AI Article Synopsis
- The study investigates the role of mesenchymal stem cells (MSCs) in inducing tolerance for kidney transplants and highlights the enzyme indoleamine 2,3-dioxygenase (IDO) as a crucial factor in this process.
- Research using both wild-type MSCs and IDO knockout MSCs showed that only the wild-type MSCs could promote allograft tolerance, characterized by normal kidney histology and specific immune responses.
- Findings suggest that IDO helps generate regulatory T cells (Tregs), which play a significant role in the immunosuppressive effects of MSCs, supporting their potential use in clinical transplantation.
Article Abstract
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 (1×10(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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| http://dx.doi.org/10.1097/TP.0b013e3181fed001 | DOI Listing |
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