The two pathways of allorecognition are the Direct and Indirect Pathways. The Direct Pathway involves intact donor MHC presenting peptide directly to host T cells whilst the Indirect Pathway refers to the presentation of donor MHC to host T cells as processed peptides loaded onto host MHC molecules.
In the Direct Pathway, following kidney transplantation, donor derived dendritic cells, triggered into maturation by the transplant Ischemic and Reperfusion Injury (IRI) as well as locally released pro-inflammatory cytokines, migrate from the kidney to the recipient lymphoid organs where they stimulate the host immune response by presenting host and donor MHC derived peptides loaded into intact donor dendritic cell MHC, to host T cells. This Direct Pathway of allorecognition is the main route for stimulating of the acute phase of the alloimmune response. In the normal immune response, only a small proportion (less than 0.1%) of host T cells will be specific for a given MHC-peptide complex, however in the alloimmune response, a high number of T cells (approximately 10%) react to the allogeneic MHC-peptide complex leading to a strong alloimmune response. Indeed depletion from the graft of donor dendritic cells prior to transplantation has been shown to lead to graft tolerance or at least a reduction in acute rejection.
In the Indirect Pathway, host dendritic cells which infiltrate the graft as part of the post transplant inflammatory process have their MHC loaded with donor peptides derived from the take up and processing of donor MHC. Following migration to the lymphoid organs, these MHC-peptide complexes are presented to host T cells. This indirect pathway is similar to the process by which antigen is presented to T cells in the normal immune response and involves a smaller number of T cells than the direct response.
A number of studies have indicated that T cell alloimmune response elicited by the Direct Pathway decreases with time post transplant whilst the T cell alloimmune response elicited via the Indirect Pathway which can also be initiated in the acute phase, sustains and contributes to chronic rejection. A third pathway the Semi-Direct Pathway of allorecognition has been described in which host antigen presenting cells acquire intact MHC molecules from donor cells thus allowing direct presentation to host T cells. This pathway may contribute to sustaining the alloimmune response.
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