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Thomas E. Starzl Transplantation Institute and Departments of Surgery and
Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, PA 15213; and
Immunex Corp., Seattle, WA 98101
IL-17 is a T cell-derived cytokine that stimulates stromal cells and macrophages to secrete proinflammatory cytokines. We hypothesized that IL-17 might play a role in alloimmune responses, and that interference with its activity might suppress allograft rejection. IL-17R:Fc or control IgG was added at the start of mouse MLR or was administered i.p. (100–500 µg/day) for different durations post-transplant to murine recipients of MHC-mismatched cardiac allografts. IL-17R:Fc (50–200 µg/ml) markedly inhibited T cell proliferation in vitro and significantly prolonged nonvascularized cardiac allograft median survival time from 13 to 20 days (100 µg/day; days 0 and 1) or to 19 days (100–300 µg/day; days 0–4). Survival of vascularized grafts was also extended significantly from 10.5 to 19 days by IL-17R:Fc (500 µg/day; days 0–6). To address a possible mechanism by which IL-17 may promote alloreactivity, we examined the influence of IL-17 on the differentiation and function of bone marrow-derived cells propagated in granulocyte-macrophage CSF with or without IL-4 to promote dendritic cell (DC) growth. A minor proportion of CD11c+ DC expressed the IL-17R. IL-17 promoted the maturation of DC progenitors, as evidenced by increased cell surface expression of CD11c, costimulatory molecules (CD40, CD80, CD86), and MHC class II Ag, and allostimulatory capacity. IL-17 had a lesser effect on the phenotype and function of more fully differentiated myeloid DC. These findings suggest a role for IL-17 in allogeneic T cell proliferation that may be mediated in part via a maturation-inducing effect on DC. IL-17 appears to be a novel target for therapeutic intervention in allograft rejection.
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J. Witowski, K. Pawlaczyk, A. Breborowicz, A. Scheuren, M. Kuzlan-Pawlaczyk, J. Wisniewska, A. Polubinska, H. Friess, G. M. Gahl, U. Frei, et al. IL-17 Stimulates Intraperitoneal Neutrophil Infiltration Through the Release of GRO{alpha} Chemokine from Mesothelial Cells J. Immunol., November 15, 2000; 165(10): 5814 - 5821. [Abstract] [Full Text] [PDF]
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 A. M. WOLTMAN, S. DE HAIJ, J. G. BOONSTRA, S. J.P. GOBIN, M. R. DAHA, and C. V. KOOTEN Interleukin-17 and CD40-Ligand Synergistically Enhance Cytokine and Chemokine Production by Renal Epithelial Cells J. Am. Soc. Nephrol., November 1, 2000; 11(11): 2044 - 2055. [Abstract] [Full Text]
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A. E. Morelli, M. A. Antonysamy, T. Takayama, H. Hackstein, Z. Chen, S. Qian, N. B. Zurowski, and A. W. Thomson Microchimerism, Donor Dendritic Cells, and Alloimmune Reactivity in Recipients of Flt3 Ligand-Mobilized Hemopoietic Cells: Modulation by Tacrolimus J. Immunol., July 1, 2000; 165(1): 226 - 237. [Abstract] [Full Text] [PDF]
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R. Schwandner, K. Yamaguchi, and Z. Cao Requirement of Tumor Necrosis Factor Receptor-Associated Factor (Traf)6 in Interleukin 17 Signal Transduction J. Exp. Med., April 3, 2000; 191(7): 1233 - 1240. [Abstract] [Full Text] [PDF]
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J. Lee, W.-H. Ho, M. Maruoka, R. T. Corpuz, D. T. Baldwin, J. S. Foster, A. D. Goddard, D. G. Yansura, R. L. Vandlen, W. I. Wood, et al. IL-17E, a Novel Proinflammatory Ligand for the IL-17 Receptor Homolog IL-17Rh1 J. Biol. Chem., January 5, 2001; 276(2): 1660 - 1664. [Abstract] [Full Text] [PDF]
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Y. Shi, S. J. Ullrich, J. Zhang, K. Connolly, K. J. Grzegorzewski, M. C. Barber, W. Wang, K. Wathen, V. Hodge, C. L. Fisher, et al. A Novel Cytokine Receptor-Ligand Pair. IDENTIFICATION, MOLECULAR CHARACTERIZATION, AND IN VIVO IMMUNOMODULATORY ACTIVITY J. Biol. Chem., June 16, 2000; 275(25): 19167 - 19176. [Abstract] [Full Text] [PDF]
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