title: Distinct subsets of dendritic cells regulate the pattern of acute xenograft rejection and susceptibility to cyclosporine therapy.
abstract: We determined whether distinct subclasses of dendritic cells (DC) could polarize cytokine production and regulate the pattern of xenograft rejection. C57BL/6 recipients, transplanted with Lewis rat hearts, exhibited a predominantly CD11c(+)CD8alpha(+) splenic DC population and an intragraft cytokine profile characteristic of a Th1-dominant response. In contrast, BALB/c recipients of Lewis rat heart xenografts displayed a predominantly CD11c(+)CD8alpha(-) splenic DC population and IL-4 intragraft expression characteristic of a Th2 response. In addition, the CD11c(+)IL-12(+) splenic DC population in C57BL/6 recipients was significantly higher than that in BALB/c recipients. Adoptive transfer of syngeneic CD8alpha(-) bone marrow-derived DC shifted a Th1-dominant, slow cell-mediated rejection to a Th2-dominant, aggressive acute vascular rejection (AVR) in C57BL/6 mice. This was associated with a cytokine shift from Th1 to Th2 in these mice. In contrast, transfer of CD8alpha(+) bone marrow-derived DC shifted AVR to cell-mediated rejection in BALB/c mice and significantly prolonged graft survival time from 6.0 +/- 0.6 days to 14.2 +/- 0.8 days. CD8alpha(+) DC transfer rendered BALB/c mice susceptible to cyclosporine therapy, thereby facilitating long-term graft survival. Furthermore, CD8alpha(+) DC transfer in IL-12-deficient mice reconstituted IL-12 expression, induced Th1 response, and attenuated AVR. Our data suggest that the pattern of acute xenogeneic rejection can be regulated by distinct DC subsets.
authors.affiliation: Multi-Organ Transplant Program, London Health Sciences Centre-University Hospital, 339 Windermere Road, London, Ontario, Canada N6A 5A5.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Arp
authors.forename: Xuyan
authors.initials: X
authors.lastname: Huang
authors.forename: Weihua
authors.initials: W
authors.lastname: Liu
authors.forename: Siobhan
authors.initials: S
authors.lastname: Ramcharran
authors.forename: Jifu
authors.initials: J
authors.lastname: Jiang
authors.forename: Bertha
authors.initials: B
authors.lastname: Garcia
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kanai
authors.forename: Weiping
authors.initials: W
authors.lastname: Min
authors.forename: Peta J
authors.initials: PJ
authors.lastname: O'Connell
authors.forename: Robert
authors.initials: R
authors.lastname: Zhong
mesh_terms: D000208:Acute Disease; D000818:Animals; D000906:Antibodies / Q000276:immunology; D016827:CD8 Antigens / Q000378:metabolism; D003331:Coronary Vessels / Q000276:immunology; D016572:Cyclosporine / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines / Q000235:genetics; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D006084:Graft Rejection / Q000188:drug therapy / Q000276:immunology* / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D016027:Heart Transplantation; D008297:Male; D051379:Mice; D009206:Myocardium / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051381:Rats; D015996:Survival Rate; D013997:Time Factors; D014183:Transplantation, Heterologous / Q000276:immunology*
chemical_list: D000906:Antibodies; D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; D016207:Cytokines; D016572:Cyclosporine