Fig. 15.48 Acute rejection of a kidney graft through the direct pathway of allorecognition. Donor dendritic cells in the graft (in this case a kidney) carry complexes of donor HLA molecules and donor peptides on their surfaces. The dendritic cells are carried via the blood to secondary lymphoid organs (a lymph node is illustrated here), where they move to the T‑cell areas. Here, they activate the recipient’s T lymphocytes, whose receptors can bind specifically to the complexes of allogeneic donor HLA (both class I and class II) in combination with donor peptides. After activation, the effector T cells travel in the blood to the grafted organ, where they attack cells that display the peptide:HLA molecule complexes for which the T cells are specific.
blood, not lymphatics. The activated alloreactive effector T cells can then circulate to the graft, which they attack directly (Fig. 15.48). This recognition pathway is known as direct allorecognition (Fig. 15.49, upper panel). Indeed, if the grafted tissue is depleted of antigen-presenting cells by treatment with antibodies or by prolonged incubation, rejection occurs only after a much longer time.
A second mechanism of allograft recognition leading to graft rejection is the uptake of allogeneic proteins by the recipient’s own antigen-presenting cells and their presentation to T cells by self MHC molecules. This is known as indirect allorecognition (see Fig. 15.49, lower panel). Peptides derived from both the foreign MHC molecules themselves and minor histocompatibility antigens can be presented by indirect allorecognition.
Direct allorecognition is thought to be largely responsible for acute rejection, especially when MHC mismatches mean that the frequency of directly alloreactive recipient T cells is high. Furthermore, a direct cytotoxic T-cell attack on graft cells can be made only by T cells that recognize the graft MHC molecules directly. Nonetheless, T cells with specificity for alloantigens presented on self MHC can contribute to graft rejection by activating macrophages, which cause tissue injury and fibrosis. T cells with indirect allospecificity are also likely to be important in the development of an antibody response to a graft. Antibodies produced against nonself antigens from the same species are known as alloantibodies.
Fig. 15.49 Direct and indirect pathways of allorecognition contribute to graft rejection. Dendritic cells from an organ graft stimulate both the direct and indirect pathways of allorecognition when they travel from the graft to secondary lymphoid tissues. The upper panel shows how the allogeneic HLA class I and II allotypes of donor type on a donor dendritic cell (donor DC) will interact directly with the T‑cell receptors of alloreactive CD4 and CD8 T cells of the recipient (direct allorecognition). The lower panel shows how the death of the same antigen‑presenting cell produces membrane vesicles containing the allogeneic HLA class I and II allotypes, which are then endocytosed by the recipient’s dendritic cells (recipient DC). Peptides derived from the donor’s HLA molecules (yellow) can then be presented by the recipient’s HLA molecules (orange) to peptide‑specific T cells (indirect allorecognition). Presentation by HLA class II molecules to CD4 T cells is shown here. Peptides derived from donor HLA can also be presented by recipient HLA class I molecules to CD8 T cells (not shown).
Graft failure dead graft Antibodies against donor blood group antigens bind vascular endothelium of graft, initiating an in˜ammatory response that occludes blood vessels Graft becomes engorged and purple-colored because of hemorrhage