ImmunologyTier 1Medical Sciences concept

Transplant rejection types - histological/immunological features (hyperacute, acute cellular, acute antibody-mediated, chronic)

Core concept

Allorecognition - the pathway predicts the timing

Direct - donor APCs (passenger dendritic cells) present donor MHC intact to recipient T cells
- No processing needed; 1-10% of the recipient T-cell repertoire responds - an enormous precursor frequency
- -> drives ACUTE cellular rejection; wanes as donor APCs die out
Indirect - recipient APCs process donor antigen and present it on self MHC
- Conventional, low-frequency, persists for the life of the graft
- -> drives CHRONIC rejection and de novo donor-specific antibody
Semi-direct - recipient APC acquires intact donor MHC by trogocytosis/exosomes
Degree of HLA mismatch predicts rejection risk; DR mismatch matters most, then B, then A

The four rejection types

	Timing	Mediator	Histology
Hyperacute	Minutes-hours, on the table	Pre-formed anti-HLA or anti-ABO antibody	Endothelial binding -> complement -> thrombosis, infarction, "black kidney"; untreatable, graft must come out
Acute T-cell-mediated (cellular)	Days-months, peak first 6 months	T cells (CD8 > CD4)	Interstitial mononuclear infiltrate + TUBULITIS; severe = intimal arteritis (v lesion)
Acute antibody-mediated (AMR)	Days-years	Donor-specific antibody	Peritubular capillaritis + glomerulitis (microvascular inflammation), C4d in peritubular capillaries, arteritis, TMA
Chronic	Months-years	Both, mostly indirect + DSA	IFTA, transplant glomerulopathy (GBM duplication), arteriolar hyalinosis, fibrous intimal thickening

Hyperacute rejection is now rare because of ABO matching and the pre-transplant crossmatch - its existence is mostly an exam question

Banff diagnostic requirements

Active AMR requires ALL THREE
- 1. Histological evidence of acute tissue injury (glomerulitis, peritubular capillaritis, arteritis, TMA, acute tubular injury)
- 2. Evidence of current/recent antibody interaction with endothelium - linear C4d in peritubular capillaries, OR at least moderate microvascular inflammation, OR a validated endothelial molecular transcript signature
- 3. Serological donor-specific antibody (or a surrogate)
Chronic active AMR - same, but with chronic morphology (transplant glomerulopathy, peritubular capillary basement membrane multilayering, fibrous intimal thickening)
*C4d is only ~50% sensitive* - a C4d-negative biopsy does not exclude AMR, which is why microvascular inflammation and molecular scores were added
TCMR grading - Banff 1A/1B by tubulitis severity, 2A/2B by intimal arteritis, 3 = transmural arteritis/fibrinoid necrosis; borderline = tubulitis below threshold

Differential on the biopsy

Mimic	Discriminating feature
Calcineurin inhibitor toxicity	Isometric tubular vacuolisation, arteriolar hyalinosis (nodular, peripheral), striped fibrosis; no tubulitis
BK virus nephropathy	Intranuclear viral inclusions, SV40 large T antigen positive, plasma cell-rich infiltrate; *C4d, intimal arteritis and HLA-DR expression favour AMR instead*; BK viraemia on PCR
ATN / delayed graft function	Tubular injury without infiltrate
Obstruction, renal artery stenosis, recurrent GN	Imaging, serology

The exam trap: BK nephropathy is treated by reducing immunosuppression, rejection by increasing it - getting it wrong loses the graft

Organ-specific patterns

Lung - risk highest in the first months and falls with time; predominantly cellular, centred on vessels (perivascular mononuclear cuffs, graded A0-A4) and airways (lymphocytic bronchiolitis, B grades)
- Chronic = bronchiolitis obliterans / CLAD; chronic vascular = accelerated graft vascular sclerosis
- AMR in lung is real but less well defined
- Favouring INFECTION over rejection: neutrophils, alveolar rather than perivascular/airway-centred inflammation, viral inclusions, organisms on special stains
Heart - endomyocardial biopsy; ISHLT grading; chronic = cardiac allograft vasculopathy (diffuse concentric intimal hyperplasia; silent because the graft is denervated)
Liver - relatively tolerogenic; portal triaditis with bile duct injury and endothelialitis; chronic = vanishing bile duct syndrome

Biopsy before treating - graft dysfunction has a broad differential and the treatments are opposed
Acute TCMR
- IV methylprednisolone pulse - >90% effective
- Steroid-resistant or vascular (Banff >=2) rejection -> lymphocyte-depleting antibody (anti-thymocyte globulin), ~95% reversal
- Optimise maintenance: tacrolimus + mycophenolate + prednisolone
Acute AMR - combination therapy, none of it high-quality evidence
- Plasma exchange + IVIg + pulsed steroid, +/- rituximab (anti-CD20), +/- bortezomib (plasma cell proteasome inhibition), +/- eculizumab for severe/TMA
- Felzartamab (anti-CD38) resolved morphological AMR in 82% vs 20% on placebo in phase 2 and is in phase 3 - promising, not yet standard
- Imlifidase (IgG-degrading enzyme) for desensitisation and hyperacute risk
Chronic rejection has no effective treatment - it is the leading cause of graft loss beyond the first year (~50% of kidneys lost by 10 years); minimise nephrotoxicity, control BP and proteinuria, ensure adherence
Number of rejection episodes correlates with graft loss and mortality; reversal of a first episode predicts a good outcome
Prevention - HLA matching, calculated PRA/virtual crossmatch, avoidance of sensitising events (transfusion, pregnancy, prior graft), induction therapy (basiliximab or ATG), adherence support, DSA surveillance

3 more sections, plus exam facts

Premium unlocks every note across every specialty, and the full exam fact library behind it.