Rejection - Professor Richard Kirk 2023

Professor Richard Kirk
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Rejection is an ever-present concern in post-transplant patients. It may occur if immunosuppression is inadequate. This may be due to an incidental illness preventing adequate absorption, altered metabolism e.g. prescription of a drug which increases the metabolism of calcineurin drugs by enhancing cytochrome P450 enzyme activity, an inflammatory illness causing upregulation of the immune system or nonadherence to the immunosuppression regime.
Graft Recognition
There are two main pathways by which donor HLA can be recognized by the recipient's immune system - the direct and indirect pathways:

The direct pathway is unique to transplantation. Recipient T cells (CD4+ or CD8+) recognise donor HLA glycoprotein on the donor APC that are passengers in the graft, leading to recipient T cell activation. This mechanism is only present for a short time after transplant until the demise of the donor APCs.

In the indirect pathway, recipient APCs present peptides or antigens derived from the donor HLA glycoprotein to recipient naïve T cells leading to their activation. These then differentiate either into T helper cells (CD4+) or cytotoxic T cells (CD8+). CD4+ cells differentiate and multiply and produce a variety of cytokines: Interferon and IL-2 promote the activation of CD8+, enhance macrophage cytotoxicity, and the synthesis of complement-fixing antibody. Other interleukins mainly trigger eosinophil activation and tumor necrosis factor which are involved in the inflammatory response.

Similarly recipient APCs present peptides or antigens derived from the donor HLA glycoprotein to B cells which, once assisted by T helper cells, leads to their activation, transition to plasma cells and the production of donor specific antibodies (DSAs).

At the time of transplant the ischemia-reperfusion injury will activate the innate system, causing graft inflammation and damage. Donor HLA will be expressed, and antigen presenting cells will present donor HLA to T & B cells which, despite induction and anti-rejection therapy, will become activated. Immunosuppression will reduce the likelihood of large clonal expansion, but it is unlikely to prevent T & B memory cells being formed. It can be assumed therefore that the immune system is primed in the peri-transplant period and that memory cells are formed to donor HLA.

can directly damage the graft or become Th+ cells which produce cytokines to activate further the inflammatory response and interact with memory B cells to produce short lived plasma cells which produce DSA to further fuel the graft damage. Endothelial damage allows the inflammatory reaction to breech the endothelial barrier and enter the myocardial interstitium leading to myocyte necrosis. This can be seen in the myocardial biopsy. Immunohistochemical staining using monoclonal antibodies directed at the various CD components of cell walls can identify the cell types in the biopsy. These will include both lymphocyte cell markers (CD3, CD4, CD19, CD20) and those of the innate system (CD68 on macrophages). Additionally activation of complement by antibodies can be assessed by staining for components of complement activation (e.g. C3d, C4d).
Authors: Richard Kirk, Nathanya Baez Hernandez
Updated: 20 June 2023
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