title: Critical role of proinflammatory cytokine IL-6 in allograft rejection and tolerance.
abstract: The proinflammatory cytokine IL-6 plays an important role in controlling T-cell differentiation, especially the development of Th17 and regulatory T cells. To determine the function of IL-6 in regulating allograft rejection and tolerance, BALB/c cardiac grafts were transplanted into wild-type or IL-6-deficient C57BL/6 mice. We observed that production of IL-6 and IFN-γ was upregulated during allograft rejection in untreated wild-type mice. In IL-6-deficient mice, IFN-γ production was greater than that observed in wild-type controls, suggesting that IL-6 production affects Th1/Th2 balance during allograft rejection. CD28-B7 blockade by CTLA4-Ig inhibited IFN-γ production in C57BL/6 recipients, but had no effect on the production of IL-6. Although wild-type C57BL/6 recipients treated with CTLA4-Ig rejected fully MHC-mismatched BALB/c heart transplants, treatment of IL-6-deficient mice with CTLA4-Ig resulted in graft acceptance. Allograft acceptance appeared to result from the combined effect of costimulatory molecule blockade and IL-6-deficiency, which limited the differentiation of effector cells and promoted the migration of regulatory T cells into the grafts. These data suggest that the blockade of IL-6, or its signaling pathway, when combined with strategies that inhibit Th1 responses, has a synergistic effect on the promotion of allograft acceptance. Thus, targeting the effects of IL-6 production may represent an important part of costimulation blockade-based strategies to promote allograft acceptance and tolerance.
authors: Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors: X
authors: X
authors: Zhao
authors: O
authors: O
authors: Boenisch
authors: M
authors: M
authors: Yeung
authors: B
authors: B
authors: Mfarrej
authors: Sunmi
authors: S
authors: Yang
authors: L A
authors: LA
authors: Turka
authors: M H
authors: MH
authors: Sayegh
authors: J
authors: J
authors: Iacomini
authors: X
authors: X
authors: Yuan
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006084:Graft Rejection / Q000503:physiopathology*; D016027:Heart Transplantation; D018836:Inflammation Mediators / Q000502:physiology*; D015850:Interleukin-6 / Q000502:physiology*; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL
chemical_list: D018836:Inflammation Mediators; D015850:Interleukin-6