Abstract
Antigen-presenting cells (APCs) play an important role in transplant rejection and tolerance. In high-risk corneal transplantation, where the graft bed is inflamed and vascularized, immature APCs in the donor corneal stroma quickly mature and migrate to lymphoid tissues to sensitize host T cells. In this study, using a mouse model of corneal transplantation, we investigated whether enrichment of tolerogenic APCs (tolAPCs) in donor corneas can enhance graft survival in corneal allograft recipients with inflamed graft beds. Treatment of donor corneas with interleukin-10 (IL-10) and transforming growth factor-β1 (TGFβ1) altered the phenotype and function of tissue-residing APCs. Transplantation of these tolAPC-enriched corneas decreased frequencies of interferon gamma (IFNγ)+ effector T cells (Teffs), as well as allosensitization in the hosts, diminished graft infiltration of CD45+ and CD4+ cells, and significantly improved corneal allograft survival compared to saline-injected controls. These data provide a novel approach for tolAPC-based immunotherapy in transplantation by direct cytokine conditioning of the donor tissue.
Highlights
In high-risk corneal allograft recipients with inflamed and vascularized graft beds, corneal transplants have survival rates of 50% or lower even after treatment with corticosteroids
In a recent study we have shown that ex vivo treatment of donor-type bone marrow-derived dendritic cells (BMDCs) with immunomodulatory cytokines (IL-10, transforming growth factor-β1 (TGFβ1)) renders them tolerogenic, and when systemically transferred to corneal transplant recipients significantly improves allograft survival[19]
Real-time PCR analysis of corneas treated with IL-10 and TGFβ1 showed significantly increased IL-10, but decreased TNF-α mRNA expression compared to saline-treated corneas (Fig. 1B), suggesting a regulatory donor tissue microenvironment in the presence of such maturation-resistant tolerogenic APCs (tolAPCs)
Summary
In high-risk corneal allograft recipients with inflamed and vascularized graft beds, corneal transplants have survival rates of 50% or lower even after treatment with corticosteroids. Antigen-presenting cells (APCs) are sentinels of the immune system and principal mediators of the adaptive immune response They are known to play an important role in transplant rejection and tolerance; our laboratory has characterized different populations of resident immature bone marrow-derived cells in the corneal stroma, including dendritic cells (DCs) and macrophages[1,2,3]. In a recent study we have shown that ex vivo treatment of donor-type bone marrow-derived dendritic cells (BMDCs) with immunomodulatory cytokines (IL-10, TGFβ1) renders them tolerogenic, and when systemically transferred to corneal transplant recipients significantly improves allograft survival[19]. In our murine model of corneal transplantation we demonstrate that treatment of donor corneal buttons with IL-10 and TGFβ1 induces phenotypic and functional changes in tissue-resident APCs, rendering them tolerogenic and capable of suppressing allosensitization in high-risk allograft recipients that swiftly reject their corneal transplants
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