Alterations in chemokine mRNA expression in animals receiving portal vein immunization and renal allo- or xenotransplantation precede altered cytokine production

We have analyzed chemokine mRNA expression in graft tissue of C3H/HEJ mice receiving allogeneic (C57BL/6) or xenogeneic [Lewis (LEW) rat donors] kidne y grafts and correlated this with graft survival. Since donor-specific port al vein (pv) immunization is known to increase allo- and xenograft survival , in some cases recipients also received pretransplant pv or intravenous (i v) immunization; other animals received the antioxidant N-acetylcysteine (N Ac) to examine the role of ischemia/reperfusion injury in the changes obser ved. Graft tissue and lymph nodes draining the respective grafts mere obtai ned at various times posttransplantation and used for quantitative polymera se chain reaction analysis of mRNAs for different chemokines. In addition, lymphocytes were restimulated in culture with donor antigen and supernatant s assayed for different cytokines. We observed that early increases in mRNA for MCP-1 preceded a polarization to type 2 cytokine production. Infusion of NAc twice daily for 4 days following transplantation further altered che mokine mRNA expression (increased MCP-1 and RANTES; decreased CINC); led to more enhanced type 2 cytokine production relative to control animals; and further increased xenograft survival. By use of heteroantibodies to differe nt chemokines, anti-MCP-1 alone, but not antibodies to MIP-1 alpha or RANTE S, abolished this early polarization in cytokine production, implying a cau sal link between MCP-1 production and polarization in cytokine production. We conclude that manipulation of chemokine production early after transplan tation might indirectly modify graft outcome by modifying cytokine producti on. (C) 1999 Academic Press.