Genetic control of rat heart allograft rejection: effect of different MHC and non-MHC incompatibilities

Klempnauer, Jürgen; Steiniger, Birte; Lück, R.; Günther, Eberhard

doi:10.1007/bf02421535

Cited by 18 publications

(12 citation statements)

References 33 publications

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“…It is known that they can become targets of CTL [25] and function as ligands for activating or inhibitory NK receptors [17], [18]. RT1-C/E/M incompatibility has been shown to induce skin and pancreas graft rejection [26] and to modulate the fate of MHC class II-mismatched heart grafts [27]. The RT1-T24-4 gene belongs to a family of genes that was originally identified as pseudogenes in the haplotype r21 [28].…”

Section: Discussionmentioning

confidence: 99%

Expression Profiling of Major Histocompatibility and Natural Killer Complex Genes Reveals Candidates for Controlling Risk of Graft versus Host Disease

et al. 2011

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BackgroundThe major histocompatibility complex (MHC) is the most important genomic region that contributes to the risk of graft versus host disease (GVHD) after haematopoietic stem cell transplantation. Matching of MHC class I and II genes is essential for the success of transplantation. However, the MHC contains additional genes that also contribute to the risk of developing acute GVHD. It is difficult to identify these genes by genetic association studies alone due to linkage disequilibrium in this region. Therefore, we aimed to identify MHC genes and other genes involved in the pathophysiology of GVHD by mRNA expression profiling.Methodology/Principal FindingsTo reduce the complexity of the task, we used genetically well-defined rat inbred strains and a rat skin explant assay, an in-vitro-model of the graft versus host reaction (GVHR), to analyze the expression of MHC, natural killer complex (NKC), and other genes in cutaneous GVHR. We observed a statistically significant and strong up or down regulation of 11 MHC, 6 NKC, and 168 genes encoded in other genomic regions, i.e. 4.9%, 14.0%, and 2.6% of the tested genes respectively. The regulation of 7 selected MHC and 3 NKC genes was confirmed by quantitative real-time PCR and in independent skin explant assays. In addition, similar regulations of most of the selected genes were observed in GVHD-affected skin lesions of transplanted rats and in human skin explant assays.Conclusions/SignificanceWe identified rat and human MHC and NKC genes that are regulated during GVHR in skin explant assays and could therefore serve as biomarkers for GVHD. Several of the respective human genes, including HLA-DMB, C2, AIF1, SPR1, UBD, and OLR1, are polymorphic. These candidates may therefore contribute to the genetic risk of GVHD in patients.

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Section: Discussionmentioning

confidence: 99%

Expression Profiling of Major Histocompatibility and Natural Killer Complex Genes Reveals Candidates for Controlling Risk of Graft versus Host Disease

et al. 2011

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“…In addition. it has been shown that the strength of an alloresponse can be haplotype dependent (Klempnauer et al 1989), which implies that certain allogeneic combinations will not lead to a response.…”

Section: Discussionmentioning

confidence: 99%

“…Regarding the few controls that appeared to be MHC class I and class I1 compatible, it should be taken into consideration that in an alloreactive process in some instances minor histocompatibility antigens can have major effects. Added differences at minor loci can overrule or enforce effects of major antigens (Klempnauer et al 1989). This study implicates MHC class I compatibility between mother and offspring in a reproductive process in cattle.…”

Section: Discussionmentioning

confidence: 99%

Involvement of major histocompatibility complex class I compatibility between dam and calf in the aetiology of bovine retained placenta

