Differential Roles of Direct and Indirect Allorecognition Pathways in the Rejection of Skin and Corneal Transplants

Background It is generally accepted that all transplants are not rejected in the same fashion. However, the extrinsic and intrinsic factors that control the recognition and rejection of a particular allograft by the host are not well characterized. Methods We compared the mechanisms underlying the response to donor antigens by T cells activated after transplantation of fully allogeneic skin and corneal grafts in mice. Results In corneal-transplanted mice, the CD4+ T cell response was exclusively mediated by T cells recognizing minor antigens in an indirect fashion and producing low levels of IL-2. In contrast, skin grafts elicited both direct and indirect CD4+ T cell responses primarily directed to MHC antigens and characterized by high IL-2 levels. While CD8+ T cells producing γIFN were activated directly in both skin- and corneal-grafted mice, only CD8+ T cells from skin-transplanted mice mounted a cytotoxic response. Next, we investigated whether failure of corneal transplants to induce a CD4+ direct alloresponse is due to their poor immunogenicity or to the site of placement (eye). We observed that corneas transplanted under the skin as well as splenocytes transplanted in the eye were both capable of inducing direct CD4+ T cell alloreactivity. Conclusions This shows that, failure of orthotopic corneal allotransplants to elicit a CD4+ T cell direct alloresponse is associated with the combination of two factors, their low immunogenicity and the immune-privileged properties of the eye

Enterobacterial infection modulates major histocompatibility complex class I expression on mononuclear cells

Major histocompatibility complex (MHC) class I expression is reduced in several viral infections, but it is not known whether the same happens during infections caused by intracellular enterobacteria. In this study, the expression of MHC class I antigens on peripheral blood mononuclear cells (PBMC) from 16 patients with Salmonella, Yersinia, or Klebsiella infection was investigated. During or after the acute infection, the expression of MHC class I antigens was markedly decreased in eight patients, all with genotype HLA-B27, and six out of eight with reactive arthritis (ReA). A significant decrease of monomorphic MHC class I was found in three patients, of HLA-B27 in eight (P < 0·05) and of HLA-A2 in two. However, patients negative for the HLA-B27 genotype, or healthy HLA-B27-positive individuals, did not have a significant decrease of MHC class I antigens. During the decreased expression on the cell surface, intracellular retention of MHC class I antigens was observed, whereas HLA-B27 mRNA levels did not vary significantly. This is the first evidence that enterobacterial infection may down-regulate expression of MHC class I molecules in vivo and that down-regulation is predominant in patients with the HLA-B27 genotype

The role of CD8+ T cells during allograft rejection

Organ transplantation can be considered as replacement therapy for patients with end-stage organ failure. The percent of one-year allograft survival has increased due, among other factors, to a better understanding of the rejection process and new immunosuppressive drugs. Immunosuppressive therapy used in transplantation prevents activation and proliferation of alloreactive T lymphocytes, although not fully preventing chronic rejection. Recognition by recipient T cells of alloantigens expressed by donor tissues initiates immune destruction of allogeneic transplants. However, there is controversy concerning the relative contribution of CD4+ and CD8+ T cells to allograft rejection. Some animal models indicate that there is an absolute requirement for CD4+ T cells in allogeneic rejection, whereas in others CD4-depleted mice reject certain types of allografts. Moreover, there is evidence that CD8+ T cells are more resistant to immunotherapy and tolerance induction protocols. An intense focal infiltration of mainly CD8+CTLA4+ T lymphocytes during kidney rejection has been described in patients. This suggests that CD8+ T cells could escape from immunosuppression and participate in the rejection process. Our group is primarily interested in the immune mechanisms involved in allograft rejection. Thus, we believe that a better understanding of the role of CD8+ T cells in allograft rejection could indicate new targets for immunotherapy in transplantation. Therefore, the objective of the present review was to focus on the role of the CD8+ T cell population in the rejection of allogeneic tissue