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BM W Illigens, NG Anosova, E Fedoseyeva, G Benichou; The Role of Immune Privilege in the Induction of CD4+ T Cell Direct and Indirect Responses to Allotransplants . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2276.
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The immune rejection of allogeneic transplants is initiated and orchestrated by recipient CD4+ T cells. Alloantigen recognition by CD4+ T cells occurs via two distinct mechanisms referred to as the direct and indirect pathways. The direct alloresponse results from the stimulation of T cells by intact allogeneic MHC molecules displayed on donor cells. This response is dictated by the migration of donor "passenger leukocytes" out of the graft to the host's lymphoid tissues. Additionally, it is known that donor antigens are presented in peptide form during acute graft rejection. The T cell recognition of processed alloantigens in association with self-MHC molecules at the surface of recipient APCs has been called indirect allorecognition. We have recently shown that fully allogeneic retinal grafts placed in the vitreous cavity and subretinal space of a recipient mouse eye induce potent direct CD4+ T cell alloresponses (N. Anosova et al. J. Clin. Invest. 108:1175, 2001). In addition, we provided direct evidence showing that this alloresponse contributed to accelerated deterioration of retinal allotransplants. We, however, never detected any indirect alloresponse in this model. Purpose: Here, we investigated whether absence of indirect alloreactivity after retinal allotransplantation in the vitreous cavity was due to the immune privileged status of the eye or of the transplanted tissue. Methods: To address this, we injected allogeneic splenocytes (nonimmune-privileged tissue) in the vitreous cavity (immune-privileged site) of a recipient eye. Ten days later, T cells from recipient draining lymph nodes (submandibular) and spleen were isolated and tested for direct and indirect alloreactivity using an ELISPOT assay. Results: Potent direct and indirect CD4+ T cell-mediated alloresponses were detected. Next, retinal allografts were placed under the skin (nonimmune-privileged site) of recipient mice. Vigorous direct and indirect alloresponses were found in these grafted mice. Conclusion: Taken together, these results show that absence of indirect alloreactivity in retinal-transplanted mice is due to the concomitant poor immunogenicity of the retina and the immune-privileged nature of the vitreous cavity of the eye.
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