IMMUNOGENETICS OF HYBRID RESISTANCE

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The long-term goal is to determine the genetic mechanism of expression of Hemopoietic histocompatibility (Hh) antigens on the surface of leukemic and normal progenitor cells and characterize the Hh molecules themselves. To that end the following Aims are described: 1. Confirm the conclusion that Hh antigenic expression on lymphoma cells is "down-regulated" by trans-acting regulatory genes. Using both in vivo and in vitro assays for hybrid resistance in which "cold target cells competition" can be measured, we observed that ACCb H-2d/H-2b loss mutants which had lost Dd gained the expression of Hhb. 2. Map the Hh genes more precisely. B10.RQDB is a new H-2 recombinant described by Chella David, which expresses Dd, Db, but not Ld. Therefore, recombination occurred between D and L and Db is really Lb. The marrow cells have lost Hhb, retained Hhd for allogenic hosts and have decreased Hhd for F1 hybrid hosts. There and other new recombinants will be used to map Hh, which should be contromeric to L since the sequence is D (R) L in the D-region. (3) Test the cis gene hypothesis, i.e. an adjacent gene regulates Hh expression. Use same new H-2 recombination to detect gene(s) between S and L which may regulate Hh expression in heterozygotes that regulated "tolerance" to parental Hh antigen. (4) Continue to test the "allogenic inhibition" hypothesis for hybrid resistance. Marrow cells from C.B-17 scid/scid donors, which cannot generate alloreactive T or B cells, nevertheless are rejected by irradiated allogeneic or F1 hybrid recipient mice. (5) Characterize Hh molecules. 2-D gels of lysates of 35S-methionine labeled EL-4 and various ACCb cell lines, followed by computer analysis of radiographs, identified a 90 kd molecule as a potential candidate for the Hhb antigen. We will generate antibodies to isolate the molecules, and study its structure.