Indoleamine 2,3-Dioxygenase Expression in Transplanted NOD Islets Prolongs Graft Survival After Adoptive Transfer of Diabetogenic Splenocytes

Alexander, Angela; Crawford, Megan; Bertera, Suzanne; Rudert, William A.; Takikawa, Osamu; Robbins, Paul D.; Trucco, Massimo

doi:10.2337/diabetes.51.2.356

Cited by 192 publications

(162 citation statements)

References 44 publications

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“…In this way we tested the hypothesis that over-expression of IDO in donor cornea would extend allograft survival. Over-expression of IDO has been shown to increase survival of pancreatic islet allografts [17]. Furthermore, we and others have shown that dendritic cells transduced or transfected with the gene encoding IDO can inhibit allogeneic T cell responses, either inducing apoptosis in the T cells or rendering them anergic to the alloantigen [31,32].…”

Section: Discussionmentioning

confidence: 90%

“…A possible role for IDO in modulating the allogeneic response to a graft was first suggested when overexpression of IDO in donor pancreatic islets prior to transplantation extended survival in an animal model [17]. We examined the cornea for the presence of functionally active IDO, testing the hypothesis that IDO is involved in maintenance of relative immune privilege by contributing to allograft acceptance.…”

Section: Introductionmentioning

confidence: 99%

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Function of indoleamine 2,3‐dioxygenase in corneal allograft rejection and prolongation of allograft survival by over‐expression

et al. 2006

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Indoleamine 2,3-dioxygenase (IDO) suppresses T cell responses by its action in catabolising tryptophan. It is important in maintenance of immune privilege in the placenta. We investigated the activity of IDO in the cornea, following corneal transplantation and the effect of IDO over-expression in donor corneal endothelium on the survival of corneal allografts. IDO expression was analysed and functional activity was quantified in normal murine cornea and in corneas following transplantation as allografts. Low levels of IDO, at both mRNA and protein levels, was detected in the normal cornea, up-regulated by IFN-c and TNF. Expression of IDO in cornea was significantly increased following corneal transplantation. However, inhibition of IDO activity in vivo had no effect on graft survival. Following IDO cDNA transfer, murine corneal endothelial cells expressed functional IDO, which was effective at inhibiting allogeneic T cell proliferation. Over-expression of IDO in donor corneal allografts resulted in prolonged graft survival. While, on one hand, our data indicate that IDO may augment corneal immune privilege, up-regulated IDO activity following cytokine stimulation may serve to inhibit inflammatory cellular responses. While increasing IDO mRNA expression was found in allogeneic corneas at rejection, over-expression in donor cornea was found to significantly extend survival of allografts.

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Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Function of indoleamine 2,3‐dioxygenase in corneal allograft rejection and prolongation of allograft survival by over‐expression

et al. 2006

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“…They have also found that tryptophan catabolism prevents T cell-driven complement activation and inflammation during pregnancy (11), suggesting that IDO plays a key role in placenta immune privilege. IDOexpressing dendritic cells suppress allogeneic T cell proliferation in vitro by tryptophan metabolites (7) and IDO action attenuates allograft injury or rejection (12)(13)(14). Tryptophan catabolism also induces regulatory cells and is a means by which CTLA-4 signaling functions in vivo (15)(16)(17) while inhibiting IDO restores antitumor immunity (18).…”

Section: Suppression Of Memory Cd8 T Cell Generation Andmentioning

confidence: 99%

“…The recombinant adenoviral vector coding IDO gene (Ad-IDO, pBluescript) contains both murine IDO DNA gene and the fluorescent marker blue fluorescent protein as previously described (12). The control viral vector Ad-LacZ was purchased from Q-Biogene.…”

Section: Islet Infection With Adenoviral Vectorsmentioning

confidence: 99%

Suppression of Memory CD8 T Cell Generation and Function by Tryptophan Catabolism

Liu

Dai

et al. 2007

The Journal of Immunology

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Dendritic cell-derived indoleamine 2,3-dioxygenase (IDO) suppresses naive T cell proliferation and induces their apoptosis by catalyzing tryptophan, and hence is essential for the maintenance of peripheral tolerance. However, it is not known whether memory T cells are subject to the regulation by IDO-mediated tryptophan catabolism, as memory T cells respond more rapidly and vigorously than their naive counterparts and are resistant to conventional costimulatory blockade. In this study, we present the evidence that memory CD8+ T cells are susceptible to tryptophan catabolism mediated by IDO. We found that overexpression of IDO in vivo attenuated the generation of both central memory CD8+ T cells (TCM) and effector memory CD8+ T cells (TEM) while suppressing IDO activity promoted their generation. Moreover, IDO overexpression suppressed the effector function of TCM cells or TCM cell-mediated allograft rejection as well as their proliferation in vivo. Interestingly, TCM cells were resistant to apoptosis induced by tryptophan catabolism. However, IDO overexpression did not suppress the effector function of TEM cells or TEM cell-mediated allograft rejection, suggesting that TEM cells, unlike TCM cells, do not require tryptophan for their effector function once they are generated. This study provides insight into the mechanisms underlying the differential regulation of memory T cell responsiveness and has clinical implications for vaccination or tolerance induction.

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“…111 Presumably, the combination of all these mechanisms predispose the islets to environmental damage both during culture and at the transplantation site, where inflammation is likely to occur shortly after implant even before alloimmune response starts. Potential approaches to avoid this situation can include the perfusion of the organs with solutions containing chemical inhibitors of apopto- Immunoregulatory genes Indoleamine 2,3-dioxygenase 222 CTLA-4Ig 203 Fas ligand 209 (although in a number of reports Fas ligand was not protective: 248 ) Adenoviral E3 genes 210 Autoantigen transfer GAD 270 Others Adenovirus E3 proteins 271 Orally administered putative autoantigens (insulin, GAD) 272À274 CD152 275 Therapeutics for type I diabetes mellitus R Bottino et al sis (ZVAD-fmk) as well as antiapoptotic genes like bcl-2, bcl-xL, and enzymes that break down, or prevent, the formation of free-radicals such as catalase, thioredoxin, heme-oxigenase-1 and superoxide dismutase. [112][113][114][115][116][117] Some of these antiapoptotic proteins fused to protein-transduction domains can successfully prevent apoptosis and significantly improve islet yield and survival following isolation.…”

Section: Insulin Replacement Strategiesmentioning

confidence: 99%

Gene- and cell-based therapeutics for type I diabetes mellitus

et al. 2003

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Indoleamine 2,3-Dioxygenase Expression in Transplanted NOD Islets Prolongs Graft Survival After Adoptive Transfer of Diabetogenic Splenocytes

Cited by 192 publications

References 44 publications

Function of indoleamine 2,3‐dioxygenase in corneal allograft rejection and prolongation of allograft survival by over‐expression

Function of indoleamine 2,3‐dioxygenase in corneal allograft rejection and prolongation of allograft survival by over‐expression

Suppression of Memory CD8 T Cell Generation and Function by Tryptophan Catabolism

Gene- and cell-based therapeutics for type I diabetes mellitus

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