Murine T lymphocytes incapable of producing macrophage inhibitory protein-1 alpha are impaired in causing graft-versus-host disease across a class I but not class II major histocompatibility complex barrier

The routine use of bone marrow transplantation is limited by the occurrence of acute and chronic graft-versus-host disease (GVHD). Current approaches to decreasing the occurrence of GVHD after allogeneic transplantation use T -cell depletion, use immunosuppressive agents, or block costimulatory molec ule function. The role of proteins in the recruitment of alloreactive lymph ocytes has not been well characterized. Chemokines are a large family of pr oteins that mediate recruitment of mononuclear cells in vitro and in vivo. To investigate the role of T-cell production of the chemokine macrophage in hibitory protein-1 alpha (MIP-1 alpha) in the occurrence of GVHD, splenocyt es either from wild-type or from MIP-1 alpha-/- mice were administered to c lass I (B6.C-H2(bm1)) and class II disparate mice (B6-C-H2(bm12)). The inci dence and severity of GVHD was markedly reduced in bm1 mice receiving splen ocytes from MIP-1 alpha-/- mice as compared with mice receiving wild-type s plenocytes. Bm1 mice receiving MIP-1 alpha-/- splenocytes had significantly less weight loss and markedly reduced inflammatory responses in the lung a nd liver than mice receiving C57BL/6 splenocytes. Bm1 mice receiving MIP-1 alpha-/- splenocytes had a markedly decreased production of antichromatin a utoantibodies and impaired generation of bm1-specific T lymphocytes versus wild-type mice. However, MIP-1 alpha-/- splenocytes easily induced GVHD whe n administered to bm12 mice. This data show that blockade of chemokine prod uction or function may provide a new approach to the prevention or treatmen t of GVHD but that chemokines that recruit both CD4(+) and CD8(+) lymphocyt es may need to be targeted. (C) 1999 by The American Society of Hematology.