Purchase this article with an account.
SO Huq, Y Liu, B Illigens, Y Qian, G Benichou, MR Dana; Direct Pathway of Allosensitization Plays a Significant Role in High Risk Corneal Transplantation . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2275.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Purpose: In solid organ transplantation, sensitization of host T cells to alloantigens is known to occur via two major routes: the direct pathway mediated by graft-derived cells including passenger leukocytes, and the indirect pathway in which foreign antigens are processed and presented by host leukocytes. The purpose of this study was to characterize the routes of sensitization in high risk corneal transplantation. Method: Orthotopic keratoplasty was performed on BALB/c mice bearing either normal (avascular) or high risk (vascularized) beds using fully mismatched C57BL/6 donors. Leukocytes were harvested from recipient spleens and cervical lymph nodes of hosts at 72 hours and at two weeks. Host T cell responses to donor antigen presenting cells (direct pathway) or to host antigen presenting cells with sonicated donor antigens (indirect pathway) were assessed using the ELISPOT assay. Specifically, the frequency of activated T cells producing IL-2 and IFN-g (typical T-helper type 1 (TH-1)cytokines)was measured. Results: At 72 hours post transplantation, the proportion of directly sensitized T cells in the high risk beds was 20-fold higher than the proportion of indirectly sensitized cells as determined by IL-2 levels (p<0.05). IFN-g levels however did not rise significantly above background and did not vary significantly between the two groups at 72 hours. At two weeks, IL-2 levels did not significantly differ between the two groups; however, the levels of IFN-g produced by splenic derived directly primed T cells exceeded those produced by indirectly primed T cells by almost 300 fold (P<0.05). Lymph node derived T cells (both directly and indirectly primed) produced very high levels of IFN-g at two weeks post transplantation. Conclusion: In a high risk graft bed, T cell sensitization occurs as early as 72 hours and is primarily of the direct type. At two weeks, directly sensitized T cells continue to orchestrate Th1 type activity by dominating IFN-g production in the spleen. The indirect pathway, however, becomes operative by two weeks in the draining lymph nodes. The differences in the nature of the cytokines generated (IL-2 early vs. IFN-g late) may suggest that primed T cells produce principally proliferative signals at the early time points. The immuno-destructive events mediated by IFN-g manifest later (seen at the two week time point) and correlate with fulminant graft rejection noted clinically after two weeks in the murine model.
This PDF is available to Subscribers Only