Effect of sCD83 on direct allosensitization after corneal transplantation

Abstract

Purpose : Immune-mediated graft rejections remain the most common cause for graft failure after organ and tissue transplantation. There is a great unmet medical need for pharmacologic strategies to promote graft survival without unduly compromising the health of the recipient. Recently, our group showed that pre-treatment of the corneal donor tissue with sCD83 improves graft survival. Here, we further elucidate the mode of action of pre-treatment of corneal donor tissue and determine the effect of sCD83 on direct allosensitization after corneal transplantation.

Methods : A murine model of high-risk corneal transplantation with C57BL/6N mice as donor and BALB/c mice as recipients was used. Corneal grafts were pre-incubated with sCD83 for 48 h. Excessive sCD83 was removed prior to transplantation by alternating incubation in hydrating and dehydrating medium (removal strategy). Corneal sCD83 content was assessed by immunoblotting and immunohistochemistry. Long-term allograft survival was determined by grading the graft opacity weekly for eight weeks. Moreover, the inflammatory phenotype of dendritic cells (DCs) and macrophages (Mφ) in the draining lymph nodes (dLNs) of the recipient was analyzed by flow cytometry eight weeks post transplantation.

Results : Applying the removal strategy to pre-incubated donor corneas resulted in a strong decrease of sCD83 in the stroma whereas sCD83 was still co-localized with immune cells of the donor cornea. Subsequent transplantation of those grafts into high-risk recipient beds improved long-term graft survival. Moreover, the frequencies of both regulatory DCs (CD11c⁺MHCII⁺CD200R⁺) as well as Mφ (F4/80⁺CD200R⁺) were significantly increased in dLNs of mice that received sCD83-modulated grafts.

Conclusions : This study demonstrates that sCD83-induced corneal graft tolerance can be mediated directly by immune cells of the donor tissue and thereby modulates direct allosensitization in corneal transplantation. Thus, targeting the initial alloimmune response can already improve the long-term outcome. This new pharmacologic strategy of "direct allotolerance" could be a seeding point for novel therapeutic approaches in which pre-treatment of grafts with sCD83 could induce tolerance to the donor tissue and avoid lifelong immunosuppressive treatment of the patient.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.