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Results for “Minor Histocompatibility Loci”

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At least 19 recordsLinked to original sources
PubMed1985

Complexity of minor histocompatibility loci.

Allografts can be rejected as a result of major histocompatibility antigen disparity or as a result of differences at any of a number of minor histocompatibility antigens. In many cases, rejection due to multiple minor histoincompatibility is as difficult to control as that induced by major histoincompatibility. Although an understanding of the molecular, biochemical, and functional parameters of the major histocompatibility loci and their products is increasing at an exponential rate, little is known about these same facets of minor histocompatibility loci and their products. It is generally accepted that minor histocompatibility loci in the murine model have a degree of polymorphism similar to that of H-2K or H-2D. This conclusion was based on typing alleles by the classic F1-skin graft test. Based on these allelic assignments, numerous unexpected findings of CTL specificity were made. Therefore, a systematic analysis was made comparing CTL specificity, F1-complementation, and allograft rejection. Based on these three parameters, the data presented using strains of mice that were bred to, and therefore presumed to, differ only at H-3 indicate that the antigen disparity of these congenic strains and the parental B10 strain as defined by CTL specificity and skin graft rejection is much more complex than originally described. One especially interesting chromosomal region is H-3/beta 2-microglobulin in the fifth linkage group of chromosome 2. Using CTL, ten specificities are defined, three of which appear to be specific for beta 2-microglobulin-A, -B, and -C. These findings raise the question of whether any minor histocompatibility locus is polymorphic or is instead a composite of multiple minor H-loci which are masquerading as a single locus.

Alleles↗
PubMed1992

What are minor histocompatibility loci? A new look at an old question.

In this article, Derry Roopenian relates the traditional view of minor histocompatibility (H) loci to recent advances in understanding of the tissue rejection process and the molecular nature of minor histocompatibility antigens. He proposes that minor H loci can be subdivided by the ability of their products to stimulate different T-cell subsets and discusses the implications of this concept in terms of the origins and behavior of minor H loci and their antigens, tumor immunology and autoimmunity.

Animals↗
PubMed1993

The functional basis of minor histocompatibility loci.

This work addresses the functional basis of classical minor histocompatibility (H) loci. We focus on the H-3 locus, which is actually a complex genetic unit to which the phenotypic trait of tissue rejection, genes whose products stimulate specific subsets of T cells, and Ir genes have been mapped. To clarify how these genes relate to one another and to the trait of tissue rejection, strains of intra-H-3 recombinant mice were produced and analyzed. These mice allowed us to selectively elicit immune responses to Ag (referred to as type I Ag) that stimulate MHC class I-restricted CTL, or Ag (referred to as type II Ag) that stimulate MHC class II-restricted Th. The splitting of H-3 in this manner resulted in a dramatic diminution of the skin allograft response, and with rare exception, an elimination of the CTL response after spleen cell immunization. A selective response to type I Ag resulted in slow, incomplete skin allograft rejection that demonstrated both CD4+ cell-dependent and -independent components. A selective response to the type II Ag failed to result in allograft rejection. The type II Ag did, however, act as an Ir gene that determined whether responses to type I Ag could occur. Altogether, the results indicate that the trait of tissue rejection associated with H-3 is a consequence of the strongly synergistic effects of Th-CTL collaboration induced by products of type I and type II genes. Moreover, the results suggest a genetic explanation for some of the Ir gene effects associated with H-3.

Animals↗
PubMed1990

Ia restriction specificity of KLH-specific T cells from allogeneic bone marrow chimeras is influenced by histocompatibility at the H-2 and minor histocompatibility loci.

