Transplant rejection

Transplant rejection is the immune attack on a graft, classified as hyperacute, acute (T-cell-mediated and antibody-mediated), or chronic.

Reviewed by Independent editorial compilation on June 23, 2026Educational reference, not medical advice

Transplant rejection is the immune-mediated injury of a transplanted organ or tissue (the allograft) by the recipient's immune system, which recognizes donor human leukocyte antigens (HLA) and other molecules as foreign.[1][2] Rejection is the principal immunologic obstacle to successful transplantation and the reason recipients of solid-organ allografts require lifelong immunosuppression.[1][3] Rejection is classified by timing and mechanism into hyperacute rejection, acute rejection (subdivided into T-cell-mediated rejection [TCMR] and antibody-mediated rejection [AMR/ABMR]), and chronic rejection.[1][2][3] In kidney and several other organs, the histologic diagnosis and grading of rejection are standardized by the internationally maintained Banff classification.[4][5]

Immunologic basis

The transplanted graft expresses HLA molecules (and minor histocompatibility and non-HLA antigens) that differ from the recipient's.[1][6] The recipient's immune system can recognize these as foreign through two principal pathways: the direct pathway, in which recipient T cells recognize intact donor HLA on donor antigen-presenting cells, and the indirect pathway, in which recipient antigen-presenting cells process donor antigens and present them to recipient T cells.[1][6] T-cell activation drives cellular rejection, while B-cell help and differentiation into plasma cells generate donor-specific antibodies (DSA) that mediate humoral (antibody-mediated) rejection.[1][6] The degree of HLA mismatch and the recipient's prior sensitization to HLA (from pregnancy, transfusion, or a prior transplant) are major determinants of rejection risk.[6][7] See Transplant immunology.

Hyperacute rejection

Hyperacute rejection occurs within minutes to hours of reperfusion and is caused by preformed circulating antibody against the donor, most often preformed anti-HLA DSA or, historically, anti-ABO isohemagglutinins in an ABO-incompatible graft.[2][3] These antibodies bind graft vascular endothelium, activate complement, and trigger rapid thrombosis, hemorrhage, and irreversible ischemic necrosis of the graft.[2][3] Hyperacute rejection is essentially untreatable once it occurs and results in graft loss.[2] It has become rare because it is largely preventable: routine pre-transplant ABO matching and the crossmatch (complement-dependent cytotoxicity, flow cytometric, or virtual) are designed to detect the preformed antibodies that cause it.[2][3][7] See ABO compatibility and Panel-reactive antibody / cPRA and sensitization.

Acute rejection

Acute rejection typically presents in the first days to months after transplantation, though it can occur at any time, particularly with inadequate immunosuppression or non-adherence.[2][3] It is divided by mechanism into T-cell-mediated and antibody-mediated rejection, which may also coexist.[2][3] Acute rejection is often clinically silent and detected by a rise in organ-specific markers (for example, serum creatinine in a kidney) or on protocol or for-cause biopsy; definitive diagnosis is histologic.[2][4]

Acute T-cell-mediated rejection (TCMR)

T-cell-mediated rejection (cellular rejection) is driven by recipient T lymphocytes that infiltrate the graft.[2][3] In the kidney, the Banff classification characterizes TCMR by tubulitis (lymphocytes within tubular epithelium) and interstitial inflammation, with more severe grades defined by intimal or transmural arteritis (endothelialitis of graft arteries).[2][4] TCMR is generally responsive to treatment; first-line therapy is typically high-dose corticosteroids, with T-cell-depleting antibody (such as antithymocyte globulin) reserved for steroid-resistant or vascular (higher-grade) rejection.[2][3] Treatment decisions are individualized clinical determinations.

Acute antibody-mediated rejection (AMR/ABMR)

Antibody-mediated rejection is driven by DSA acting on the graft microvascular endothelium.[2][5][8] Its diagnosis in the kidney has historically rested on a triad: (1) histologic evidence of acute tissue injury, characteristically microvascular inflammation (glomerulitis and peritubular capillaritis); (2) evidence of current or recent antibody interaction with the endothelium, classically C4d deposition in peritubular capillaries (a complement split product marking antibody-triggered classical-pathway activation) or, in its absence, validated molecular/transcript evidence; and (3) the presence of DSA.[5][8] C4d staining is therefore a key immunopathologic marker of AMR, although C4d-negative AMR is recognized when microvascular inflammation and DSA are present.[5][8] Treatment of AMR is less standardized and less effective than for TCMR, and commonly combines antibody removal (plasmapheresis), intravenous immunoglobulin, and B-cell-, plasma-cell-, or complement-directed agents.[2][8] See Donor-specific antibodies (DSA).

