The Host Response in Graft versus Host Disease: II. The Emergence of Host Protective Cells is in Part Determined by Background Genomic Compatability

Abstract

Murine graft versus host (GVH) disease takes two forms depending on the parental/F1 strain combination employed. In an accompanying paper (Singh et al., Clin Immunol. 151, 1993) many of the clinical features of these two forms of GVH disease are described. In addition to these clinical characteristics, acute lethal GVH (ALGVH) disease is characterized by diminished natural killer cell activity, whereas chronic GVH disease is characterized by normal or increased natural killer cell activity. Previously we have reported that this marked disparity in disease expression can be attributed to radiosensitive host cells which protect the F1 mouse from parental anti-F1 cytotoxicity (CTX) in mice undergoing chronic GVH (CGVH) disease. These cells fail to functionally emerge in mice undergoing ALGVH disease. We now report that the background genome, presumably the minor lymphocyte stimulatory loci, of the donor cells determines whether these host cells emerge and thereby dictates the form of GVH disease which is induced. C57BL/6 (B6) cells (H-2 b, minor lymphocyte stimulatory locus (Mls) b) and B10.D2 cells (H-2 d, Mls b) were found to induce ALGVH disease when adoptively transferred to [C57BL/6xDBA/2]F1 (B6D2) (H-2 b/d, Mls-1 a/b, Mls-2 a/b) recipient mice. DBA/2 cells (H-2 d, Mls-1 a, Mls-2 a) and Balb/c cells (H-2 d, Mls-1 a, Mls-2 b) induced CGVH disease in B6D2 mice. Using Mls congenic strains we have demonstrated that donor cell reactivity against Mls-2 a was necessary and sufficient to induce ALGVH disease as determined by anemia, lymphopenia, anti-F1 cytotoxicity, and loss of cytotoxicity against allogeneic targets. Such Mls-2 a reactivity correlated with the impaired induction of a host protective cell capable of vetoing self-directed CTX. Failure of this host protective cell to emerge in turn correlated with donor anti-host CTX and the emergence of ALGVH disease.