Ia restriction specificity involved in T cell proliferative responses to keyhole limpet hemocyanin (KLH) has been analyzed using a variety of allogeneic bone marrow chimeras. The chimeric mice were prepared by reconstituting irradiated AKR, SJL, B10.BR and B10.A(4R) mice with bone marrow cells from B10 mice. When such chimeric mice had first been primed with KLH in complete Freund's adjuvant (CFA), T cells from H-2 incompatible fully allogeneic chimeras showed significantly higher responses to KLH in the presence of antigen-presenting cells (APC) of donor strain (B10) than APC of recipient strain. However, in H-2 subregion compatible chimeras, [B10----B10.A(4R)], which were matched at the H-2D locus and at minor histocompatible loci, the T cells could mount vigorous responses to KLH with antigen-presenting cells (APC) of either donor or recipient type. The same results were obtained as well with chimeras that had been thymectomized after full reconstitution of lymphoid tissues by donor-derived cells. A considerable proportion of KLH-specific T cell hybridomas established from [B10----B10.A(4R)] chimeras exhibited both I-Ab and I-Ak restriction specificities. The present findings indicate that the bias to donor Ia type of antigen specific T cells is determined by donor-derived APC present in the extrathymic environment but that cross-reactivity to the recipient Ia is influenced to some degree by histocompatibility between donor and recipient mice, even though the histocompatible H-2D locus and minor histocompatibility loci seem not to be directly involved in the I-A restricted responses studied herein.

Animals↗
PubMed1987

Maternal humoral immune response to incompatibility at multiple minor histocompatibility loci in mice.

Mice of the H-2b haplotype were mated with males of the same MHC haplotype, but differing at multiple minor histocompatibility loci. Mice were bled during each pregnancy and at 2-day intervals post-partum. The sera were assayed by indirect immunofluorescence for evidence of a humoral immune response to paternal minor histocompatibility antigens. Alloantibody was first detected in the post-partum period following the third pregnancy, and was also detected during the fourth pregnancy. Thereafter, alloantibody levels dropped and by the post-partum period following the fifth pregnancy, fell to control values. Assays on a panel of cells from mice of different inbred strains revealed specificity of the alloantibody to H-3.1, H-4.1 and H-7.1 antigens. A conventional dye exclusion cytotoxicity test revealed the pregnancy-induced alloantibody did not exhibit complement-dependent cytotoxicity. These findings are discussed in relation to the regulation and functional significance of the humoral immune response in allogeneic pregnancy.

Animals↗
PubMed1985

Maternal-fetal disparity at multiple minor histocompatibility loci affects the weight of the feto-placental unit in mice.

Inbred mice from selected unrelated and congenic strains were mated to determine the relative effects of maternal-fetal disparity at major histocompatibility complex (H-2) and non-H-2 minor histocompatibility antigens on the feto-placental unit at 14 days of gestation. A significant increase in weight of the feto-placental unit was observed only when mother and fetus differed at multiple minor histocompatibility loci. No increase in the weight of the feto-placental unit was observed when mother and fetus differed only at H-2. These results suggest that immunostimulation of the fetus results from a maternal response to minor histocompatibility antigens and not to H-2 antigens.

Animals↗
PubMed1996

Anterior chamber-associated immune deviation promotes corneal allograft survival.

PURPOSE: To determine whether anterior chamber-associated immune deviation (ACAID) promotes corneal allograft survival. METHODS: CB6F1 mice were grafted with orthotopic corneal transplants from C3H donors (mismatch at the entire major histocompatibility complex plus multiple minor histocompatibility loci) and from NZB donors (mismatch only at multiple minor histocompatibility loci). ACAID was induced by priming in the anterior chamber (AC) with either Ia- spleen cells, Ia+ spleen cells, corneal endothelial cells, or corneal epithelial cells from corneal allograft donors before orthotopic transplantation. The role of ACAID in promoting corneal allograft survival was examined by determining the fate of corneal allografts in splenectomized and eusplenic mice. RESULTS: Anterior chamber priming produced a modest enhancement of the survival of fully allogeneic C3H corneal allografts. By contrast, AC priming with Ia- NZB spleen cells or NZB corneal endothelial cells results in the permanent acceptance of NZB corneal grafts in 60% and 90% of the CB6F1 hosts, respectively. Abolition of ACAID by splenectomy resulted in a sharp increase in the incidence of graft rejection in donor-host combinations involving multiple minor histocompatibility disparity. CONCLUSIONS: Anterior chamber priming with alloantigens promotes corneal allograft survival in nonimmune and preimmune hosts. Disruption of the camero-splenic axis prevents the induction of ACAID and greatly increases the risk for corneal allograft rejection.

