RESUMO
The genetic structure of the H-2 system has been traditionally interpreted as consisting of multiple regions controlling histocompatibility antigens. Recently however, many difficulties have been encountered in attempts to construct a single, consistent linear H-2 map on this basis. We have shown that the genetic, serological, and biochemical findings on the H-2 system can be more readily explained by the assumption that there are only two histocompatibility regions (loci) in the H-2 system, H-2D and H-2K, which are separated by loci controlling serum proteins (Ss-Slp), immune response (Ir-1), and perhaps others. Evidence supporting such an interpretation of the H-2 system was obtained by a transplantation analysis of the 14 well-defined H-2 crossovers. F(1) hybrids between different H-2 crossovers were produced and challenged with skin grafts from third party strains. The donor-recipient relationships in these combinations were such that in at least 10 cases the skin grafts should have been rejected if the multiple-region H-2 map is correct but should survive permanently if the two-region model is correct. In all instances, the skin grafts survived permanently, providing further evidence for the two-region map of the H-2 complex.
Assuntos
Genes , Histocompatibilidade , Imunogenética , Isoantígenos , Modelos Biológicos , Animais , Troca Genética , Camundongos , Camundongos Endogâmicos , Transplante de Pele , Imunologia de Transplantes , Transplante HomólogoRESUMO
We have examined the MLR reaction in two sets of recombinants that differ in the I-J subregion. In both cases, significant stimulation was mediated by antigens controlled by genes in the I-J subregion. This stimulation was inhibitable by the addition of the culture of antisera directed against the I-J gene products on the stimulator cell. The specificity of this inhibition was shown by specific blocking of the relevant gene product on F1 hybrid stimulator cells. MLR stimulation was also eliminated by pretreatment of the stimulator population with anti-I-J sera plus complement. Pretreatment of F1 hybrid stimulator T cells with anti-I-J sera directed against either parental I-J product in the presence of complement, completely eliminated stimulation, indicating that there is no allelic exclusion of the relevant I-J products. Pretreatment with an anti-I-E/I-C serum and complement also eliminated stimulation, suggesting that the stimulating T cells express both I-J and I-E/I-C subregion products. This assay offers a potentially more direct and practical method for serological detection of the I-J products.
Assuntos
Biossíntese de Proteínas , Linfócitos T/imunologia , Animais , Antígenos , Proteínas do Sistema Complemento/farmacologia , Soros Imunes/farmacologia , Linfonodos/citologia , Teste de Cultura Mista de Linfócitos , Camundongos , Camundongos EndogâmicosRESUMO
A significant within-strain correlation has been demonstrated between the levels of Ss and hemolytic complement (C) activity in two Ss-high strains. Mouse serum specifically depleted of Ss by absorption with F(ab')2 fragments of anti-Ss had negligible C activity. In control experiments, Ss-specific antigen-antibody complexes formed with F(ab')2 fragments did not fix rabbit C, and bovine serum albumin-specific antigen-antibody complexes formed with F(ab')2 fragments did not fix mouse C. Therefore the removal of C activity by anti-Ss [F(ab')2] was apparently not due to C fixation. These results suggest that the Ss protein is a necessary component of the C system.
Assuntos
Proteínas Sanguíneas , Proteínas do Sistema Complemento , Hemólise , Animais , Testes de Fixação de Complemento , Soros Imunes , Imunodifusão , Imunogenética , Fragmentos Fab das Imunoglobulinas , Imunoglobulina G , Masculino , Camundongos , Camundongos Endogâmicos , Coelhos/imunologia , Soroalbumina BovinaRESUMO
We have shown that the Ia determinants expressed on nylon wool-purified T lymphocytes reactive to concanavalin A (Con A) in serum-free media are coded in a single I subregion of the H-2 gene complex. This region, I-J, is defined by two pairs of intra-H-2 recombinant haplotypes: H-2t3, H-2t4 and H-2i3, H-2i5, carried by B10.HTT, B10.S(9R), B10.A(3R), AND B10.A(5R), respectively. No activity against Con A-reactive T cells has been detected in any antiserum that was produced in strain combinations which shared a common I-J region. This suggests that Ia antigens expressed on Con A-reactive T cells are restricted to the I-J subregion.
