title: CXCL9 antagonism further extends prolonged cardiac allograft survival in CCL19/CCL21-deficient mice.
abstract: CCL19/MIP-3beta and CCL21/SLC are essential for chemotactic recruitment of mature dendritic cells (DC) to T-cell areas of secondary lymphoid tissue. Paucity of lymph node T-cells (plt/plt) mice lack CCL21-serine (ser) and CCL19 expression. We tested plt/plt and wild type (wt) BALB/c (H2d) mice as recipients of heart or skin allografts from C57BL/10J (H2b) donors. Donor DC trafficking to secondary lymphoid tissue was markedly reduced in plt heart but not skin allograft recipients. Heart, but not skin grafts survived significantly longer in plt recipients. Accordingly, T cells from plt heart transplant recipients demonstrated poor anti-donor responses in ex vivo MLR, compared to wt heart or wt and plt skin recipients. Moreover, donor-reactive T cells from plt heart recipients exhibited Th2-skewing in comparison to T cells from wt heart or skin graft recipients. Anti-CXCL9/Mig was administered for 2 weeks post-transplant to determine whether impairment of activated T-cell migration could further prolong cardiac allograft survival in plt recipients. CXCL9-antagonism extended graft survival significantly only in plt mice, likely due, in part, to retention of alloactivated T cells in secondary lymphoid tissue/reduction of graft-infiltrating T cells. Thus, targeting DC and activated T-cell migration concomitantly has additive effects in prolonging heart graft survival with potential for therapeutic application.
authors.affiliation: Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, USA.
authors.forename: Bridget L
authors.initials: BL
authors.lastname: Colvin
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Wang
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakano
authors.forename: WenHan
authors.initials: W
authors.lastname: Wu
authors.forename: Terutaka
authors.initials: T
authors.lastname: Kakiuchi
authors.forename: Robert L
authors.initials: RL
authors.lastname: Fairchild
authors.forename: Angus W
authors.initials: AW
authors.lastname: Thomson
mesh_terms: D000818:Animals; D002470:Cell Survival; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D054370:Chemokine CXCL9; D018925:Chemokines / Q000378:metabolism; D019742:Chemokines, CC / Q000235:genetics / Q000502:physiology*; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors*; D003713:Dendritic Cells / Q000166:cytology; D004797:Enzyme-Linked Immunosorbent Assay; D006085:Graft Survival; D016027:Heart Transplantation / Q000379:methods*; D007150:Immunohistochemistry; D015847:Interleukin-4 / Q000378:metabolism; D008198:Lymph Nodes / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015233:Models, Statistical; D012694:Serine / Q000737:chemistry; D016038:Skin Transplantation / Q000379:methods; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells; D013997:Time Factors; D014184:Transplantation, Homologous / Q000379:methods
chemical_list: C515461:Ccl19 protein, mouse; C515479:Ccl21c protein, mouse; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D054370:Chemokine CXCL9; D018925:Chemokines; D019742:Chemokines, CC; D019743:Chemokines, CXC; C485969:Cxcl9 protein, mouse; D015847:Interleukin-4; D012694:Serine