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S.O. Huq, B. Illigens, G. Benichou, M.R. Dana; Direct Pathway of Allosensitization- A Critical Pathway of Graft Rejection in High Risk Corneal Transplantation . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3211.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: In solid organ transplantation, sensitization of host T cells to donor antigens is known to occur via two major routes: the direct pathway mediated by graft-derived cells including ‘passenger leukocytes' that migrate out of the graft shortly after transplantation, and the indirect pathway in which foreign antigens are processed and presented by host antigen-presenting cells (APC). Previously, the indirect pathway was thought to be essentially the sole route of allosensitization in corneal transplantation. Methods: Orthotopic keratoplasty was performed on BALB/c mice bearing either normal (avascular; low risk [LR]) or high risk (HR) (vascularized) beds using fully mismatched C57BL/6 donors. Lymphocytes were harvested from recipient animals' cervical lymph nodes of hosts at 72 hours and at two weeks post surgery. Host T cell responses to donor APC (direct pathway) were assessed using the ELISPOT assay. The frequencies of activated T cells producing IL-2 and IFN-g (T-helper 1 [Th1] cytokines) were measured. Graft survival was assessed in HR transplant recipients where the direct pathway was inactivated by using class II major histocompatibility antigen (MHC) knock out animals as donors. Results: Directly sensitized T cells were detected in HR transplant recipients as early as 72 hours post transplantation (determined by IL-2 production in the ELISPOT assay). At two weeks post transplantation, T-cells obtained from HR graft recipients continued to produce a strong Th1 direct response by generating both IL-2 and IFN-g. In the LR transplantation setting, no directly primed T-cells were detected. Finally, eliminating the direct pathway in HR transplantation significantly slowed both the tempo and rate of rejection. Conclusions: In a HR graft bed, directly sensitized T cells are generated as early as 72 hours. At two weeks, directly sensitized T cells continue to orchestrate Th1 type activity by generating IFN-g production. Elimination of the direct response in the HR transplantation setting ameliorates the tempo of graft rejection and improves graft survival. This, taken with the finding that almost no directly primed T-cells are generated in LR graft recipients suggests that the fulminant rejection noted in high risk transplantation is, at least in part, due to the activation of the direct pathway.
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