Assuntos
Mapeamento Cromossômico , Genes , Antígenos de Histocompatibilidade , Linfócitos T/imunologia , Animais , Anticorpos , Concanavalina A/farmacologia , Epitopos , Ativação Linfocitária , Camundongos , Recombinação Genética , Baço/imunologiaRESUMO
Lymphocytic choriomeningitis virus (LCMV) and ectromelia virus-specific T-cell-mediated cytotoxicity was assayed in various strain combinations using as targets peritoneal macrophages which have been shown to express Ia antigens. Virus-specific cytotoxicity was found only in H-2K- or D-region compatible combinations. I-region compatibility was not necessary nor alone sufficient for lysis. Six different I-region specificities had no obvious effect on the capacity to generate in vivo specific cytotoxicity (expressed in vitro) associated with Dd. Low LCMV-specific cytotoxic activity generated in DBA/2 mice was caused by the non-H-2 genetic background. This trait was inversely related to the infectious virus dose and recessive. Non-H-2 genes, possibly involved in controlling initial spread and multiplication of virus, seem to be, at least in the examples tested, more important in determining virus-specific cytotoxic T-cell activity in spleens than are Ir genes coded in H-2.
Assuntos
Genes , Antígenos de Histocompatibilidade , Imunidade Celular , Vírus da Coriomeningite Linfocítica/imunologia , Linfócitos T/imunologia , Animais , Antígenos Virais , Mapeamento Cromossômico , Testes Imunológicos de Citotoxicidade , Genes Recessivos , Ligação Genética , Isoantígenos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos , Vaccinia virus/imunologiaRESUMO
Growth of three transplantable reticulum cell sarcomas (RCS) was studied in a variety of F1 hybrids of SJL/J mice by determination of lymph node (LN) and spleen: body weights ratios 7 and 14 d after intravenous injection of RCS cells. Comparison of BIO.S x SJL and A.SW x SJL with SJL/J showed a negative effect of both the A and the BIO non-H-2 genes, particularly on growth in LN. F1 hybrid resistance was noted with F1 hybrids that carried H-2Dd and was much more evident with F1 hybrids from BIO- than from A-background mice. This resistance was less marked at 14 than at 7 d and was partially overcome by injection of higher tumor doses. Changing the I region in the F1 parent from H-2d to H-2b or H-2f had no effect on growth, but changing to H-2k or H-2d virtually abolished the ability to support tumor growth. This effect appeared partially as a result of the I-E/C and partially of the I-A(B) region and was not overcome by higher tumor dose or longer intervals after injection. There also appeared to be a negative influence on growth of H-2Kk, but this was difficult to differentiate from the I-Ak effect with the available strains. The known proliferative responsiveness that SJL/J Lyt-1 T cells exhibit to Ia determinants on gamma-irradiated RCS cells in vitro was also compared with that of cells from various F1 hybrids. Responsiveness of F1 LN cells was expressed as a percentage of the response in SJL/J LN cells to the same RCS cells, measured as [3H]thymidine incorporation. There was a striking degree of correlation between proliferative responsiveness of F1 LN cells to RCS and the ability of the F1 mice to support tumor growth. This correlation was especially clear with respect to the negative influences of non-H-2 genes, and of H-2 loci in the I region, particularly of I-Ak or -d and of I-E/Ck or -d, but there also appeared to be a (smaller) negative effect of I-Ab or -f. Negative influence of H-2Dd on growth, however, was not reflected in a similarly large effect on the proliferative response. Additional findings showed that LN cells from all F1 hybrids exhibited equivalent syngeneic mixed lymphocyte responses in the presence of polyethylene glycol to mitomycin-treated spleen cells from both the SJL/J and the other parent. The extra high response of F1 cells to RCS cells, as compared with SJL spleen cells, however, was always absent when Ik or -d was contributed by one of the F1 parents. The results suggest a promoting effect of the proliferative response on RCS growth in vivo and, furthermore, an interesting effect of I-A and I-E/C genes, possibly via an interaction product, on the ability of LN cells to be stimulated by Ia determinants on RCS cells.
