MHC CLASS II INDUCTION IN ALLOGRAFT REJECTION

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MHC class II Antigen (Ag) induction is seen in allografts undergoing rejection and is considered to be an important event in the cascade of allograft rejection. But presently, it is not clear if this induction is causal or an epiphenomenon in rejection. Cell surface expression of MHC Ag in allograft rejection is well studied, but the expression of these genes and the mechanism responsible for their induction has not been studied. Our goal is to determine the relevance and mechanism of MHC class II gene expression in allograft rejection. We will critically test the hypothesis that strength of rejection is influenced by quantitative variations in donor MHC class II expression. For this, we will test the following predictions resulting from this hypothesis in cardiac allografts between congenic strains of mice: (1) Magnitude and/or kinetics of class II induction in allografts enjoying prolonged survival are different than those in rapidly rejected grafts, (2) In an allograft enjoying prolonged survival, induction of rejection is preceded by an increase in basal expression of class II in that graft, and (3) Increased expression of class II in donor organs accelerates rejection in "slow rejector" strain combination and conversely, decreased expression of class II delays rejection. Discrimination of donor specific class II expression necessary for these experiments is possible with our allele I- A specific oligonucleotide probes. Quantitative analysis of mRNA content in allografts will be done to provide objective parameters necessary to verify the predictions. Allele specific I-E oligo probes will be developed to test if differential expression of I-A versus I-E occurs in allografts and is more relevant to allorecognition. Immunoperoxidase staining will be performed to identify the donor cell type on which class II induction occurs and also to ascertain that mRNA expression correlates with cell surface expression. Mechanism of class II induction in allografts will be studied by sequential analysis of IFN and TNF gene expression in the allograft to determine temporal relation of expression of these genes to induction of class II genes. This study will not only provide data regarding the relevance of class II expression in allorecognition, but will also provide insight in the mechanism of this important gene expression. This knowledge may be applied in the future to reduce immunogenicity of an allograft to circumvent rejection.