The natural resistance of F1 hybrid mice against parental bone marrow grafts is thought to be mediated by natural killer (NK)-like effector cells. However, unlike the NK cell activity against a wide range of tumors and normal cells, hybrid resistance is characterized by the immunogenetic specificity controlled by a set of unique noncodominant genes denoted as Hh. Two alternative hypotheses can account for the specificity. Thus, the specificity may reflect either the Hh restriction of effectors or the Hh gene control of mechanisms regulating non-Hh-restricted effector activity. In this study, therefore, we tested the recognition specificity of putative effectors mediating hybrid resistance in lethally irradiated H-2b/d and H-2b/k F1 hybrid mice to the engraftment of parental H-2b bone marrow. As a direct means of defining the effector specificity, rejection of parental bone marrow grafts was subjected to competitive inhibition in situ by irradiated tumor cells. Of the 16 independent lines of lymphoma and other hemopoietic tumor cells tested, the ability to inhibit hybrid resistance was the exclusive property of all tumors derived from mice homozygous for the H-2Db region, regardless of whether the tumor cells were susceptible or resistant to NK cell-mediated cytotoxicity in vitro. Four cell lines heterozygous for the H-2Db were noninhibitory, including one that is susceptible to natural killing. Pretreatment of the F1 hosts with an interferon inducer augmented the resistance with no alteration in the recognition specificity of effector cells. Therefore, natural resistance to parental H-2b bone marrow grafts was mediated by effectors restricted by the H-2Db/Hh-1b gene(s), and not by the nonrestricted NK cells detectable in conventional in vitro assays.

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.

In certain strains of mice, bone marrow grafts from parental donors fail to grow in first-generation hybrid mice. This "hybrid resistance" of nonsensitized F1 hybrid mice to the engraftment of parental hematopoietic transplants contradicts the classical laws of transplantation and is dependent on a radioresistant but immunogenetically specific effector mechanism. Studies in a new in vitro model reveal that committed hematopoietic precursors of parental origin can be inactivated by direct contact with natural killer-like splenic effectors from F1 mice. The reaction requires genetically restricted recognition, since only parental competitors syngeneic to the target bone marrow cells partially reversed this inactivation. Models of this type may be useful in studying the possible role of natural resistance in bone marrow transplantation in humans.

We have studied the effect of removing donor T cells by treatment with the monoclonal antibody Leu-1 and complement before marrow transplantation on the regeneration of functionally competent T lymphocytes in the blood at selected times after transplant. Using sensitive limiting-dilution methods that allow us to enumerate helper, cytotoxic, and proliferating T lymphocyte precursors, we report that regeneration of a functional T cell compartment is more severely impaired for the first 180 days after transplantation in those patients given T cell-depleted bone marrow than in recipients of untreated marrow. After this first 6 months, however, patients given T cell- depleted bone marrow had blood T cell frequencies comparable to those observed in patients given untreated marrow. Diminished frequencies of reactive T cells in recipients of depleted marrow could leave them more susceptible to infection or to the recurrence of neoplastic cells.

We have studied the effect of removing donor T cells by treatment with the monoclonal antibody Leu-1 and complement before marrow transplantation on the regeneration of functionally competent T lymphocytes in the blood at selected times after transplant. Using sensitive limiting-dilution methods that allow us to enumerate helper, cytotoxic, and proliferating T lymphocyte precursors, we report that regeneration of a functional T cell compartment is more severely impaired for the first 180 days after transplantation in those patients given T cell-depleted bone marrow than in recipients of untreated marrow. After this first 6 months, however, patients given T cell- depleted bone marrow had blood T cell frequencies comparable to those observed in patients given untreated marrow. Diminished frequencies of reactive T cells in recipients of depleted marrow could leave them more susceptible to infection or to the recurrence of neoplastic cells.