Assuntos
Ativação Linfocitária , Linfoma não Hodgkin/imunologia , Linfócitos T/imunologia , Animais , Feminino , Genótipo , Sobrevivência de Enxerto/efeitos da radiação , Antígenos H-2 , Hibridização Genética , Linfoma não Hodgkin/genética , Linfoma não Hodgkin/patologia , Masculino , Camundongos , Camundongos Endogâmicos , Sarcoma Experimental/imunologiaRESUMO
Direct microcytotoxicity testing and absorption analyses were employed to determine whether H-2K, H-2D, and Ia antigens are present on murine islet of Langerhans cells. Products of the H-2K and H-2D loci were found on beta-cells from three different mouse strains, but I-region (Ia) antigens were not detected. The absence of Ia gene products from islet cells may be of importance in explaining the survival of islet allografts across major histocompatibility barriers.
Assuntos
Antígenos H-2/análise , Ilhotas Pancreáticas/imunologia , Isoantígenos/análise , Animais , Antígenos de Superfície/análise , Citotoxicidade Imunológica , Feminino , Complexo Principal de Histocompatibilidade , Masculino , CamundongosRESUMO
We have demonstrated in an anti-Ia serum the presence of specific antibodies reacting with T cells, as well as with B cells, using a highly sensitive dye exclusion test. This antiserum reacts with both spleen and lymph node in a characteristic biphasic titration curve killing up to 70% of these cells. It also reacts with cortisone-resistant thymocytes. The A.TH-alpha-A.TL serum can be absorbed with spleen, lymph node, cortisone-resistant thymus, or normal thymus cells. Further in vivo absorptions in BALB/c nude cannot remove all of the cytotoxic activity for normal BALB lymph node lymphocytes, while completely removing the activity for nude cells. A Thy-1 positive cell line derived from a C57Br leukemia is reactive with this anti-Ia serum.
Assuntos
Formação de Anticorpos , Genes , Antígenos de Histocompatibilidade , Linfócitos T/imunologia , Animais , Especificidade de Anticorpos , Soro Antilinfocitário , Cortisona/farmacologia , Testes Imunológicos de Citotoxicidade , Eritrócitos/imunologia , Linfonodos/citologia , Camundongos , Camundongos Endogâmicos/imunologia , Coelhos/imunologia , Ovinos/imunologia , Baço/citologia , Linfócitos T/efeitos dos fármacosRESUMO
The results of studies on the reticulum cell sarcoma (RCS) tumors of SJL/J mice presented here, indicate that spontaneous tumors, which arise in older mice, also possess the capacity to induce the vigorous proliferative response in syngenetic T lymphocytes that are characteristic of the transplantable RCS lines. Analysis of cell surface antigens revealed the presence of Ia determinats on gradient-purified transplantable RCS tumor cells; however, these cells did not express Thy 1.2, nIg, or, any of the viral proteins that were tested for by specific antisera. Pretreatment of RCS cells with anti-Ia sera and complement-deleted cells that were stimulatory for syngenetic T lymphocytes, and addition of anti-Ia sera directly to cultures blocked the proliferative response at the stimulator (RCS) cell level. Lymph node cells from H-2(8) strains other than SJL/J, including A.SW and B10.S also gave proliferative responses to RCS cells, although lower in magnitude. A requirement on the part of responding cells for identity with RCS cells at the Ir region was indicated by the finding that A.TH but not A.TL lymph node cells responded to RCS. It is concluded that RCS cells stimulate Ir-region identical T cells (without evidence of presensitization) through a modification in the expression of Ia antigens on the surface of the tumor cells.
