Journal
TRANSPLANTATION
Volume 90, Issue 12, Pages 1312-1320Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/TP.0b013e3181fed001
Keywords
Tolerance; Regulatory T cells; Mesenchymal stem cells; Kidney transplantation; Indoleamine 2,3-dioxygenase
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Funding
- Kidney Foundation of Canada
- Heart and Stroke Foundation of Ontario [T6318, NA6904]
- Heart and Stroke Foundation of Canada
- Roche Organ Transplantation Research Foundation
- Canada Foundation for Innovation
- Multi-Organ Transplant Program-London Health Sciences Centre
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Background. The immunoregulatory properties of mesenchymal stem cells (MSCs) have been observed in vitro and in vivo. However, the underlying mechanisms of this immunomodulation remain undefined. Recent research demonstrated that MSCs express the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO), known to suppress T-cell responses. This study was designed to address whether MSCs induce kidney allograft tolerance and whether IDO contributes to the immunoregulatory functions of MSCs in vivo. Methods. MSCs (1 x 10(6), intravenously) from wild-type (WT-MSCs) or IDO knockout (IDO-/--MSCs) C57BL/6 mice were injected into BALB/c recipients 24 hr after receiving a life-supporting orthotopic C57BL/6 renal graft. Results. WT-MSC-treated recipients achieved allograft tolerance with normal histology and undetectable antidonor antibody levels. Tolerant recipients demonstrated increased circulating kynurenine levels and significantly high frequencies of tolerogenic dendritic cells. They also exhibited significantly impaired CD4(+) T-cell responses consisting of decreased donor-specific proliferative ability and a Th2-dominant cytokine shift. In addition, high frequencies of CD4(+) CD25(+) Foxp3(+) regulatory T cells (Tregs) were found in recipient spleens and donor grafts, with antibody-induced CD25(+) cell depletion confirming the critical role of Tregs in the MSC-induced tolerance. Interestingly, renal allograft recipients treated with WT MSCs concomitant with the IDO inhibitor 1-methyl-tryptophan, or those treated with IDO-/--MSCs alone, were unable to achieve allograft tolerance-revealing that functional IDO was necessary for the immunosuppression observed with WT-MSC treatment. Conclusions. IDO secreted by MSCs was responsible, at least in part, for induction of kidney allograft tolerance through generation of Tregs. This study supports the clinical application of MSCs in transplantation.
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