ANALYSIS OF GRAFT-VERSUS-HOST DISEASE (GVHD) AND GRAFT-REJECTION USING MHC CLASS I-DEFICIENT MICE

GVHD is a major complication in allogeneic bone marrow transplantation (BMT). MHC class I mismatching increases GVHD, but in MHC-matched BMT minor histocompatibility antigens (mH) presented by MHC class I resul t in significant GVHD. To examine the modification of GVHD in the abse nce of cell surface MHC class I molecules, beta(2)-microglobulin-defic ient mice (beta(2)m-/-) were used as allogeneic BMT recipients in MHC- and mil-mismatched transplants. beta(2)m-/- mice accepted MHC class I- expressing BM grafts and developed significant GVHD. MHC (H-2)-mismatc hed recipients developed acute lethal GVHD. In contrast, animals trans planted across mil barriers developed indolent chronic disease that wa s eventually fatal. Engrafted splenic T cells in all beta(2)m-/- recip ients were predominantly CD3(+) alpha beta TCR+ CD4(+) cells (15-20% o f all splenocytes). In contrast, CD8(+) cells engrafted in very small numbers (1-5%) irrespective of the degree of MHC mismatching. T cells proliferated against recipient strain antigens and recognized recipien t strain targets in cytolytic assays. Cytolysis was blocked by anti-MH C class II but not anti-CD8 or anti-MHC class I monoclonal antibodies (MoAbs). Cytolytic CD4(+) T cells induced and maintained GVHD in mil-m ismatched beta(2)m-/- mice, supporting endogenous mil presentation sol ely by MHC class II. Conversely, haematopoietic beta(2)m-/- cells were unable to engraft in normal MHC-matched recipients, presumably due to natural killer (NK)-mediated rejection of class I-negative cells. Don or-derived lymphokine-activated killer cells (LAK) were unable to over come graft rejection (GR) and support engraftment.