title: Acute cellular rejection of human renal tissue by adoptive transfer of allogeneic human peripheral blood mononuclear cells into chimeric rats: sequential gene expression of cytokines, chemokines and cytolytic effector molecules, and their regulation by CTLA-4-Ig.
abstract: T(h)1- and T(h)2-related cytokines (IFN-gamma, IL-2, IL-4, IL-10), beta-chemokines (RANTES, macrophage inflammatory protein-1beta) and their receptor [chemotatic cytokine receptor (CCR) 5], and the cytolytic effector molecule [Fas ligand (FasL)] play an essential role in regulating and co-ordinating acute renal allograft rejection. A chimeric model of acute cellular rejection which involves subcapsular grafting of human renal tissue in the kidneys of immunodeficient rats and subsequent i.p. infusion of allogeneic human peripheral blood mononuclear cells (PBMC) was used to study cellular infiltration patterns and sequential intragraft gene expression of these key inflammatory mediators. We found that while all molecules are expressed within the human renal implant at specific time points following infusion of allogeneic human PBMC, peak mRNA expression of IFN-gamma, IL-2, RANTES and CCR5 is associated with a phase of human mononuclear infiltration and accumulation, prior to graft destruction (induction phase). A short burst of FasL gene expression is found at the end of induction and at the onset of graft deterioration. IL-4 mRNA, which is hardly detectable, and IL-10 mRNA, which appears early and persists throughout follow-up at high levels, both peak after the induction phase with the advent of graft destruction. Furthermore, treatment with CTLA-4-Ig, which hardly affects migration of human effector cells into graft tissue, is associated with a temporary reduction in gene transcript levels for all inflammatory mediators, especially IL-2 and IL-4, reduced apoptosis in the graft and amelioration of tissue injury. Thus, development of acute cellular rejection in our chimeric model involves a co-ordinated pattern of gene expression, in which CTLA-4-Ig promotes its effects by transient inactivation of infiltrating human cells.
authors.affiliation: Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: B
authors.initials: B
authors.lastname: Dekel
authors.forename: W O
authors.initials: WO
authors.lastname: Böcher
authors.forename: H
authors.initials: H
authors.lastname: Marcus
authors.forename: A
authors.initials: A
authors.lastname: Yussim
authors.forename: Y
authors.initials: Y
authors.lastname: Reisner
mesh_terms: D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000494:pharmacology*; D060908:CTLA-4 Antigen; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism; D018925:Chemokines / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D018796:Immunoconjugates; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D016030:Kidney Transplantation; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D011923:Rats, Nude; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D013997:Time Factors; D018183:Transplantation Chimera / Q000276:immunology; D014184:Transplantation, Homologous; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018946:Chemokine CCL5; D018925:Chemokines; C556707:Ctla4 protein, mouse; D016207:Cytokines; D018796:Immunoconjugates; D007376:Interleukin-2; D012333:RNA, Messenger; D019713:Receptors, CCR5; D019014:fas Receptor; D016753:Interleukin-10; D015847:Interleukin-4; D000069594:Abatacept; D007371:Interferon-gamma