Dr. Batal reviewed the pathology of T-cell-mediated rejection (TCMR) and antibody-mediated rejection (AMR), emphasizing that these are not two purely distinct entities: while one usually dominates the clinical picture, cell-mediated and antibody-mediated responses often coexist.

T-cell-mediated rejection (TCMR)

• Recipient immune cells recognize donor MHC molecules either by direct presentation (donor-derived antigen-presenting cells (APCs) present alloantigens to recipient T cells) or indirect presentation (recipient APCs capture alloantigen and present them to T cells).
• CD4+ helper T cells cause interstitial inflammation in the graft, and CD8+ cytotoxic T cells cause tubulitis and vasculitis.
• Morphologic features of acute TCMR include interstitial inflammation, tubulitis, and intimal arteritis.
• The evolution of induction and maintenance therapies has seen a decline in fulminant acute TCMR. TCMR remains important, however: it is associated with graft dysfunction and can be a predictor for subsequent de novo DSA formation.
• Chronic-active TCMR now poses particular ongoing diagnostic and therapeutic challenges.
• Inflammation in scarred areas of interstitial fibrosis and tubular atrophy (i-IFTA) is now recognized as a diagnostic feature of chronic-active TCMR in the 2017 (Revised) Banff Criteria, provided other causes of i-IFTA have been excluded (e.g. BK-virus nephropathy, pyelonephritis).

Antibody-mediated rejection (AMR)

• Rejection resulting from antibodies against donor antigens
• Stages of AMR (per Colvin J Am Soc Nephrol 2007)
  I. Donor-specific antibody (DSA) in circulation
  II. C4d staining in graft
  III. Morphological injury in graft
  IV. Graft dysfunction
• Diagnosis depends on serologic, immunologic, and morphologic evidence, the sensitivity and specificity of which can be influenced by several factors.
• Serologic
  DSA detection (usually by Luminex)
  Complicating issues include:
  • DSA absorption by the graft (‘sponge’ effect) ⇒ sensitivity
  • Non-HLA antibodies (e.g. AT-1)
  • IgG subclasses, mean fluorescence index (MFI) values, complement-activating vs. not, and pre-formed vs. de novo: all influence the course of AMR
• Immunologic
  C4d linear staining along peritubular +/- glomerular capillaries on kidney biopsy via immunofluorescence (IF) or immunohistochemistry (IHC) (C4d covalently binds to tissue, so is a more useful indicator of activation of the classical pathway of complement than e.g. C1 which has a very short half-life)
  Complicating issues include:
  • C4d may be negative in the presence of DSA which do not activate complement
  • C4d may be negative when a severe injury causes endothelial sloughing
  • C4d staining can be positive in the absence of AMR (e.g. with accommodation of anti-ABO Abs)
• Morphologic
  Acute tubular injury (ATI), peritubular capillaritis (PTC), glomerulitis (g), fibrinoid necrosis, and thrombotic microangiopathy (TMA) are all morphologic features of AMR.
  Complicating issues include:
  • Inter-observer variability
  • Features may be absent early in the course of AMR
  • Features are non-specific and can be observed in other diseases, possibly leading to overdiagnosis of AMR
• The diagnostic use of endothelial-associated gene expression profiles (microarray on frozen kidney biopsy samples) in AMR has been a recent research focus. While currently used in some centers, it remains to be validated for wider use.
• 2017 (Revised) Banff Criteria for AMR
  Morphologic evidence: 1 or more of g>0 (in the absence of GN), ptc>0, v>0, acute TMA (in the absence of any known cause), ATI (in the absence of any known cause).
  Antibody interaction with endothelium: 1 or more of C4d staining, g+ptc≥2, expression of genetic transcripts (endothelial injury & NK cell-associated, if thoroughly validated).
  Serologic evidence: DSA (HLA or other antigens). C4d staining or validated transcript expression may substitute for DSA.
• Treatment of AMR can involve steroid therapy, plasmapheresis and/or intravenous immunoglobulin (IVIG). These are often insufficiently effective, resulting in chronic transplant glomerulopathy.

Selected References

https://www.ncbi.nlm.nih.gov/pubmed/25855773

https://www.ncbi.nlm.nih.gov/pubmed/10505698

https://www.ncbi.nlm.nih.gov/pubmed/17360947

https://www.ncbi.nlm.nih.gov/pubmed/29243394

https://www.ncbi.nlm.nih.gov/pubmed/23414212

https://www.ncbi.nlm.nih.gov/pubmed/22429309