to class I (H2K/D) MHC alloantigens was examined. Proliferation in response to allo-K/D antigenic stimulation, but not to allo-Ia, was markedly inhibited by the addition of monoclonal anti-responder Ia antibodies to cultures in the absence of C. This anti-Ia blocking was observed in responses against both allelic and mutant class I antigens. Partial blocking was observed by using an anti-I-A or anti-I-E monoclonal antibody alone, whereas marked inhibition was seen with these two reagents together when the proliferating cells derived from a responder strain expressing both IA and IE gene products. Syngeneic Ia molecules appear to function as restriction elements, because they are required even in the presence of a source of exogenous second signal, phorbol myristic acetate or IL 1. The K/D-specific response required a responding cell that bears both Lyt-1 and -2 antigens, whereas responses generated to alloantigenic differences, including the I region, require only an Ly-1+ cell. The implications of these data with respect to the repertoire of the alloreactive proliferating T cell and the expression of the Lyt-2 antigen by such cells are discussed.

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