Treatment of donor corneal tissue with immunomodulatory cytokines: a novel strategy to promote graft survival in high-risk corneal transplantation

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.

Identification and characterization of dendritic cell subtypes in preserved and cultured cadaveric human corneolimbal tissue on amniotic membrane

“…Depending on the DC lineage (myeloid or lymphoid) and activation signals from the surrounding microenvironment, mature DC can activate different types of T cell‐mediated immune responses (Tahvildari et al. ). There are two developmental lineages of DCs: myeloid and lymphoid, with different biological properties.…”

Regulatory T cells promote corneal endothelial cell survival following transplantation via interleukin-10

“…[43][44][45][46] For the low-risk model, C57BL/6 donor corneas were grafted onto normal BALB/c host beds. [43][44][45][46] For the low-risk model, C57BL/6 donor corneas were grafted onto normal BALB/c host beds.…”

“…Two well-established models of allogeneic corneal transplantation were used, as described previously. [43][44][45][46] For the low-risk model, C57BL/6 donor corneas were grafted onto normal BALB/c host beds. For the high-risk model, 3 intrastromal 11-0 sutures were placed in the central cornea of BALB/c recipient mice 14 days prior to transplantation to induce an inflamed and vascularized host bed.…”

“…A standard protocol for murine orthotopic corneal transplantation was followed, as described previously. [43][44][45][46] Briefly, a 2-mm central corneal button was excised from donor C57BL/6 mice, grafted onto a 1.5-mm BALB/c recipient bed, and secured with 8 interrupted 11-0 nylon sutures. All procedures were performed with mice under anesthesia with intraperitoneal injection of ketamine (120 mg/kg) and xylazine (20 mg/kg).…”

Regulatory T Cell Modulation of Cytokine and Cellular Networks in Corneal Graft Rejection

“…Our group has previously demonstrated that systemic transfer of these cells to corneal transplant recipients result in increased frequencies of Tregs and Foxp3 expression in draining LNs and significantly improves allograft survival. In another study we have also demonstrated that treatment of donor corneal buttons with IL-10 and TGF-β1 induces phenotypic and functional changes in tissue-resident APCs, rendering them tolerogenic and capable of suppressing allosensitization in high-risk allograft recipients [111]. It has been previously shown that the beneficial effect of tolAPCs on corneal graft survival is mediated through expansion of CTLA-4 expressing Tregs [112].…”