Article

IDO and regulatory T cell support are critical for cytotoxic T lymphocyte-associated Ag-4 Ig-mediated long-term solid organ allograft survival.

Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, A-6020 Innsbruck, Austria.
The Journal of Immunology (impact factor: 5.79). 11/2011; 188(1):37-46. DOI:10.4049/jimmunol.1002777 pp.37-46
Source: PubMed

ABSTRACT Costimulatory blockade of CD28-B7 interaction with CTLA4Ig is a well-established strategy to induce transplantation tolerance. Although previous in vitro studies suggest that CTLA4Ig upregulates expression of the immunoregulatory enzyme IDO in dendritic cells, the relationship of CTLA4Ig and IDO in in vivo organ transplantation remains unclear. In this study, we studied whether concerted immunomodulation in vivo by CTLA4Ig depends on IDO. C57BL/6 recipients receiving a fully MHC-mismatched BALB/c heart graft treated with CTLA4Ig + donor-specific transfusion showed indefinite graft survival (>100 d) without signs of chronic rejection or donor specific Ab formation. Recipients with long-term surviving grafts had significantly higher systemic IDO activity as compared with rejectors, which markedly correlated with intragraft IDO and Foxp3 levels. IDO inhibition with 1-methyl-dl-tryptophan, either at transplant or at postoperative day 50, abrogated CTLA4Ig + DST-induced long-term graft survival. Importantly, IDO1 knockout recipients experienced acute rejection and graft survival comparable to controls. In addition, αCD25 mAb-mediated depletion of regulatory T cells (Tregs) resulted in decreased IDO activity and again prevented CTLA4Ig + DST induced indefinite graft survival. Our results suggest that CTLA4Ig-induced tolerance to murine cardiac allografts is critically dependent on synergistic cross-linked interplay of IDO and Tregs. These results have important implications for the clinical development of this costimulatory blocker.

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Keywords

costimulatory blocker
 
CTLA4Ig + donor-specific transfusion
 
CTLA4Ig upregulates expression
 
CTLA4Ig-induced tolerance
 
donor specific Ab formation
 
graft survival comparable
 
IDO inhibition
 
immunoregulatory enzyme IDO
 
indefinite graft survival
 
induce transplantation tolerance
 
markedly correlated
 
MHC-mismatched BALB/c heart graft
 
murine cardiac allografts
 
postoperative day 50
 
regulatory T cells
 
synergistic cross-linked interplay
 
vitro studies
 
vivo organ transplantation
 
well-established strategy
 
αCD25 mAb-mediated depletion