Indoleamine 2,3-dioxygenase (IDO) can promote tryptophan metabolism to kynurenine and modulate regulatory T cells (Tregs), thereby maintains lower efficiency to induce tolerance. Our aim is to investigate the mechanism of tolerance induction by a IDO metabolite named Immutol.
Methods: We established rat heterotopic heart transplantation models and treated them with Immutol, cyclosporine A (CsA) and 1-methyl-DL-tryptophan (1-MT) in vivo. The drugs were administered via gavage to all but the control group one day before surgery. CsA was gavaged continually for 20 days and Immutol for 60 days; after withdrawal of the drugs, the recipients were observed for at least 10 months. Immune cells were analyzed by flow cytometry. The IDO signaling pathway was evaluated by Western blotting, RT-PCR and immunochemical staining. Enzyme-linked immunosorbent assays (ELISAs) were used to detect changes in cytokines.
Results: CsA or Immutol alone prolonged survival but did not induce tolerance after withdrawal. Immutol+CsA inhibited acute rejection, and the grafts survived more than 400 d, with tolerance detected in most rats (13/15). Increased protein IDO and kynurenine could regulate the accumulation of CD4+Tregs, CD8+Tregs and pDC to induce immune tolerance. I-MT specifically blocked IDO, weakened the expression of IDO and kynurenine, and produced grafts rejection. Additionally, Tregs could down-regulate immune responses through production of the immunosuppressive cytokines IL-10 and TGF-beta, thus induce immune tolerance. CD8+ Tregs produce IFN-γ, and tolerance is dependent on both IFN-γ and IDO.
Conclusion: Immutol combined with CsA can control acute rejection and induce tolerance in rats with cardiac allografts after withdrawal. Immutol may become a novel drug for future clinical use.
Keywords: 1-Methyl-DL-tryptophan; Heart transplantation; Immune tolerance; Immutol; Indoleamine 2,3-dioxygenase.
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