Transplant Rejection: T-Cell Mediated

T-cell mediated rejection (TCMR), also called acute cellular rejection, is the most common form of allograft rejection, driven by recipient T-lymphocyte recognition of donor major histocompatibility complex (MHC) antigens (HLA molecules) on transplanted tissue. Recognition occurs through two pathways: the direct pathway (recipient T-cells directly recognize intact donor MHC molecules on donor antigen-presenting cells — predominant in early post-transplant period) and the indirect pathway (recipient APCs process and present donor MHC peptide fragments to recipient T-cells — predominant in chronic rejection). Upon allorecognition, naive CD4+ T-helper cells differentiate into Th1 cells that secrete IL-2 and IFN-gamma, activating CD8+ cytotoxic T-lymphocytes (CTLs) and macrophages. CTLs infiltrate the graft and destroy donor cells through perforin-granzyme and Fas-FasL pathways, while activated macrophages cause delayed-type hypersensitivity responses with tissue inflammation and damage. Calcineurin inhibitors (tacrolimus, cyclosporine) block T-cell activation by inhibiting the calcineurin-NFAT signaling pathway required for IL-2 transcription, which is why they are the cornerstone of maintenance immunosuppression. TCMR is classified histologically by the Banff classification: borderline (suspicious), Grade IA/IB (tubulointerstitial), Grade IIA/IIB (vascular — more severe), and Grade III (transmural arteritis —...