Regulatory T-cell generation and kidney allograft tolerance induced by mesenchymal stem cells associated with indoleamine 2,3-dioxygenase expression.
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.
Department of Surgery, University of Western Ontario, London, ON, Canada.
Wei
W
Ge
Jifu
J
Jiang
Jacqueline
J
Arp
Weihua
W
Liu
Bertha
B
Garcia
Hao
H
Wang
D000714:Anastomosis, Surgical; D000818:Animals; D001012:Aorta, Abdominal / Q000601:surgery; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000172:deficiency / Q000235:genetics*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D016030:Kidney Transplantation / Q000276:immunology* / Q000379:methods; D008213:Lymphocyte Activation / Q000276:immunology*; D008212:Lymphocyte Depletion; D008297:Male; D059630:Mesenchymal Stem Cells / Q000201:enzymology / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D012082:Renal Veins / Q000601:surgery; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D023001:Transplantation Tolerance; D014184:Transplantation, Homologous / Q000276:immunology; D014682:Vena Cava, Inferior / Q000601:surgery
C508018:Il2ra protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D053645:Interleukin-2 Receptor alpha Subunit