Scientific Report 2003-2004 - Cleveland Clinic Lerner Research ...

THE FAIRCHILDLABORATORYPOSTDOCTORAL INVESTIGATORSHiroyuki Amano, M.D.Motoo Araki, M.D.Anton Gorbachev, Ph.D.Eun-jie Oh, M.D.Qi-Wei Zhang, M.D., Ph.D.GRADUATE STUDENTTarek El-SawyRESEARCH TECHNOLOGISTSMichael Auerbach, B.S.Danielle Kish, B.S.COLLABORATORSSuneel Apte, M.B.B.S., D. Phil. 1Joshua Farber, Ph.D. 2Stuart Flechner, M.D. 3David Goldfarb, M.D. 3Peter Heeger, M.D. 4Venkatesh Krishnamurthi, M.D. 3Charles Modlin, M.D. 3Andrew Novick, M.D. 3Daniel Remick, M.D. 5Randall Starling, M.D. 6Robert Strieter, M.D. 7Mohamed Yamani, M.D. 6James Young, M.D. 61Dept. of Biomedical Engineering,CCF2NIAID, NIH, Bethesda, MD3Urological Inst., CCF4Dept. of Immunology, CCF5Dept. of Pathology, Univ. ofMichigan, Ann Arbor6Dept. of CardiovascularMedicine, CCF7Div. of Pulmonary and CriticalCare Medicine, UCLA, LosAngeles90Mechanisms of T-Lymphocyte-MediatedInflammation in Skin Diseaseand TransplantationThe focus of this laboratory is to definemechanisms involved in T-cell-mediatedinflammation in skin disease and during therejection of transplanted allografts. Based on resultsfrom our laboratory, we have developed the hypothesisthat T-cell responses are preceded by inflammatoryprocesses that are mediated by innate componentsof the immune response and that the innatecomponents regulate the magnitude and duration ofthe T-cell response.One model we have been using to study theinflammatory T cells involves the priming andactivity of T cells in responseto epidermal application ofhaptens. Challenge of haptensensitizedanimals results in animmune response contacthypersensitivity (CHS), acommon dermatologicalproblem (e.g., poison ivy). Wehave demonstrated the effectorrole of CD8 + T cells and theregulatory role of CD4 + T cellsin this immune response.Recent studies have indicatedthat CD4 + T cells mediate thisregulation by killing off thehapten-presenting dendritic cellsthat carry the hapten from theskin to the draining lymphoidtissues where the T cells are.This killing restricts the windowof time that the effector CD8 +T cells can be primed to the hapten and limits thesize of the reactive T cell compartment.Recruitment of the primed effector CD8 + Tcells to the antigen challenge site is controlled by theproduction of chemoattractant cytokines, orchemokines, such as Groα. This recruitment and theGorbachev, A.V., Heeger, P.S., and R.L. Fairchild (2001) CD4+ and CD8+ T cell primingfor contact hypersensitivity occurs independently of CD40-CD40L interactions. J.Immunol. 166:2323-2332.Baldwin, W.W., Fairchild, R.L., and C.P. Larsen (2001) Innate immune responses totransplants: a significant variable with cadaver donors. Immunity 14:369-376.el-Sawy, T., Fahmy, N.M., and R.L. Fairchild (2002) Chemokines: directing leukocyteinfiltration into allografts. Curr. Opin. Immunol. 14:562-568.Gorbachev, A.V., and R.L. Fairchild (2002) Mechanisms of T cell priming for contacthypersensitivity. Crit. Rev. Immunol. 21:451-472.Kobayashi, H., Novick, A.C., Toma, H., Fairchild (2002) Chronic antagonism of Miginhibits cellular infiltration and promotes survival of class II MHC disparate skinallografts. Transplantation 74:387-395.Fahmy, N.M., Yamani, M.H., Starling, R.C., Ratliff, N.B., Young, J.B., McCarthy, P.M.,Feng, J., Novick, A.C., and R.L. Fairchild (2003) Chemokine and chemokine receptorThe Department of ImmunologyCHS response is blocked by treatment with Groαantibodies. Groα does not directly recruit effectorCD8 + T-cells to the challenge site but recruitsneutrophils that are, in turn, stimulated to produce (asyet) unidentified chemoattractants for the T-cells.Depletion of neutrophils or blocking their functionalso inhibits effector T-cell recruitment into thechallenge site and the CHS response. Althoughprimed T-cell recruitment and the CHS response arenot observed to low doses of antigen challenge,manipulating neutrophil infiltration into the challengesite results in T-cell infiltration and the CHSresponse. These studies emphasizethe critical role of innate immunecomponents on the recruitment andactivities of antigen-specific T cells.These studies have also demonstratedthe ability to manipulate T-cell-mediated immune responsesthrough the innate immune system.The second model used tostudy T-cell-mediated inflammationis allogeneic tissue transplantation.The recruitment of alloantigenspecificT-cells to the graft siteinitiates allograft rejection. Thefactors directing alloantigen-primedT-cells to the allograft duringrejection are poorly defined. Duringrejection of skin and heart allograftsRobert L. Fairchild, Ph.D. in mice, chemokines produced earlyfollowing transplantation mediateneutrophil and macrophagerecruitment to the allograft. As this productionsubsides, chemokines that mediate alloantigenprimedT-cell recruitment are produced. We aretesting the ability of anti-chemokine antibodies todelay or abrogate allograft rejection. In a murineheart allograft model, recipient treatment withantibodies to an IFN-γ-induced chemokine, Mig,inhibits T-cell recruitment into the allograft andacute graft rejection. In situ hybridization studieshave demonstrated that Mig is derived from bothdonor and recipient. Current experiments areutilizing Mig-deficient heart allograft donors and/or recipients to further test the role of thisrecruiting factor in acute and chronic rejection andto define the Mig mediated mechanisms directingalloantigen-primed T cells into allografts. Similar toCHS, antagonism of innate immune components inheart allograft recipients attenuates T-cell graftinfiltration and acute rejection. We are participatingin a study with both the cardiac and renal transplantteams at the Cleveland Clinic to investigatethese aspects of the immune response in clinicaltransplantation. The understanding of thesemechanisms is essential to the design of practicalclinical strategies to maintain allograft acceptancein transplant recipients.