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Indoleamine 2, 3-dioxygenase (IDO)-mediated regulation of tryptophan metabolism plays an important role in immune tolerance in transplantation, but it has not been elucidated which mechanism specifically induces the occurrence of immune tolerance. Our study revealed that IDO exerts immunosuppressive effects through two pathways in mouse heart transplantation, 'tryptophan depletion' and 'tryptophan metabolite accumulation'. The synergism between IDO + DC and TC (tryptophan catabolic products) has stronger inhibitory effects on T lymphocyte proliferation and mouse heart transplant rejection than the two intervention factors alone, and significantly prolong the survival time of donor-derived transplanted skin. This work demonstrates that the combination of IDO + DC and TC can induce immune tolerance to a greater extent, and reduce the rejection of transplanted organs., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: Immunomodulation by indoleamine 2,3-dioxygenase (IDO) has been documented in many studies yet its underlying mechanisms remain undefined, especially in solid organ transplantation. Recent research demonstrated that the active expression of IDO in dendritic cells (DCs) regulates immune reaction. This study assessed whether DCs transfected with IDO gene inhibit T cells responses and suppress cardiac allograft rejection., Methods: Adenovirus vector containing IDO gene was transfected into DCs to obtain IDO-positive DCs (IDO(+) DCs). To evaluate the effect of IDO(+) DCs on T cells in vitro, CD4(+) T cell proliferation and apoptosis was assessed in mixed lymphocyte reactions and measured by flow cytometry, respectively. IDO(+) DCs from C57BL/6 mice were injected into BALB/c recipients before heterotopic cardiac transplantation., Results: Supernatant fluids from cultures of IDO(+) DCs had decreased tryptophan and increased kynurenine levels, reflecting IDO activity. IDO(+) DCs suppressed CD4(+) T cell responses in vitro, as reflected by decreased proliferation and increased apoptosis. In the transplant model, IDO(+) DCs prolonged survival and alleviated rejection of cardiac allograft in recipients injected with IDO(+) DCs. In vivo, IDO(+) DCs also significantly impaired CD4(+) T cell responses promoting increased apoptosis and a Th2-dominant cytokine shift., Conclusions: IDO overexpression in DCs suppressed T cells alloresponses in vitro, and IDO(+) DCs attenuated acute allograft rejection in vivo. Regulation of tryptophan catabolism by means of IDO overexpression in DCs may be a useful approach in cardiac transplantation and immunological tolerance., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: To study the suppressive effect of indoleamine 2, 3-dioxygenase on transplantation rejection in mice heterotopic cardiac transplantation., Methods: Adenovirus vector containing IDO gene was used to infect donor (C57BL/6) DC to obtain IDO(+)DC. Mouse heterotopic cardiac transplantation models were established (C57BL/6-BALB/c) and the following groups were set up, including the control group, DC injection group, TC injection group, IDO(+)DC injection group and co-injection group of IDO(+)DC and TC, 12 donors and 12 recipients in each group.Survival time of the donor heart in every group was observed. Meanwhile, donor hearts were harvested 7 days post transplantation for different examinations, including pathological examination, mRNA expression of IDO through real-time PCR, IDO protein expression through Western blot. Peripheral blood of recipients was also harvested for CD3(+)T lymphocyte apoptosis rate examination through fluorescence-activated cell sorting.One-way ANOVA and Kaplan-Meier Survival Analysis were used for statistic analysis of IDO expression, CD3(+)T lymphocyte apoptosis rate and survival time of the donor heart respectively., Results: Cadiac allograft median survival time of each group were 7.0, 7.5, 11.0, 17.5, 24.0 days respectively. Compared with control and DC injection group, IDO(+)DC, TC and co-injection group significantly prolonged the survival time of donor hearts (t = 3.523-8.449, P < 0.01). Both IDO mRNA and protein expression showed significant increase(t = 5.974-16.176, P < 0.01). The CD3(+)T lymphocyte apoptosis rate was also significantly increased (t = 6.324-38.120, P < 0.01). Compared with IDO(+)DC or TC group alone, co-injection group significantly prolonged the survival time of the donor heart (t = 5.971 and 2.831, P < 0.05). Both IDO mRNA and protein expression showed significant increase (t = 2.853-15.194, P < 0.01).Furthermore, the CD3(+)T lymphocyte apoptosis rate was significantly increased as well (t = 26.069 and 7.643, P < 0.05)., Conclusions: Suppressive effect of co-injection of IDO(+)DC and TC is much more effective than administration of IDO(+)DC or TC alone, which suggests that IDO achieved immune suppressive effect through the pathway of tryptophan depletion and accumulation of TC.