INDUCTION OF A GLUCOCORTICOID-SENSITIVE F-1-ANTI-PARENTAL MECHANISM THAT AFFECTS ENGRAFTMENT DURING GRAFT-VERSUS-HOST DISEASE

Studies have shown that graft-vs-host disease (GVHD) in animal models induces persistent elevated levels of circulating adrenal glucocortico ids. In this report, we investigated the effects of endogenous glucoco rticoids on the outcome of GVHD by adrenalectomizing (ADX) unirradiate d (C57BL/6 X A)F-1 (BGAF(1)) mice before GVHD induction. GVHD was indu ced by injection of 20 x 10(6) A strain parental lymphoid cells into B 6AF(1) mice. Our results demonstrated that non-ADX recipient mice expe rienced features characteristic of GVHD on day 13, which became progre ssively more severe by days 18 to 21. The GVHD features included sever e immunosuppression, reversal in the host splenic CD4(+)/CD8(+) ratio, histopathologic lesions in different tissues, and high parental cell chimerism in the spleens and lymph nodes. In contrast, ADX F-1 recipie nt mice experienced GVHD features on day 13 similar to their non-ADX c ounterparts; however, ADX animals recovered rapidly from GVHD by days 18 to 21. Flow cytometry showed that, although a relatively high frequ ency of parental cells was detected in the spleens and lymph nodes of ADX mice on day 13, nearly all of the parental cells in the peripheral lymphoid organs disappeared on days 18 to 21, the time of recovery fr om GVHD. The marked reduction of parental cells and recovery from GVHD were prevented by treating ADX F-1 mice with either exogenous glucoco rticoid? anti-asialoGM1, or anti-CD8, but not anti-NK1.1 Ab. These res ults suggest that a dramatic recovery from GVHD was induced by a cell- mediated, steroid-sensitive F-1-anti-parental mechanism. The F-1-anti- parental phenomenon described herein is different from classical hybri d resistance.