Expression profiling of rat MHC and NKC genes in skin explant assays reveals genes that are regulated in GVHD

ABSTRACT: Expression profiling of rat major histocompatibility complex and natural killer complex genes in skin explant assays reveals genes that are regulated in graft versus host disease. The major histocompatibility complex (MHC) is the most important genomic region that contributes to the genetic risk of graft rejection and graft versus host disease (GVHD) after haematopoietic stem cell transplantation. Therefore, MHC matching is most essential for the success of clinical transplantations. However, the MHC contains in addition to MHC class I and class II genes that are genotyped for selection of donors further so far unidentified genes that also contribute significantly to the risk to develop acute GVHD. It is difficult to identify these MHC genes by genetic association studies alone due to linkage disequilibrium in this region. Therefore, we aimed to identify MHC genes that might be involved in the pathohysiology of GVHD by expression profiling. To reduce the complexity of our model, we used genetically well-defined inbred rat strains (PVG and BN) and skin explant assays, an in-vitro-model of graft versus host reaction (GVHR), to analyse the expression of MHC and natural killer complex (NKC) genes in a cutaneous GVHR by a custom microarray. A higher percentage of genes in these immunologically highly important genomic regions were regulated than in the rest of the genome. We observed a statistically significant regulation of 25 MHC and 6 NKC genes and 168 other genes (i.e., 4.9%, 14.0%, and 6.6%, respectively) in rat skin explants cultured in the presence of pre-stimulated allogeneic lymphocytes compared to control samples cultured in the presence of syngeneic lymphocytes. Seven MHC and 3 NKC genes were selected for analysis by quantitative real-time polymerase chain reaction PCR. Most of the results of the microarray were confirmed in the same experimental set that was used for the microarray analysis and in a second independent experimental set of skin explant samples. In addition, GVHD-affected skin lesions of transplanted rats were analysed and similar regulations of most of the selected MHC and NKC genes were observed. Thus, our skin explant model of GVHR is informative for the gene regulation during GVHD. Interestingly, the human homologues of several of the regulated genes are polymorphic and could therefore contribute to the genetic risk of GVHD. These genes include RT1-Dmb, C2, Aif1, Spr1, Ubd, and Olr1. The human homologues of these genes might be useful for risk assessment and diagnosis of GVHD in patients.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE17928 | GEO | 2011/01/04

SECONDARY ACCESSION(S): PRJNA119865

REPOSITORIES: GEO