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 result in significant GVHD. To examine the modification of GVHD in the absence of cell surface MHC class I molecules, β 2 ‐microglobulin‐deficient mice (β 2 m‐/‐) were used as allogeneic BMT recipients in MHC‐ and mH‐mismatched transplants. β 2 m‐/‐ mice accepted MHC class I‐expressing BM grafts and developed significant GVHD. MHC (H‐2)‐mismatched recipients developed acute lethal GVHD. In contrast, animals transplanted across mH barriers developed indolent chronic disease that was eventually fatal. Engrafted splenic T cells in all β 2 m‐/‐ recipients were predominantly CD3 +  αβ TCR +  CD4 + cells (15–20% of 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 recipient strain targets in cytolytic assays. Cytolysis was blocked by anti‐MHC class II but not anti‐CD8 or anti‐MHC class I monoclonal antibodies (MoAbs). Cytolytic CD4 + T cells induced and maintained GVHD in mH‐mismatched β 2 m‐/‐ mice, supporting endogenous mH presentation solely by MHC class II. Conversely, haematopoietic β 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. Donor‐derived lymphokine‐activated killer cells (LAK) were unable to overcome graft rejection (GR) and support engraftment.