Animals↗
PubMed2004

Application of discordant sib-pair linkage analysis for mapping minor histocompatibility antigen loci in a novel graft-vs-host-disease model.

Graft-vs-host disease (GVHD) is an adverse effect of allogenic bone marrow transplantation. Although a major cause of GVHD following bone marrow transplantation is incompatibility of major histocompatibility antigen (human leukocyte antigen, HLA) in donor-recipient pairs, the incompatibility of minor histocompatibility antigen (mHa) is known as another cause, especially in HLA-matched donor-recipient pairs. In 1998, Lunetta and Rogus proposed the use of discordant sib-pair (DSP) linkage analysis for detecting mHa and calculated the statistical power using the GVHD model, assuming single mHa locus with multiple alleles. Recently, we proposed a different GVHD model, assuming multiple mHa loci with two alleles (biallelic), considering the single-nucleotide polymorphisms. When the effect of each mHa locus on the occurrence of GVHD is independent, the possible triangle for DSP proposed by Lunetta and Rogus is not optimum, but a new possible triangle, named here as GVHD region, is needed. We evaluated, based on Monte Carlo simulation, the test criteria [log of odds (lod) score cutoffs] and power of DSP using the GVHD region for various parameter sets. The GVHD region showed a higher power than the DSP and entire regions in plausible situations. Our results suggest that the application of GVHD region to DSP is effective for the screening of mHa loci.

Genetic Linkage↗
PubMed1986

The fate of allogeneic and xenogeneic neuronal tissue transplanted into the third ventricle of rodents.

Neural grafts from day 17-19 fetal rats or mice survived well when transplanted into syngeneic, or immunodeficient hosts, thus demonstrating that there are no non-immunological barriers to cross-species transplantation of neuronal tissue in rats and mice. However, intraventricular grafts from rat to mouse, or vice versa, in immunocompetent animals were rejected in less than 30 days. By this time all graft tissue had been destroyed and scavenged, presumably by the macrophages seen infiltrating the grafts within 10 days of grafting. Rat allografts from major histocompatibility complex disparate donors disparate donors survived well as did grafts between rats differing only at minor histocompatibility loci. However, allografts from donors that differed from recipients at both major and minor histocompatibility complex loci had a variable survival time. When neural tissue was grafted into immunologically primed recipients, it was rejected as was similar tissue grafted beneath the kidney capsule of an allogeneic host. Concomitant grafting of allogeneic tissue under the kidney capsule and into the third ventricle was followed by rejection in both sites. A striking observation in these studies was the induction of Class I major histocompatibility complex antigens on grafted neuronal tissue. High levels of antigen expression were correlated with a vigorous host response and poor graft survival but lower levels were not indicative of impending graft destruction. Whilst the brain can be regarded as an immunologically privileged site, the privilege is not absolute and caution needs to be exercised in the interpretation of results from allogeneic or xenogeneic grafts.

Animals↗
PubMed1992

Classical transplantation tolerance in the adult: the interaction between myeloablation and immunosuppression.

Allogeneic bone marrow transplantation in the neonate is an effective way of inducing permanent tolerance to donor tissue. To do the same in the immunocompetent adult requires immunosuppression to counter host-versus-graft alloreactivity. Conditioning with monoclonal antibodies (mAb) to CD4 and CD8 has been sufficient where donor and recipient are mismatched at only multiple "minor" histocompatibility loci, or at major histocompatibility complex (MHC) class I plus "minor" loci, but not where the mismatch involves the entire MHC. Tolerance across the MHC barrier requires extra conditioning with agents that happen to be both immunosuppressive and myeloablative, so obscuring the assessment of which effect is important. By using dimethylmyleran as a selective "space"-creating myeloablative agent, and CD4 plus CD8 mAb as sole immunosuppressive agents, we have been able to dissect the relative requirements for immunosuppression and myeloablation. We show here that transplantation tolerance could only be achieved when both types of agent were combined together so as to guarantee sufficient donor-type hemopoietic chimerism. We argue that the donor marrow, given sufficient space, will engraft and provide a sustained source of tolerogen overriding any host resistance that antibodies cannot control.