Assuntos
Antígenos de Neoplasias , Linfoma não Hodgkin/imunologia , Linfócitos T/imunologia , Animais , Antígenos Virais , Divisão Celular/efeitos dos fármacos , Membrana Celular/imunologia , Epitopos , Feminino , Raios gama , Antígenos de Histocompatibilidade , Soros Imunes , Linfonodos/imunologia , Linfoma não Hodgkin/radioterapia , Masculino , Camundongos , Camundongos EndogâmicosRESUMO
Eleven strains of mice bearing recombinant H-2 chromosomes derived from known crossover events between known H-2 types were immunized with a series of branched, multichain, synthetic polypeptide antigens [(T,G)-A--L, (H,G)-A--L, and (Phe,G)-A--L]. Results with nine of the eleven H-2 recombinants indicated that the gene(s) controlling immune response to these synthetic polypeptides (Ir-1) is on the centromeric or H-2K part of the recombinant H-2 chromosome. Results with two of the eleven recombinant H-2 chromosomes indicated that Ir-1 was on the telomeric or H-2D part of the recombinant H-2 chromosome. Both of these recombinants were derived from crossovers between the H-2K locus and the Ss-Slp locus near the center of the H-2 region. One of these recombinants, H-2(y), was derived from a known single crossover event. These results indicate that Ir-1 lies near the center of the H-2 region between the H-2K locus and the Ss-Slp locus. The results of a four-point linkage test were consistent with these results. In 484 offspring of a cross designed to detect recombinants between H-2 and Ir-1, only two putative recombinants were detected. Both of these recombinants were confirmed by progeny testing. Extensive analysis of one of them has shown that the crossover event occurred within the H-2 region. (Testing of the second recombinant is currently under way.) Thus, in the linkage test, recombinants between H-2 and Ir-1 are in fact intra-H-2 crossovers. These results permit assignment of Ir-1 to a position between the H-2K locus and the Ss-Slp locus.
Assuntos
Antígenos , Mapeamento Cromossômico , Genes , Histocompatibilidade , Imunogenética , Camundongos Endogâmicos/imunologia , Animais , Troca Genética , Camundongos , Peptídeos , Recombinação Genética , Transplante de PeleRESUMO
Genes mapping in the I region of the H-2 complex control a system of lymphocyte alloantigens (Ia) which are expressed on a subpopulation of T cells and on most B cells. Specific anti-Ia serum in the presence of rabbit complement removed the splenic T-cell subpopulation responsive to Con-A, but did not affect the response to phytohemagglutinin (PHA) or Leucoagglutinin. Antibodies specific for Ia, H-2K, or H-2D membrane antigens were used without complement to pretreat spleen cells. These antibody pretreated cells responded normally to Con-A and PHA.
Assuntos
Concanavalina A/farmacologia , Antígenos HLA , Antígenos de Histocompatibilidade , Soros Imunes/farmacologia , Lectinas/farmacologia , Linfócitos T/imunologia , Animais , Especificidade de Anticorpos , Membrana Celular/imunologia , Mapeamento Cromossômico , Proteínas do Sistema Complemento , Genes , Técnicas In Vitro , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Linfócitos T/efeitos dos fármacosRESUMO
The protective activity of anti-Listeria-immune T cells assayed in an adoptive transfer system in H-2 restricted. As shown in the present studies, the demonstration of the restriction is directly dependent on the dose and the relative protective activity of spleen cells. In addition, some H-2-unrestricted protection is conferred predominantly by other than immunoglobulin-negative spleen cells. Thus, the activity of Listeria-immune T cells appears to be 'absolutely' restricted and is in this respect comparable to in vivo T-cell-mediated anti-viral protection. The predominant genetic region of H-2 coding for the structures which are mainly involved in this restriction in T-cell immunity to this prototype intracellular bacterium is the I region. The specificity of Listeria-immune T cells is determined by the H-2 haplotype of the donor. Thus, F1 hybrids seem to possess at least two separable sets of T cells, each specific for one parental haplotype. As is true in the virus model, the results cannot distinguish between an altered-self or a dual recognition model of T-cell recognition to explain H-2 restriction. They are, however, compatible with the idea and I-coded cell surface structures may serve as receptors for cell-specific differentiation signals, which trigger direct or lymphokin-mediated activation of macrophages to manifest increased bactericidal capacity. The interesting parallels in self-marker recognition of T cells in the virus and intracellular bacterium systems, respectively, appear to be reasonably explained by the different types of signals transmitted by T cells to various target cells via the distinctly different self-markers employed (i.e., K or D vs I).
