期刊
AMERICAN JOURNAL OF TRANSPLANTATION
卷 6, 期 6, 页码 1297-1311出版社
WILEY
DOI: 10.1111/j.1600-6143.2006.01308.x
关键词
donor specific transfusion; immunosuppression; indirect pathway; lymphocyte activation; transplantation
资金
- NCI NIH HHS [R01 CA100893] Funding Source: Medline
- NHLBI NIH HHS [R01 HL 077545, R01 HL 075512, R21 HL 69725] Funding Source: Medline
- NIAID NIH HHS [R21 AI55027, R01 AI41011, R21 AI57958, R01 AI57698] Funding Source: Medline
- NIDDK NIH HHS [R01 DK49745] Funding Source: Medline
Tolerance induction against donor allo-antigens (allo-Ag) remains one of the most challenging aspects of transplant immunology. The ability of dendritic cells (DC) to participate in immunity and tolerance makes them an excellent tool for tolerance induction. Here, we employed the immunosuppressive properties of apoptotic cells to deliver simultaneously an inhibitory signal and donor allo-Ag to recipient DC for treatment of allograft rejection. DC that captured apoptotic cells remained immature and activated deficiently anti-donor CD4(+) T cells that were unable to upregulate T-cell activation markers, to secrete IL-2 and IFN-gamma and to survive under homeostatic conditions due to low expression of Bcl-X-L, IL-7R and IL-15R. Administration of donor apoptotic cells decreased the systemic anti-donor T- and B-cell response and prolonged cardiac allograft survival in mice. The effect was donor specific and required the interaction of donor apoptotic cells with recipient quiescent CD8 alpha(+) DC. When combined with CD40-CD154-blockade, administration of donor apoptotic cells resulted in indefinite graft survival mediated by generation of regulatory T cells. The use of the inhibitory effects of apoptotic cells on the anti-donor response provides a new approach to treat transplant rejection.
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