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Biomedical subjects

B Benacerraf

Publications and source records attributed to B Benacerraf.

At least 289 records · Page 16Linked to original sources
PubMed1975

Inhibition of T-lymphocyte-mediated tumor-specific lysis by alloantisera directed against the H-2 serological specificities of the tumor.

After appropriate in vivo or in vitro immunization, cytotoxic T lymphocytes (CTL) are generated which efficiently kill cells bearing particular membrane antigens in common with the immunizing cell (reviewed in reference 1). Such CTL have been most thoroughly studied in mice, employing alloimmunization with cells differing at the major histocompatibility locus, H-2. in such cases, the predominant cell surface antigens recognized by the CTL appear to be the molecules carrying the serologically defined H-2 specificities, coded for by the K and D regions of the H-2 complex (2). In other syngeneic models of cell-mediated specific cytolysis, involving lymphocyte chariomeningitis (LCM) virus- or ectromelia virus-infected cells or TNP-modified lymphoid cells, thymus-derived cells also constitute the main effector cell type. The CTL generated in these latter systems function most efficiently when virus-infected or TNP-modified target cells share identitites at the H-2K or H-2D loci with the effector CTL and stimulator cells (3-5). Another set of experimental systems in which CTL are generated and play a significant biological role is that of immunity to tumor-associated antigens (TAA) (6). The nature of the TAA which the CTL recognize is only beginning to be understood. Several recent reports indicated the existence of physiochemical and/or antigenic relationships between TAA and H-2 antigens (7,8). These relationships, together with the genetic restrictions cited above in the generation of CTL involving products of the H-2K or H-2D loci suggested the possibility that in certain tumor systems, the TAA which are able to most effectively stimulate CTL responses might be structurally similar to, or linked with, the H-2K or H- 2D molecules on the tumor surface. It has been previously demonstrated in allogenic models that antisera specific for the appropriate H-2K or H-2D products present on a target cell could specifically block CTL-mediated lysis (1,9). This report demonstrates that certain anti-H-2 alloantisera specific for the target tumor cells can block lysis of those target cells mediated by syngeneic tumor-specific CTL effector cells.

Animals↗
PubMed1975

Mapping of the immune response genes in the major histocompatibility complex of the Rhesus monkey.

Interest in the Ir genes of rheus monkeys stems from their phylogenetic relationship to man and the extensive data already available on the major histocompatibility complex of the monkey. At least two independent dominant H-linked Ir genes have been identified in the rhesus. These genes control the ability of monkeys to respond to the random linear copolymer of glutamyl alanine (GA), or the dinitrophenyl conjugate of glutamyl lysine (DNP-GL). These synthetic polymers can elicit weak delayed-type skin reactions and strong humoral responses in some monkeys. In a series of unrelated monkeys phenotyped for the serologically defined RhL-A specificities of both segregant series, there were no correlations between any RhL-A specificity and responder status to the GA or DNP-GL polymers. However, segregation analysis of 21 rhesus families sired by 3 fathers indicated the capacity of the offspring to form antibodies was associated with genes coded for in the RhL-A complex. In three monkeys, verified recombination within the RhL-A complex between the genes coding for the serologically defined determinants (SD loci) and the gene(s) controlling the lymphocyte-activating determinants (Lad loci) responsible for mixed lymphocyte reactivity was established. In two of these monkeys the immune response genes controlling the DNP-GL response segregated with the Lad genes, while in the third case the Ir-GL gene segregated with the SD loci, tentatively localizing the Ir-GL gene between the SD and Lad loci. In addition, we have shown that genetically distinct genes control responsiveness to DNP-GL and GA. These genes were separated by recombination, thus one monkey inherited the Lad, Ir-GL, and SD loci from one paternal haplotype and by crossing over inherited the gene controlling GA responsiveness from the other paternal haplotype. The fine structure mapping of the RhL-A gene complex is compared with the H-2 and HL-A gene complexes. Several striking similarities were noted.

Alanine↗
PubMed1975

Induction of T-lymphocyte responses to a small molecular weight antigen. II. specific tolerance induced in azebenzenearsonate (ABA)-specific T cells in Guniea pigs by administration of low doses of an ABA conjugate of chloroacetyl tyrosine in incomplete Freund's adjuvant.

