Phenotypes of the major histocompatibility complex in wild rats of different geographic origins.
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Biomedical subjects
Publications and source records attributed to T J Gill.
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Immunization of high responding PVG female rats with poly(Glu52Lys33Tyr15) agrregated with methylated bovine serum albumin was associated with a decreased ability of their offspring to make an antibody response to the antigen. The amount of antigen given to the mothers was important in determining the magnitude of the antibody production in the offspring. The depression of antibody production was time-dependent: the first and second F1 litters from immunized mothers had significantly decreased antibody responses while no decrease was observed in the third F1 litter. Similarly, this alteration in the antibody response could be transmitted to the F2 generation but not to the F3 generation. These results suggest that aggregated antigen persists in the mother and crosses the placenta to interact with the developing immune system of the fetus. In the high-responding PVG strain, this interaction is associated with a decreased ability to respond to the antigen at a later time.
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Inbred strains of rats can currently be classified into eight Ag-B groups. Within an Ag-B group, individual strains generally share identity both the Ag-B histocompatibility antigens and mixed lymphocyte responses. In this report we present data from three strains which are Ag-B and mixed lymphocyte reaction (MLR) disparate: KGH (Ag-B7, MLR-1), MNR (Ag-B4, MLR-5), and B3 (Ag-B3, MLR-4). Popliteal lymph node assays involving these three strains and standard inbred strains demonstrate that the graft-versus-host reaction and MLR reactions in the rat are closely related. Positive graft-versus-host reactions were observed only in strain combinations incompatible for the MLR and were unaffected by differences in their Ag-B histocompatibility antigens. The close association of the MLR and graft-versus-host reaction provides additional evidence that the Ag-B/MLR disparity in these strains is the result of natural genetic recombinations within the major histocompatibility complex.
The cellular kinetics of antibody production in high and low responder rats immunized with poly(Glu52Lys33Tyr15) or with poly(Glu52Lys33Tyr15)/MeBSA were characterized: serum antibody and IgG and IgM antibody-forming cells in the spleen and in selected lymph nodes were assayed in male and female rats following immunization by several routes. Aggregation of the antigen with MeBSA enabled the poorly responding F344 rats to produce antibody, which was almost exclusively IgG. High responder ACI rats, under the same conditions, produced antibody of both IgG AND IgM classes. These data suggest that in low responders one defect, possibly at the T-cell level, can be overcome by aggregation but that a second defect, involving the regulation of IgM production, still exists.
This study examined IgM antibody produced by highly responding ACI and poorly responding F344 rats follwing immunization with poly(Glu52Lys33Tyr15) or poly(Glu52Lys33Tyr15) aggregated with methylated bovine serum albunim (MeBSA). The ACI rats produced both IgM and IgG plaque-forming cells (PFC) following immunization with either form of antigen. The F344 rats did not respond to unaggregated poly(Glu52Lys33Tyr15), but they produced significant amounts of IgG PFC and extremely small amounts of IgM PFC after immunization with poly(Glu52Lys33Tyr15)/MeBSA. Both high and low responder rats had similar kinetic profiles of IgM antibody production, and this antibody had nearly identical avidity in both strains with no evidence for any maturation in avidity. thus, one of the genetic defects in the antibody response to poly(Glu52Lys33Tyr15) is an inability of the F344 strain to produce large amounts of IgM in response to this antigen.
Two haplotypes of the major histocompatibility complex of the rat, Ag-B7 and Ag-B8, have been compared with known H-1 haplotypes using the F1 skin-graft test and the dextran haemagglutination test. Both of these Ag-B haplotypes were different from the known H-1 haplotypes and determined different private specificities. The Ag-B7 haplotype was denoted as H-1g and the Ag-B8 haplotype as H-1k. The complex structure of the serologically detected antigenic products of these haplotypes was determined by means of H-1 congenic lines.
The strongly cross-reacting haplotypes of the inbred strains DA, ACI, ACP, MR, BD V and AS2, and of the congenic lines LEW.1A, LEW.1D and LEW.1F, were explored. All of these inbred strains and these congenic lines type with anti-Ag-B4 antisera raised against the DA strain, which behaved as operationally mono-specific in previously reported studies of the eight currently defined Ag-B haplotypes. Serological analyses showed that this cross-reactivity was due to antibodies against public antigenic specificities which were not previously recognized as being in the anti-Ag-B4 antisera, due to the fact that the LEW.1D and LEW.1F animals were not available for testing. With the use of appropriate antisera and of absorption studies, two haplotypes in the H-1 system were found not to have been previously identified in the Ag-B system. The animals carrying the H-1d haplotype (MR, BD V and LEW.1D) have been designated as Ag-B9, and those carrying the H-1f haplotype (AS2 and LEW.1F) have been designated as Ag-B10. With the proper absorptions, an anti-Ag-B4 antiserum can be prepared which reacts only with the DA, ACI and ACP strains, and it will henceforth be used as the operationally mono-specific Ag-B4 typing reagent. A variety of typing experiments showed that the results using antisera raised in Pittsburgh and in Prague and using the Ficoll and dextran haemagglutination methods were the same.
The offspring of low responder F344 female rats that were immunized with poly(Glu52Lys33Tyr15) aggregated with MeBSA prior to mating showed a higher antibody response to the polypeptide antigen than did the offspring of unimmunized females. Immunization of the mothers with unaggregated polypeptide, or with DNP-BGG, did not affect the antibody response of the offspring even when high doses of antigen were used. When the polypeptide used to immunize the mothers was given as an aggregate, some crossed the placenta to the fetus. The antigen was first detected in the placenta, blood and liver of the fetus at 15 days of gestational age. After birth, it was in the liver and spleen up to 6 weeks af age, and thereafter it was present only in the bone marrow.
The ability to decrease the antibody response to poly(Glu52Lys33Tyr15) in the DA and PVG strains of rats by prior immunization with its D-amino acid enantiomorph poly(DGlu48DLys38DTyr14) was tested as part of a continuing investigation into the role of optical isomerism in the ability of an antigen to induce an antibody response. The results showed that prior immunization with the D-amino acid polymer decreased the immune response to the isomeric L-polypeptide in both strains.
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Three different alloantisera were raised by using Ag-B/MLR disparate rats, and the cytotoxic activity remaining after absorption with erythrocytes to remove anti-Ag-B antibodies was examined. The alloantisera detected surface antigens present only on B cells and segregation studies demonstrated that the genes that code for these antigenic specificities were linked to the major histocompatibility complex. The reactivity of the alloantisera with splenic lymphocytes from a panel of strains representative of the currently known Ag-B groups showed that multiple specificities were present in two of the three antisera and that these specificities were shared by many inbred strains. The appropriate absorption studies showed, however, that each antiserum detected an unique specificity that was found only in those inbred strains that shared the same mixed lymphocyte reactivity (MLR) phenotype as the donor strain. The alloantiserum produced against the KGH strain inhibited the MLR reactions involving this strain only when it was used as the stimulating cell population. The antigens detected by the three alloantisera described here have the characteristics of Ia antigens, and they have tentatively been designated Ia.1 (ACI anti-KGH), Ia.3 (B3 anti-BN) and Ia.4 (MNR anti-DA).
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