Hybrid resistance of lethally irradiated (C57BL/6 X DBA/2)F1 and (C57BL/10 X C3H)F1 hybrid mice to the engraftment of parental C57BL/6 or C57BL/10 bone marrow cells is controlled by the H-2-linked Hh-1 locus. This resistance can be specifically blocked or inhibited by the injection of irradiated spleen cells from lethally irradiated, marrow reconstituted donor mice of certain strains. By testing the ability of regenerating spleen cells from various donor strains to block the resistance, we studied the genetic requirements for the expression of putative cell-surface structures recognized in hybrid resistance to H-2b marrow cells. Strains of mice bearing informative intra-H-2 or H-2/Qa-Tla recombinant haplotypes provided evidence that the Hh-1 locus is located telomeric to the H-2S region complement loci and centromeric to the H-2D region class I locus in the H-2b chromosome. Two mutations that affect the class I H-2Db gene have no effect on Hh-1b gene expression. The H-2D region of the H-2s haplotype contains an allele of the Hh-1 locus indistinguishable from that of the H-2Db region, as judged by the phenotypes of relevant strains and F1 hybrids. Collectively these data indicate that the Hh-1 locus is distinct from the class I H-2D (L) locus in the H-2b or H-2s genome, and favor the view that the expression or recognition of the relevant determinants is not associated with class I gene products.
Hybrid resistance to parental H-2b bone marrow grafts is directed to a cell surface structure controlled by the Hh-1 locus in or near the H-2D region. The nature of this surface structure is not known. Since homozygosity at the class I H-2D locus or loci in this haplotype would seem a necessary but not sufficient condition for the grafts' susceptibility to resistance, we tested whether the expression of this phenotype is dependent on the expression of class I H-2Db determinants. Cloned variants of H-2b tumor RBL-5 were obtained by immunoselection for the absence of H-2Db expression, as determined by the inability to bind specific antibody and to induce or react with alloreactive cytotoxic T lymphocytes. The three clones used in this study were H-2Db negative but H-2Kb positive and were natural killer cell resistant. When tested in vivo as competitive inhibitors the variant cells were capable of blocking hybrid resistance to parental H-2b bone marrow grafts as were unselected H-2Db-positive parental line cells. Therefore, H-2Db expression is irrelevant for Hh-1b expression. An incidental observation was that YAC-1 cells, a non-H-2b tumor with pronounced susceptibility to natural killing, were able to block hybrid resistance. This reactivity, not observed in our previous studies, raises the possibility that at least some of the effector cells are cross-reactive or capable of dual recognition.
Natural resistance to hemopoietic allograft results in functional elimination of the graft from the host within 24 to 48 h. The resistance is specific and is directed to the cell surface target structures of an unidentified nature. These determinants are controlled by the major histocompatibility complex-linked hemopoietic histocompatibility (Hh) loci and expressed by cells of the hemopoietic system. In this study, the susceptibility of various hemopoietic progenitors, as well as the nature and the kinetics of the early rejection process, were examined by directly following the functional survival of the grafted progenitors by periodic sampling. In both F1 hybrid and inbred allogeneic hosts, multipotential progenitors for granulocyte-erythrocyte-monocyte-megakaryocyte lineages, bipotential progenitors for granulocyte-monocyte lineages and unipotential progenitors of erythrocyte, granulocyte and monocyte were susceptible to elimination. Therefore, within the limited range of comparisons, neither the lineage, nor the degree of commitment or differentiation determines the susceptibility of hemopoietic progenitors to resistance. Functional elimination of the grafted progenitors from the recipient spleen was irreversible upon cultivation in semisolid medium. The frequency of seeding in the spleen at 3 h was comparable in resistant and susceptible hosts; elimination commenced shortly afterwards and by 24 h after transplantation less than 10% of clonogenic progenitors remained functional. Activation of natural killer cells strengthened pre-existing resistance, but did not convert genetically susceptible mice to resistant. Therefore, the resistance is dependent on an effector mechanism with predetermined specificity.
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