Distinct subsets of dendritic cells regulate the pattern of acute xenograft rejection and susceptibility to cyclosporine therapy.
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.
Wang
Hao
H
Multi-Organ Transplant Program, London Health Sciences Centre-University Hospital, 339 Windermere Road, London, Ontario, Canada N6A 5A5.
Arp
Jacqueline
J
Huang
Xuyan
X
Liu
Weihua
W
Ramcharran
Siobhan
S
Jiang
Jifu
J
Garcia
Bertha
B
Kanai
Nobuyuki
N
Min
Weiping
W
O'Connell
Peta J
PJ
Zhong
Robert
R
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*
D000906:Antibodies; D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; D016207:Cytokines; D016572:Cyclosporine