Glycemic control in diabetic donors promotes corneal graft survival in recipients

Abstract

Purpose : Diabetes mellitus (DM) is one of the most prevalent diseases globally, and its prevalence is projected to increase by >50% globally by 2050. Corneal transplantation is the most common form of tissue grafting, with ~85% survival rates. Several clinical studies have suggested that a history of DM in corneal donors could increase the risk of graft rejection. In this study, we evaluate the immune response in recipients of corneal grafts derived from insulin-treated vs. non-insulin treated diabetic donors.

Methods : Type-1(“insulin-dependent”) DM was induced in BALB/c mice using streptozotocin. Four weeks post-induction, hyperglycemia was controlled in half of the mice by treatment with sustained insulin release for 4 weeks. Subsequently, the corneas were transplanted in non-diabetic BALB/c mice. After 2 weeks, grafted corneas & draining lymph nodes(DLNs) were harvested for immunofluorescence, flow cytometry, or ELISPOT evaluation. In the remaining mice, the transplanted corneas were examined weekly for 8 weeks & graded per a standard opacity grading system.

Results : CEnC remained unchanged in grafts derived from insulin-treated & non-treated diabetic mice compared to non-diabetic controls. The frequency of antigen-presenting cells(APCs) was significantly higher in corneas derived from insulin-treated(p=0.044) & untreated(p=0.015) diabetic mice compared to non-diabetic mice; however, the APC frequencies were comparable between the insulin-treated & non-treated mice (p=0.10). APC maturation, measured by MHC-II(p=0.048), CD86(p=0.019) & CCR7(p=0.024), were significantly lower in insulin-treated compared to non-treated(p=0.02) mice. Additionally, the expression of IL-1β(p=0.034), IL-6(p=0.001) & IL-12(p=0.029) were significantly lower in corneas harvested from insulin-treated mice compared to non-treated diabetic mice. The sensitization of naïve T-cells by migratory APCs resulted in a significantly higher frequency of IFN-γ⁺ CD4⁺ T cells in the recipient DLNs with grafts derived from insulin untreated mice compared to insulin treated mice (p=0.013). Finally, grafts from insulin treated mice showed a significantly higher survival rate than those from non-treated donors (60%vs.0%,p<0.0001).

Conclusions : This study evaluates the immunological response in hosts transplanted with corneal tissue derived from diabetic donors & underlines the deleterious effect of uncontrolled hyperglycemia in donors on corneal graft survival.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.