Lethally X-irradiated F
1 hybrid mice of some strains do not accept bone marrow transplants from one or another of the parental strains, and normal unirradiated F
1 mice often exert resistance against the graft-vs-host reaction (GvHR)-associated immunosuppression induced by lymphocytes from a certain parental strain. Moreover, normal F
1 mouse spleen cells can respond to parental antigen coded for by the major histocompatibility complex (MHC) and generate cytotoxic T lymphocytes, which specifically kill target cells bearing the homozygous parental MHC antigens, in primary in vitro cultures. All of these phenomena are apparently a violation of the basic law of classical transplantation immunity in which the co-dominant phenotypic expression of histocompatibility gene products in F
1 hybrid animals has been established. Therefore, the study on the mechanisms of these phenomena, called hybrid resistance (HyR), embraces many important yet unexplained aspects of transplantation immunity, and offers current immunology an intriguing issue to be explored.
To explore complex genetic events that lead to HyR at cellular level, we have studied in detail the in vitro primary F
1 anti-parental cytotoxic responses as well as the F
1 resistance against parental lymphocyte-induced GvHR by using various kinds of inbred mouse strains carrying well-characterized genetic background. The regulation of both types of the HyR was found to be controlled in appearance by genes located either in the MHC or non-MHC regions. However, our careful experiments have demonstrated that, in most cases, neither the MHC haplotype alone nor the non-MHC background alone can foretell whether a certain F
1 mouse strain exerts the HyR or not. In a certain F
1 mouse strain, it has been demonstrated that conspicuous combined action of the MHC and non-MHC genes determines the HyR. Implications of this key observation with respect to the immunologic significance of the HyR, together with the discovery of a new mouse minor H-42 histocompatibility locus, are described in detail in the present review article.
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