The experiments presented in this paper demonstrate that the induction of tolerance on the one hand and the induction of delayed sensitivity on the other hand can be accomplished by administration of similar doses of azobenzene-arsonate conjugated to N-chloracetyl tyrosine (ABA-T) to guinea pigs with the determining factor being the absence or presence, respectively, of activating bacterial products in the adjuvant mixture used. Thus, complete, persistent ABA-T-specific T-cell tolerance can be induced in adult guinea pigs with 20 mug of ABA-T given intradermally in incomplete Freund's adjuvant (IFA) whereas this same dose of ABA-T induces ABA-specific immunity when administered in complete Freund's adjuvant. This tolerance was not reversible by administration of ABA-T and IFA in the presence of bacterial lipopolysaccharide, was generated before the formation of primed T cells, and persisted for at least 3 mo after initiation. Moreover, cell transfer studies performed herein demonstrate that the unresponsiveness resulting from administration of ABA-T in IFA reflects the activity of suppressor cells to induce and maintain a state of unresponsiveness could only be demonstrated in unprimed animals may indicate a severe limitation on the potential clinical usefulness of such an approach to regulation of the immune system.

Acetates↗
PubMed1975

Induction of T-lymphocyte responses to a small molecular weight antigen. III. T-T cell interactions to determinants linked together: suppression vs. enhancement.

The experiments presented in this paper demonstrate the existence of T-T cell interactions in responses to azobenzenearsonate (ABA)-protein conjugates, and also make the point that the spectrum of T-cell regulation from facilitation (i.e., help) at one end to suppression at the other, which has been well documented in T-B cell interactions, is also followed in T-cell regulation of other T lymphocytes. The data extend the activity of ABA-specific suppressor cells, which were shown to specifically suppress the development of delayed hypersensitivity to ABA-T, to T cells responsible for delayed hypersensitivity to protein antigens provided immunization is carried out with ABA conjugates of these antigens. Thus, suppressor T cells acting on the development of delayed hypersensitivity are not limited in their effects to T cells bearing the same specificity but can effectively suppress responses on immunologically unrelated T cells if they are specific for carrier antigens covalently linked to the ABA-T determinant. Moreover, these studies demonstrate that, as is true of T-B cell interactions, the most efficient T-T cell interactions occur to determinants linked together on the same molecule thus supporting the concept that development of effector T-cell function may involve participation of at least two distinct precursor cells, each of which may convey independent determinant specificities and/or genetic control.

Animals↗
PubMed1975

Genetic control of immune responses in vitro. VI. Experimental conditions for the development of helper T-cell activity specific for the terpolymer L-glutamic aicd60-L-alanine30-L-tyrosine10 (GAT) in nonresponder mice.

Mice which are genetic nonresponders to the random terpolymer of L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT) not only fail to develop GAT-specific antibody responses when stimulated with soluble GAT either in vivo or in vitro, but develop GAT-specific T cells which suppress the GAT-specific plaque-forming cell response of normal nonresponder mice stimulated with GAT complexed to methylated bovine serum albumin (MBSA).Thus, both responder and nonresponder mice have T cells which recognize GAT. However, nonresponder mice can develop GAT-specific helper T cells if immunized with GAT bound to MBSA or to macrophages. The relevance of Ir gene-controlled responses is discussed.

Age Factors↗
PubMed1975

Cell interactions between histoincompatible T and B lymphocytes. VII. Cooperative responses between lymphocytes are controlled by genes in the I region of the H-2 complex.

The results of this study provide compelling evidence for the existence of the gene or genes controlling optimal T-B-cell cooperative interactions in the designated I region of the H-2 gene complex. Previously, we have speculated that the relevant gene(s) involved may well be located in this region based on several observations from our earlier work in this area (3, 5, 6). Thus, in the preceding paper, we showed that T and B cells from B10.BR and A strain mice developed effective cooperative interactions in vitro to DNP-KLH in a system identical to the one reported herein. Since these mice differ for genes in the S and D regions of H-2 but are identical for K and I region genes, we were able to localize the critical genes to the K-end of H-2.

Animals↗
PubMed1975

Inuction of immunological tolerance in immunoglobulin E B lymphocytes in rats.

Immunological tolerance has been induced in 2,4-dinitrophenyl (DNP)-specific bone marrow-derived or B lymphocytes of the IgE AND IgG antibody classes by treatment of rats with the DNP derivative of D-amino acid copolymer, D-glutamic acid, D-lysine (D-GL). The tolerant state is manifested as an inability of treated rats to produce serum anti-DNP antibodies and the failure of peritoneal cells from tolerant animals to release histamine following in vitro antigen challenge. The implications of these and related observations for potential therapeutic measures in clinical hypersensitivity states are discussed.

Aminocaproates↗
PubMed1975

Complementation of H-2-linked Ir genes in the mouse.

