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] kidney grafts and correlated this with graft survival. Since donor-specific portal vein (pv) immunization is known to increase allo- and xenograft survival, in some cases recipients also received pretransplant pv or intravenous (iv) immunization; other animals received the antioxidant N-acetylcysteine (NAc) to examine the role of ischemia/reperfusion injury in the changes observed. Graft tissue and lymph nodes draining the respective grafts were obtained at various times posttransplantation and used for quantitative polymerase chain reaction analysis of mRNAs for different chemokines. In addition, lymphocytes were restimulated in culture with donor antigen and supernatants 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 chemokine 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 different chemokines, anti-MCP-1 alone, but not antibodies to MIP-1alpha or RANTES, abolished this early polarization in cytokine production, implying a causal link between MCP-1 production and polarization in cytokine production. We conclude that manipulation of chemokine production early after transplantation might indirectly modify graft outcome by modifying cytokine production.
Ramakrishna
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CCRW 2-855, The Toronto Hospital, 200 Elizabeth Street, Toronto, Ontario, M5G2C4, Canada.
Hu
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Lei
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J
Li
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Gorczynski
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RM
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D018932:Chemokine CCL2 / Q000502:physiology; D018925:Chemokines / Q000235:genetics*; D016207:Cytokines / Q000096:biosynthesis*; D006085:Graft Survival; D007114:Immunization; D016030:Kidney Transplantation; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D011169:Portal Vein / Q000276:immunology*; D012333:RNA, Messenger / Q000032:analysis*; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000276:immunology; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous
D018932:Chemokine CCL2; D018925:Chemokines; D016207:Cytokines; D012333:RNA, Messenger; D000111:Acetylcysteine