H-2 crossovers and their parental strains were arranged into 35 combinations in which the adult donor of spleen cells differed from the newborn recipient in the whole H-2 complex, or in three, two, or one region of the complex. A Simonsen splenomegaly assay was then used to test the contribution of the individual H-2 regions to the graft-versus-host reaction (GVHR).

It was shown that the strongest GVHR was associated with the Ir region. Differences in the Ir region caused significant splenomegaly in spite of the fact that no antigens detectable by conventional serological methods have thus far been associated with this region. Differences in the K and D regions showed only a borderline effect on GVHR in spite of the fact that these regions code for most, if not all, of the antigens detectable by conventional serological and transplantation methods. The K region alone caused no stronger GVHR than the D legion alone; however, K + Ir region differences led to much stronger GVHR than D region differences. The Ss-Slp region also showed only a borderline effect on GVHR. Differences in two or more H-2 regions usually caused greater splenomegaly than differences in each of the regions separately.

On the basis of these findings it is concluded that the strongest GVHR is caused by genes distinct from the known histocompatibility genes of the H-2 complex. It is speculated that the GVHR genes are identical with the mixed lymphocyte reaction (MLR) and Ir genes and that the product of these genes are receptors on the surface of the thymus-derived lymphocytes (T cells).

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