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: 4.92). 11/2011; 188(1):37-46. DOI: 10.4049/jimmunol.1002777
Source: PubMed


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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    • "In vitro cell culture experiments further demonstrate the immunosuppressive nature of IDO showing that elevated IDO activity can permit tumor cell escape from immune surveillance through depletion of L-Trp in the DC and T cell microenvironment [161]. In vivo experiments have shown that IDO knockout mice experience acute rejection of transplanted MHC mismatched grafts, while wild-type mice with high tryptophan catabolism experienced long-term graft survival [162]. Further emphasizing the requirement for IDO in suppression of DC activation, experimental reduction in the levels of pDCs in the pancreas of NOD mice was shown to be accompanied by increased insulitis and a localized reduction in IDO levels [76]. "
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    • "Many studies have confirmed the ability of CD4+ CD25+ Treg cells to prevent the rejection of xenogeneic grafts in vitro [45], [46]. Activated Treg cells may also down-regulate CD80/CD86 expression on host APCs, leading to the inhibition of cytokine production by DCs or IDO expression [47]–[49]. The current study implies that synergistic cross-linked interplay of pCTLA4-IgG4-modified-imDC and Tregs may play a critical role in transplantation tolerance. "
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