Animals↗
PubMed1998

HLAs and risk of acute graft-vs.-host disease after marrow transplantation from an HLA-identical sibling.

We explored the relationship between individual human leukocyte antigens (HLAs) and the risk of acute graft-vs.-host disease (GVHD) after allogeneic marrow transplantation from HLA-identical siblings. If the repertoire of polymorphic peptides encoded by minor histocompatibility loci is limited such that certain major histocompatibility complex molecules might not present any peptides that cause GVHD, then certain HLA alleles should be associated with a relatively reduced risk of GVHD and others should be associated with a relatively increased risk. Contrary to results reported in previous studies, we found no convincing evidence for associations between HLA antigens and risk of acute GVHD after HLA-identical marrow transplantation. These results are consistent with the hypothesis that the variety of minor histocompatibility antigens is not constrained by the repertoire of peptides collectively encoded by minor histocompatibility loci.

Bone Marrow Transplantation↗
PubMed1972

Renal transplantation between HL-A identical donor-recipient pairs. Functional and morphological evaluation.

16 patients underwent renal transplantation from a sibling donor who was prospectively determined to be ABO compatible and HL-A identical with the recipient. Unidirectional mixed leukocyte reactions were performed; in each instance, lymphocyte stimulation in either direction was not observed. The plasma creatinine 10-68 months after transplantation in these 16 patients ranged between 0.9 and 1.9 mg/100 ml. The creatinine clearance ranged from 48 to 113 ml/min, and the blood urea nitrogen (BUN) ranged between 12 and 35 mg/100 ml. Urine protein excretion varied from 0.11 to 1.86 g/day. Six patients exhibited no detectable clinical episodes of acute rejection; they were treated with azathioprine alone and each of them demonstrated normal or near normal renal histology when biopsy specimens were obtained more than 6 months after transplantation. Nine patients experienced acute rejection episodes that required the use of steroid therapy. The severity of these rejection episodes was variable; they included a mild reduction in renal function with an immediate steroid-induced restoration of function and eventual discontinuance of steroid therapy to severe reduction in function requiring prolonged and moderate doses of steroids without return to normal renal function. Renal histological observations in this group ranged from mild to marked cellular and structural changes which fit the criteria of the rejection. One patient demonstrated a gradual loss of renal function with heavy proteinuria. Biopsy of this allograft demonstrated the recurrence of original disease, i.e., lobular glomerulonephritis. The marked variability in the clinical course and allograft morphology in these 16 patients could be explained by antigenic differences at non-HL-A loci. The presence of minor histocompatibility loci has been well documented in other mammalian species and they are most certainly present in man. The need for their identification and definition is stressed.

Adult↗
PubMed1985

Studies addressing the mechanism of anti-asialo GM1 prevention of graft-versus-host disease due to minor histocompatibility antigenic differences.

In mice, as in humans, lethal graft-versus-host disease (GVHD) with skin involvement often occurs in immunoincompetent recipients of donor hematopoietic cells in spite of matching at major histocompatibility loci and nonreactivity in mixed lymphocyte culture, if donor and recipient are disparate at several minor histocompatibility loci. In mice, both death and skin disease can be prevented by the use of an antiserum containing antibodies to a cell surface glycolipid, asialo GM1 (ASGM1). Because treatment of only the recipients with anti-asialo GM1 substantially reduces the subsequent proliferation of infused donor lymphoid cells, we infer that anti-asialo GM1 interferes with a host minor-antigen-presenting cell, so that donor lymphocytes fail to see minor host antigens as immunogenic. Of the tissues examined by immunofluorescence microscopy, ASGM1 was found on the epidermal Thy-1+ dendritic cell, on dendritic cells in the thymus, and as has been previously described, on lung and spleen cells. Following the intravenous administration of anti-asialo GM1, only the spleen showed an obvious change, losing approximately 80% of its ASGM1 + cells. Further analysis of spleen cells bearing ASGM1 may better define the phenotype of the inferred minor antigen-presenting cell and lead to a method of improving the outcome of human bone marrow transplantation.

Animals↗