We have observed that mutations at the H-2Kb locus can alter histocompatible tumor resistance. The model system of P815 mastocytoma (DBA/2 origin) transplanted into DBA/2 or (C57BL/6 x DBA/2)F1 mice has been extensively characterized. The standard B6D2F1 hybrids consistently live approximately 30% longer than the DBA/2 mice. This hybrid effect is transplantable into lethally irradiated DBA/2 mice with anti-thy-1-plus-C-treated B6D2F1 bone marrow. Using combinations of B6D2F1 and DBA/2 mice, radiation chimera studies demonstrate that this hybrid effect is conferred by F1 bone marrow cells which function optimally if they mature in, or under the influence of, F1 thymus epithelium. Comparing the combinations (B6 mutant x DBA/2)F1 to B6D2F1 after P815 injection, there are several different "mutant hybrids" (B6mD2F1) which die well before B6D2F1 and at least one B6mD2F1 which may have an increased life span compared to the "wild type" hybrid B6D2F1. Several of the mutant H-2Kb molecules from these B6 mutant parental strains have been shown to differ by only one or two amino acids. This means that subtle amino acid changes in the H-2K molecule of one haplotype in the histocompatible host can profoundly influence tumor resistance. The purpose of this project is to extend these genetic observations using additional mutant and formal segregation studies and to perform chimera experiments to determine whether the genetic requirements for bone marrow and thymus epithelium can function through the H-2Kb molecule. These studies are important because they could reveal how a single amino acid substitution on a single product of the major histocompatibility complex can influence resistance to a histocompatible tumor.