1991

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The possibility was examined that in cattle compatibility of major histocompatibility complex (MHC) products between dam and calf might negatively influence the placental maturation and expulsion, and therefore increase the risk of retained placenta in healthy, normally calving cattle. Fifteen combinations of a single dam and two offspring were selected; the placenta of the first offspring was normally expelled (control) and the placenta of the second one was retained (case). The MHC class I and class I1 antigens of the animals were typed by immunoprecipitation and by one-dimensional isoelectric focusing (1D-IEF). Compatibility or incompatibility of class I or class I1 antigens was established by comparison of the IEF banding patterns of dam and calves. Analysis revealed that MHC class I compatibility between dam and calf increased the risk of retained placenta. In this study, the effect of class I1 compatibility was not significant, nor was the effect of the interaction of class I and class 11. In a subsequent, additional sample the experimental design was extended: induction of tolerance against non-inherited maternal antigens (NIMA) might be implicated in the occurrence of the disorder within the group of class I incompatible cases. In three out of the five class I incompatible retained placenta cases, the banding pattern of the incompatible haplotype of the calf was identical to that of the haplotype of the granddam that was not inherited by the dam (NIMA). Notably, within the nine class I incompatible controls, there were none in which the offspring shared a paternal class I type with the granddam. This might suggest a toleranceinducing effect of NIMA in cattle in relation to retained placenta. The results for the nine cases and 11 controls analysed in this second set confirmed the results of the first set: again there appeared to be an increased risk of retained placenta due to class I compatibility (direct or through NIMA). We suggest that retention of the placenta is, at least in part, the result of the lack of alloreactive mechanisms.

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“…An overview of used strains and the corresponding MHC immunogenetics is given in Table 1 . Detailed information are described elsewhere [ 21 ]. All animal procedures are approved by Niedersächsisches Landesamt für Verbraucherschutz und Lebensmittelsicherheit (animal protection number 02/528).…”

Section: Methodsmentioning

confidence: 99%

Application of Allogeneic Bone Marrow Cells in View of Residual Alloreactivity: Sirolimus but Not Cyclosporine Evolves Tolerogenic Properties

et al. 2015

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BackgroundApplication of bone marrow cells (BMC) is a promising strategy for tolerance induction, but usually requires strong depletion of the host immune system. This study evaluates the ability of immunosuppressants to evolve tolerogenic properties of BMC in view of residual alloreactivity.MethodsThe rat model used a major histocompatibility complex (MHC) class II disparate bone marrow transplantation (BMT) setting (LEW.1AR1 (RT1auu) → LEW.1AR2 (RT1aau)). Heart grafts (LEW.1WR1 (RT1uua)) were disparate for the complete MHC to recipients and for MHC class I to BMC donors. Limited conditioning was performed by total body irradiation of 6 Gy. Cyclosporine (CsA) or Sirolimus (Srl) were administered for 14 or 28 days. Transplantation of heart grafts (HTx) was performed at day 16 or at day 100 after BMT. Chimerism and changes in the T cell pool were detected by flow cytometry.ResultsMixed chimeras accepted HTx indefinitely, although the composition of the regenerated T cell pool was not changed to a basically donor MHC class II haplotype. Non-chimeric animals rejected HTx spontaneously. BMC recipients, who received HTx during T cell recovery at day 16, accepted HTx only after pre-treatment with Srl, although chimerism was lost. CsA pre-treatment led to accelerated HTx rejection as did isolated application of BMC.ConclusionSrl evolves tolerogenic properties of allogeneic BMC to achieve indefinite acceptance of partly MHC disparate HTx despite residual alloreactivity and in particular loss of chimerism.

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Genetic control of rat heart allograft rejection: effect of different MHC and non-MHC incompatibilities

Cited by 18 publications

References 33 publications

Expression Profiling of Major Histocompatibility and Natural Killer Complex Genes Reveals Candidates for Controlling Risk of Graft versus Host Disease

Expression Profiling of Major Histocompatibility and Natural Killer Complex Genes Reveals Candidates for Controlling Risk of Graft versus Host Disease

Involvement of major histocompatibility complex class I compatibility between dam and calf in the aetiology of bovine retained placenta

Application of Allogeneic Bone Marrow Cells in View of Residual Alloreactivity: Sirolimus but Not Cyclosporine Evolves Tolerogenic Properties

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