Chronic rejection

Chronic rejection (chronic allograft injury) develops over months to years and is a leading cause of late graft loss.[2][3][9] It represents slowly progressive, often irreversible structural injury arising from sustained immunologic (and non-immunologic) insults, with persistent or recurrent DSA and indolent antibody-mediated injury frequently implicated.[3][9] Its pathology is organ-specific: chronic active antibody-mediated rejection in the kidney is marked by transplant glomerulopathy and peritubular capillary basement-membrane multilayering; the heart develops cardiac allograft vasculopathy; the lung develops chronic lung allograft dysfunction (CLAD), including bronchiolitis obliterans syndrome; and the liver may develop ductopenia (vanishing bile duct syndrome).[2][3][9] Chronic rejection responds poorly to current therapy, so prevention, through adequate immunosuppression, adherence, and limiting HLA mismatch and DSA formation, is emphasized.[3][9]

The Banff classification

The Banff classification of allograft pathology is the international consensus system, first established in 1991 and periodically revised at the Banff meetings, that standardizes the histologic diagnosis and grading of rejection.[4][5] It uses defined lesion scores (for example, in the kidney: interstitial inflammation [i], tubulitis [t], glomerulitis [g], peritubular capillaritis [ptc], intimal arteritis [v], and C4d) to assign diagnostic categories including TCMR, AMR, and chronic active forms.[4][5] The Banff 2022 Kidney Meeting Report reappraised the role of microvascular inflammation and biopsy-based transcript (molecular) diagnostics, introducing the entities "probable antibody-mediated rejection" and "microvascular inflammation, DSA-negative and C4d-negative."[5] Banff criteria are versioned and evolve; the current version should be confirmed at the time of clinical use.[4][5]

Diagnosis and surveillance

Because acute rejection is frequently asymptomatic, programs monitor graft function with organ-specific laboratory markers and imaging, perform for-cause biopsy when dysfunction is detected, and in some programs perform protocol (surveillance) biopsy at predefined intervals.[2][4] Endomyocardial biopsy is the traditional standard for heart-allograft surveillance.[3] Emerging non-invasive markers, including donor-derived cell-free DNA and gene-expression profiling, are used in some settings to risk-stratify and reduce biopsies, though biopsy remains the diagnostic reference.[2][5] DSA monitoring complements histology in assessing antibody-mediated risk.[8] See Donor-specific antibodies (DSA).

References

Justiz Vargas AN, Sharma S, et al. Transplantation Immunology. StatPearls. NBK538218. https://www.ncbi.nlm.nih.gov/books/NBK538218/
Naik RH, Ali S, Hassanein M, Shawar SH. Acute Renal Transplantation Rejection. StatPearls. NBK553074. https://www.ncbi.nlm.nih.gov/books/NBK553074/
Acute Transplantation Rejection. StatPearls. NBK535410. https://www.ncbi.nlm.nih.gov/books/NBK535410/
Roufosse C, Simmonds N, Clahsen-van Groningen M, et al. A 2018 Reference Guide to the Banff Classification of Renal Allograft Pathology. Transplantation. 2018;102(11):1795-1814. PMID:30028786. https://pubmed.ncbi.nlm.nih.gov/30028786/
Naesens M, Roufosse C, Haas M, et al. The Banff 2022 Kidney Meeting Report: Reappraisal of microvascular inflammation and the role of biopsy-based transcript diagnostics. Am J Transplant. 2024;24(3):338-349. PMID:37931897. https://pubmed.ncbi.nlm.nih.gov/37931897/
Ingulli E. Mechanism of cellular rejection in transplantation. Pediatr Nephrol. 2010;25(1):61-74. PMID:21476023. https://pmc.ncbi.nlm.nih.gov/articles/PMC2778785/
Tait BD, Süsal C, Gebel HM, et al. Consensus guidelines on the testing and clinical management issues associated with HLA and non-HLA antibodies in transplantation. Transplantation. 2013;95(1):19-47. PMID:23238534. https://pubmed.ncbi.nlm.nih.gov/23238534/
Loupy A, Haas M, Roufosse C, et al. The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection. Am J Transplant. 2020;20(9):2318-2331. PMID:32463180. https://pubmed.ncbi.nlm.nih.gov/32463180/
Chronic Transplantation Rejection. StatPearls. NBK535435. https://www.ncbi.nlm.nih.gov/books/NBK535435/

This article is an educational reference for the donation and transplant workforce and the public. It is not medical advice, and it does not replace institutional policy, OPTN policy, or clinical judgment.

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