The immune response to the random linear terpolymer of L-glutamic acid, L-lysine, and L-phenylalanine (GLphi) is under dominant H-2-linked Ir gene control in the mouse. Matings between two nonresponder strains produced responder F1 hybrids, demonstrating complementation of the nonresponder alleles. This observation, coupled with the fact that several intra H-2 recombinant strains derived by recombination between two nonresponder parental haplotypes are also GLphi responders, indicated at least two dominant loci are concerned with responsiveness to this terpolymer. The complementary genes were termed alpha (tentatively localized in a new subregion of the H-2 complex, I-F) and beta, which maps in the I-A subregion. Generally, both the alpha(+) and beta(+) alleles are required for responsiveness. However, in the (C57BL/6J X SJL)F1 hybrid we noted complementation between two parental nonresponder strains, each of which carried beta genes derived from different H-2 haplotypes, yet lacked functional alpha genes. The possible cell levels at which these genes may function in the regulation of the immune response are discussed.

Animals↗
PubMed1975

Deoxyribonucleic acid synthetic response of mouse lymphoid cells in microculture with T-lymphocyte-dependent mitogens.

Various numbers of mouse thymus, lymph node, or spleen cells were cultured in serum-containing medium with concentrations of 0.06 to 64 mug. per ml. of concanavalin A (Con A), using our version of the microculture technique. Maximal DNA synthetic responses were obtained with 1.0 million thymocytes (highest number used) at 4 mug. per ml. of Con A and with 0.75 million lymph node cells or 0.5 million spleen cells at 1 mug. per ml. of Con A. At optimal Con A concentration the magnitudes of response of 0.25 million thymus, compared with the same number of lymph node cells, were very similar. However, the response of lymph node cells was superior to that of thymocytes when 0.5 million initial cells were used, whereas 1.0 million thymocytes gave a better response than did the same number of lymph node cells. Regardless of the cell concentration, a comparison of responses by the three different cell types with the same cell number showed that the Con A concentration-DNA synthetic response curve was broadest for spleen cells, narrow for thymus cells, and intermediate for lymph node cells. Results in replicate experiments were highly reproducible, and the data indicated that peak DNA synthetic responses were not directly proportional to cell number when certain numbers of cells were used; the actual proportionality of response to cell number varied with the cell type and the mitogen concentration. When examined throughout the culture period, concentrations of Con A which were above the optimal for stimulation of DNA synthesis resulted in significant decreases in the number of viable cells. Time course experiments with Con A (or phytohemagglutinin)-stimulated BALB/c spleen cells showed that the initiation of DNA synthesis occurred between 12 and 24 hours of culture, with peak levels of 3H-thymidine incorporation occurring during the 2nd and 3rd days of culture. The presence or absence of fetal calf serum had essentially no effect on the Con A- or phytohemagglutinin-stimulated DNA synthetic responses during the 3rd day of culture. These results demonstrate that detailed evaluation of culture variables and mitogen concentrations is required for the most meaningful use of mitogen-stimulated DNA synthesis as a parameter for comparing different lymphoid cell populations.

Animals↗
PubMed1975

Binding of poly (Glu-60 Ala-30 Tyr-10) by thymic lymphocytes from genetic responder and non-responder mice: effect of antihistocompatibility serum.

The binding of 125-I-labeled GAT by murine thymocytes was studied by autoradiography. GAT binding was highly temperature dependent. Significantly more thymocytes bound GAT at 37 degrees C than at 4 degrees C. GAT bound at 37 degrees C was usually distributed in a "cap" over one pole of the cell. Preincubation of thymocytes with specific anti-H-2 serum markedly inhibited the subsequent binding of GAT. The frequency of antigen-binding thymocytes was not significantly affected by preincubation of thymocytes with anti-Thy-1 serum or a number of anti-immunoglobulin sera. The immune response to GAT is controlled by an H-2 linked immune response gene(s). Mice of strains that are H-2p, H-2q or H-2s (non-responders) fail to develop effective T cell helper function necessary for a humoral immune response to GAT under most conditions. However, both responder and non-responder strains had similar numbers of thymocytes capable of binding GAT in vitro, indicating that T cells from non-responder strains of mice do possess a recognition mechanism for GAT.

Alanine↗
PubMed1975

Cell interactions between histoincompatible T and B lymphocytes. VIII. In vivo cooperative responses between lymphocytes are controlled by genes in the K-end of the H-2 complex.

The genetic restrictions for successful carrier-primed T cell and hapten-primed B cell cooperative interactions were established in a totally in vivo double adoptive transfer system. In complementation experiments, we have demonstrated that genes localized in the K-end of the H-2 complex control successful T-B cell cooperative interactions. Thus, DBA/2 KLH-primed T cells cooperated with (C3H times C3H.OH)F1 and (C3H times C3H.OL)F1 DNP-primed B cells to make a secondary response to DNP-KLH, but not with (C3H times C3H.A)F1 DNP-PRImed cells. The presence of foreign histocompatibility determinants on the F1 B cells did not prevent successful physiologic cell cooperation provided the T and B cells shared common cell interaction genes coded for in the K-end of the H-2 complex.

Aminocaproates↗