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-lg

T(h)1- and T(h)2-related cytokines (IFN-gamma, IL-2, IL-4, IL-10), beta-che mokines (RANTES, macrophage inflammatory protein-1 beta) and their receptor [chemotatic cytokine receptor (CCR) 5], and the cytolytic effector molecul e [Fas ligand (FasL)] play an essential role in regulating and co-ordinatin g acute renal allograft rejection. A chimeric model of acute cellular rejec tion which involves subcapsular grafting of human renal tissue in the kidne ys of immunodeficient rats and subsequent i.p. infusion of allogeneic human peripheral blood mononuclear cells (PBMC) was used to study cellular infil tration patterns and sequential intragraft gene expression of these key inf lammatory mediators. We found that while all molecules are expressed within the human renal implant at specific time points following infusion of allo geneic human PBMC, peak mRNA expression of IFN-gamma, IL-2, RANTES and CCR5 is associated with a phase of human mononuclear infiltration and accumulat ion, prior to graft destruction (induction phase). A short burst of FasL ge ne expression is found at the end of induction and at the onset of graft de terioration. IL-4 mRNA, which is hardly detectable, and IL-10 mRNA, which a ppears early and persists throughout follow-up at high levels, both peak af ter 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 t ranscript levels for all inflammatory mediators, especially IL-2 and IL-4, reduced apoptosis in the graft and amelioration of tissue injury. Thus, dev elopment of acute cellular rejection in our chimeric model involves a co-or dinated pattern of gene expression, in which CTLA-4-Ig promotes its effects by transient inactivation of infiltrating human cells.