Evidence for a role of IL-17 in organ allograft rejection: IL-17 promotes the functional differentiation of dendritic cell progenitors.
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 microg/day) for different durations post-transplant to murine recipients of MHC-mismatched cardiac allografts. IL-17R:Fc (50-200 microg/ml) markedly inhibited T cell proliferation in vitro and significantly prolonged nonvascularized cardiac allograft median survival time from 13 to 20 days (100 microg/day; days 0 and 1) or to 19 days (100-300 microg/day; days 0-4). Survival of vascularized grafts was also extended significantly from 10.5 to 19 days by IL-17R:Fc (500 microg/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.
Antonysamy
M A
MA
Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh, PA 15213, USA.
Fanslow
W C
WC
Fu
F
F
Li
W
W
Qian
S
S
Troutt
A B
AB
Thomson
A W
AW
D000276:Adjuvants, Immunologic / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002828:Choristoma / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D004431:Ear, External / Q000098:blood supply; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology*; D016027:Heart Transplantation / Q000276:immunology / Q000473:pathology; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016167:Integrin alphaXbeta2 / Q000096:biosynthesis; D020381:Interleukin-17 / Q000378:metabolism / Q000502:physiology*; D008213:Lymphocyte Activation / Q000235:genetics; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics; D053722:Receptors, Interleukin-17; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D013234:Stem Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D013601:T-Lymphocytes / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
D000276:Adjuvants, Immunologic; C109985:IL17RA protein, human; C491673:Il17ra protein, mouse; D007141:Immunoglobulin Fc Fragments; D007166:Immunosuppressive Agents; D016167:Integrin alphaXbeta2; D020381:Interleukin-17; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins