Role of Cytokines in Allograft Rejection

Abstract

This review examines the evidence, both from experimental models and numerous clinical settings, that has suggested that suppression of acute allograft rejection correlates with a relative decrease in type-1 cytokine production and an increase in type-2 cytokine production. This correlation has spurred studies on cytokine gene polymorphisms, to assess evidence that certain cytokine-producing genotypes are associated with increased incidence of transplant rejection, and also an interest in the value of monitoring cytokine profiles post-transplantation in long-term follow-up of transplant patients. An appraisal is given of the potential for cytokine gene therapy in transplantation, using both dendritic cells (DC) and graft tissue itself as target cells. Along the same lines, gene-targeting of DCs to increase or decrease expression of molecules (CD40/CD80/CD86/CD200) believed to control the polarization of T cell development (and cytokine production) is discussed. The review concludes with consideration of the possibility that one future goal of the pharmaceutical industry will be to develop novel immunosuppressants with selective inhibitory action on the production of distinct cytokines.

Soluble Fibrinogen-Like Protein 2/Fibroleukin Exhibits Immunosuppressive Properties: Suppressing T Cell Proliferation and Inhibiting Maturation of Bone Marrow-Derived Dendritic Cells

“…Both IL-4 and IL-10 have been shown to antagonize the development of Th1 cells, likely through decreasing expression/function of the cytokine IL-12, while promoting the differentiation of Th2 cells. In human and animal studies, polarization toward type 2 cytokine production has been associated with improved survival of allogeneic transplants (21,35). Whether soluble fgl2 would affect graft survival in transplantation remains to be examined.…”

“…BM-derived DC were prepared as described elsewhere (21). Briefly, BM cells were removed from femurs and tibias of BALB/c (H-2 d ) mice and filtered through nylon mesh.…”

“…Where CTL induction was assayed, cultures were allowed to continue for 5 days (in the presence/absence of s fgl2), before cells were harvested. These effector cells were assayed in standard 4-h 51 Cr release assays at various E:T ratios with 51 Cr-labeled 72-h Con A-activated A/J blast target cells, as described elsewhere (21). Data were expressed as a percent specific lysis at 50:1 E:T.…”

Gene therapy with adenovirus‐delivered indoleamine 2,3‐dioxygenase improves renal function and morphology following allogeneic kidney transplantation in rat

“…Central players in this concerted attack are the T lymphocytes, which intervene in the rejection process both by directly killing the foreign cells of the allograft (mainly the cytotoxic T cells), as well as by secreting a plethora of modulatory cytokines (mainly the helper T cells), which will further influence the activity of other immune cells. Generally, Th1 and Th17 cells are considered to drive the rejection of transplanted organs , whereas Th2 cells counteract this . The alloimmune response will also trigger the activation of regulatory T cells, which comprise a subset of T cells, mostly with the CD4+ CD25highfox3+ phenotype, that are able to steer the immune response towards tolerance .…”

Stable T-cell reactivity after successful tapering of azathioprine in HLA-identical living-related kidney transplant recipients despite minor histocompatibility antigen mismatches

“…interleukin (IL)-13] directed to donor antigens. Both types of cytokines have been associated with acute rejection [22,23], while Th2-cytokines also have been suggested with graft acceptance [24,25].…”