Graft Rejection: The Basics


Organ failure results in major human morbidity and economic burden. Quality of life and life expectancy are optimised with organ transplantation, usually occurring across histocompatibility barriers. The molecular mechanisms of graft rejection are based on recognition of foreign transplanted cells or tissues by the expression of polymorphic, codominant genes coded by the major histocompatibility complex (MHC) of human leukocyte antigens (HLA) or genes on chromosome 6 by recipient T cells and by the generation of donor‐specific antibodies to HLA and other donor‐specific immunogenic antigens. Advances in histocompatibility and immunosuppression have improved short‐term graft and patient survival rates, but rates of accelerated graft loss due to humoral alloimmunity have remained largely unchanged.

Key Concepts

  • In the ‘direct’ pathway of antigen presentation, MHC molecules on donor APCs from the graft tissue present graft‐derived peptides to host T cells.
  • In the ‘indirect’ pathway of antigen presentation, host APCs take up graft antigens and present donor‐derived processed peptides on host MHC molecules to host T cells.
  • HLA antibodies and endothelial cell activation are important regulators of immunogenicity, recruiting leukocytes to the site of inflammation.
  • Acute rejection can be classified by presentation into hyperacute (occurring within minutes), acute (occurring within days to weeks), late acute (occurring after 3 months) or chronic (occurring months to years after transplantation).
  • Acute rejection can be classified according to pathophysiological changes (cellular‐interstitial, vascular, antibody‐endothelial) or underlying immunologic mechanisms (adaptive or innate immune injury) or severity (histologic injury graded by the Banff schema).
  • Acute rejection can be clinical or subclinical (based on the presence or absence of associated renal dysfunction).
  • Acute rejection can be treatment resistant or sensitive (based on clinical and histologic resolution of diagnostic histology 4–6 weeks after treatment intensification).

Keywords: alloantibodies; allograft; antigen‐presenting cells; autograft; chronic rejection; cytokines; endothelial cells; hyperacute rejection; immunosuppression; inflammation; major histocompatibility complex; T cells; transplantation; xenograft

Figure 1. Histopathology of hyperacute rejection in human renal allografts: microscopic view (original magnification ×160) of a glomerulus in a biopsy taken from a human renal allograft that experienced hyperacute rejection. Tissue sections of the fixed biopsy specimen were stained with haematoxylin and eosin to reveal morphology. Note that most of the capillaries in the glomerulus are occluded with light pink thrombus (T). Some darker‐staining red blood cells are also present. In addition, polymorphonuclear leucocytes (P) can be found within the glomerular tissues. In normal kidneys, the capillaries of the glomerulus have clear nonoccluded lumens, and no polymorphonuclear neutrophils are present.
Figure 2. Histopathology of acute rejection in human renal allografts: microscopic view (original magnification ×160) of renal tubules in a biopsy taken from a human renal allograft that experienced acute rejection. Tissue sections of the fixed biopsy specimen were stained with periodic acid–Schiff to reveal morphology. Note that the tubules (T), each of which is surrounded by a red band of basement matrix, are widely separated by large numbers of infiltrating leucocytes (infiltrated regions indicated by stars), each containing a dark blue nucleus. The small white arrows identify leucocytes that have invaded the renal tubule, resulting in the tubulitis that is diagnostic for acute renal allograft rejection. In normal kidneys, there is no leucocytic infiltration and the renal tubules are juxtaposed to one another.
Figure 3. Histopathology of chronic rejection in human renal allografts: microscopic view (original magnification ×80) of a large artery in a biopsy taken from a human renal allograft that experienced chronic rejection. Tissue sections of the fixed biopsy specimen were stained with haematoxylin and eosin to reveal morphology. Note that the central lumen (L) is quite small. At the time of transplantation, the lumen occupied a space that began just inside the internal elastic lamina (E). The material that now occupies this space (the tissue between paired, opposing, black arrows) is neointima (N). This neointima, which is a diagnostic feature of chronic rejection, is composed of several cell types (blue nuclei) imbedded in large amounts of extracellular matrix.
Figure 4. A Schematic showing the major pathways for direct and indirect antigen presentation, T‐cell mediated rejection, B‐cell activation and antibody‐mediated rejection, complement‐mediated injury and endothelial activation and injury. These pathways are variably activated during a graft rejection response.


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Further Reading

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Roedder S, Li L, Alonso MN, et al. (2014. pii: ASN.2013111239. PMID: 25429124) A three‐gene assay for monitoring immune quiescence in kidney transplantation. Journal of the American Society of Nephrology.

Roedder S, Sigdel T, Salomonis N, et al. (2014) The kSORT assay to detect renal transplant patients at high risk for acute rejection: results of the multicenter AART study. PLoS Medicine 11 (11): e1001759. DOI: 10.1371/journal.pmed.1001759. eCollection 2014 Nov. Erratum in: PLoS Med. 2015 Feb;12(2):e1001790. PMID: 25386950.

Sarwal MM, Ettenger RB, Dharnidharka V, et al. (2012) Complete steroid avoidance is effective and safe in children with renal transplants: a multicenter randomized trial with three‐year follow‐up. American Journal of Transplantation 12 (10): 2719–2729. DOI: 10.1111/j.1600-6143.2012.04145.x. Epub 2012 Jun 13. PMID: 22694755.

Weaver TA, Charafeddine AH, Agarwal A, et al. (2009) Alefacept promotes co‐stimulation blockade based allograft survival in nonhuman primates. Nature Medicine 15 (7): 746–749. DOI: 10.1038/nm.1993. Epub 2009 Jul 5. PMID: 19584865.

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Sarwal, Minnie M, and Sarwal, Reuben D(Nov 2015) Graft Rejection: The Basics. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0001232.pub2]