Assuntos
Antígenos de Histocompatibilidade , Listeriose/imunologia , Linfócitos T/imunologia , Animais , Soro Antilinfocitário , Relação Dose-Resposta Imunológica , Epitopos , Imunidade Celular , Imunização Passiva , Técnicas Imunológicas , Teste de Cultura Mista de Linfócitos , Camundongos , Camundongos Endogâmicos , Receptores de Antígenos de Linfócitos B , Baço/transplanteRESUMO
Mouse antiserums prepared against Ia antigens, which are products of I (immune response) region genes of the H-2 complex, can inhibit both primary (immunoglobulin M) and secondary (immunoglobulin G) immune responses in vitro by mouse spleen cultures to heterologous erythrocytes. Antiserums directed specifically at products of either the H-2K or H-2D loci have no effect on this response.
Assuntos
Formação de Anticorpos , Genes , Isoanticorpos , Isoantígenos , Animais , Eritrócitos/imunologia , Ligação Genética , Antígenos de Histocompatibilidade , Soros Imunes , Tolerância Imunológica , Imunoglobulina G/biossíntese , Imunoglobulina M/biossíntese , Técnicas In Vitro , Camundongos , Perissodáctilos/imunologia , Baço/imunologiaRESUMO
A high frequency of Hb J Tongariki (alpha 115 Ala --> Asp) was found in a Kilenge village in New Britain. Heterozygotes had 45 to 50 percent of the Hb J component (determined by cellulose acetate electrophoresis). Two homozygotes for Hb J had no Hb A, suggesting that in this family only one Hbalpha structural locus is present.
Assuntos
Genes , Hemoglobinas Anormais/análise , Homozigoto , Peptídeos/análise , Aminoácidos/análise , Eletroforese das Proteínas Sanguíneas , Quimotripsina , Eritrócitos Anormais , Genética Populacional , Humanos , Concentração de Íons de Hidrogênio , Melanesia , Linhagem , TripsinaRESUMO
Cross sensitization between the products of the H-2K and H-2D loci has been demonstrated by an experimental design in which recipients were sensitized with tissue bearing determinants controlled by one locus (e.g., H-2K), and then challenged with skin grafts expressing determinants controlled by the other locus (e.g., H-2D). In one combination, experimental grafts were rejected faster than first-set control grafts. Cellular rather than humoral mechanisms appeared to mediate this effect. In a second combination, prolonged survival of experimental grafts were observed. This enhanced survival may have been influenced by serum antibody, either to H-2 or Ia determinants.
Assuntos
Reações Cruzadas , Antígenos de Histocompatibilidade , Transplante de Pele , Imunologia de Transplantes , Animais , Radioisótopos de Cromo , Testes Imunológicos de Citotoxicidade , Epitopos , Feminino , Rejeição de Enxerto , Imunização , Imunização Secundária , Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos , Baço/citologiaRESUMO
Absorption analyses were conducted on antisera which had previously been shown to detect cross reactivity between the H-2K and H-2D gene products. These analyses revealed that the cross reactions were due to known public H-2 specificities. Identification of cross reactive anti-H-2.3 and anti H-2.5 antibodies confirmed earlier predictions that genes controlling these specificities should be localized at opposite ends of the H-2 complex. The finding of H-2.29 activity on both sides of the S region clarified ambiguities encountered in assigning this specificity to certain recombinant types. Results with H-2.36 support the suggestion that this determinant may also be specified by both H-2K and H-2D genes.
Assuntos
Reações Cruzadas , Epitopos , Antígenos de Histocompatibilidade/análise , Biossíntese de Proteínas , Absorção , Animais , Especificidade de Anticorpos , Antígenos de Histocompatibilidade/classificação , Camundongos , Camundongos EndogâmicosRESUMO
Antisera directed at I-region gene products coded for by genes in the I-J subregion effectively block macrophage function in the primary in vitro response to burro erythrocytes. Pretreatment of macrophages with normal serum, nonappropriate anti-Ia antibodies, or anti-H-2 serum had no inhibitory effect. Similar antiserum pretreatment of macrophage-depleted cells did not affect their ability to function with untreated adherent splenic macrophages. The results suggest that the Ia molecule has an active role in antigen presentation by the macrophage or in macrophage-lymphocyte interaction in the primary IgM response.