Search

"S" (survivor) mutants were produced in mice for genetic analysis of host resistance to metastatic cancers. S-mutants S-27 and S-31 resist transplantation of lymphoma EL4 of parental C57BL/6J (B6) mice while they accept parental skin grafts. Mutant S-27 also resists formation of spontaneous metastases from intradermally growing EL4 tumor into lymph nodes; mutant S-31 is highly susceptible to EL4 metastases. Another mutant, H-2bm26 (bm26), resists EL4 and rejects B6 skin grafts. Major histocompatibility complex (MHC) class I and class II gene expression was compared in these mutants and normal B6 mice. All three mutants tested, S-27, S-31, and bm26, expressed a low amount of Kb mRNA in organ-specific fashion. Mutants bm26 and S-31 expressed a low amount of Abb mRNA and of Ab antigen on their spleen cells. Some oligonucleotide probes designed to hybridize to the second exon of the class II MHC gene Abb did not hybridize with DNA from all three mutants. These findings suggest extensive sequence alterations in the Abb gene in mutants S-27, S-31, and bm26; they also suggest a major role of MHC in the control of host resistance to spontaneous metastases of the EL4 tumor.

Two mechanisms of major histocompatibility complex (MHC) mutations have been described in mice; gene conversion and homologous but unequal recombination. However, our knowledge of mutations in MHC is incomplete because studies have been limited almost exclusively to two haplotypes, H-2b and H-2d, while hundreds of haplotypes exist in nature; it has been biased by the use of only one procedure of screening for mutation, skin grafting. We used three procedures to screen for MHC mutations: (1) conventional techniques of skin grafting, (2) syngeneic tumor transplantation and (3) typing with monoclonal anti-MHC antibodies (mAbs) and complement. The faster technique of tumor transplantation detected mutants similar to those discovered by skin grafting technique. Screening with mAbs allowed us to detect both mutants that are capable of rejecting standard skin grafts and those that are silent in skin grafting tests, and which therefore resulted in a higher apparent mutation frequency. Two mutants of the H-2a haplotype were found that carry concomitant class I and class II antigenic alterations. Both MHC mutants silent in skin grafting tests and mutants carrying concomitant class I and class II alterations have never been studied before and are expected to reveal new mechanisms of generating MHC mutations. 1-Ethyl-1-nitrosourea (ENU) failed to induce de novo MHC mutations in male mice in our skin grafting series.