Transplant biology principles, including human leucocyte antigen (HLA)

Overview

Transplant outcome is determined by how different the graft looks to the recipient immune system, and by how effectively that response is suppressed


Autograft	Self to self
Isograft	Identical twin - no rejection
Allograft	Same species, different genotype - the usual case
Xenograft	Different species

HLA class I - HLA-A, B, C; on all nucleated cells; presents endogenous peptide to CD8
HLA class II - HLA-DR, DQ, DP; on APCs, B cells, activated endothelium; presents exogenous peptide to CD4
Most polymorphic gene system in the human genome

~1,500 solid organ transplants per year in Australia; kidney is the majority
Sensitisation (pre-formed HLA antibody) in ~30% of the kidney waiting list
- Three sensitising events: pregnancy, transfusion, previous transplant
Australian allocation uses HLA matching, waiting time, and access for highly sensitised recipients (paired kidney exchange programme)

HLA genes lie together on chromosome 6p and are inherited as a block - a haplotype - with each individual inheriting one haplotype from each parent
- Recombination within the MHC is rare (<1-2%)
- -> among full siblings: 25% HLA-identical, 50% haploidentical, 25% completely mismatched
- -> parent and child are always at least haploidentical
Explains why sibling donors are sought first and why haplotypes track in families
Linkage disequilibrium - certain allele combinations co-occur far more often than chance (A1-B8-DR3), which is why disease associations map to haplotypes

Direct - recipient T cells recognise intact donor MHC on donor APCs
- Very high precursor frequency -> drives early acute cellular rejection
Indirect - recipient APCs process donor MHC into peptide
- Drives chronic rejection and de novo DSA formation
Semi-direct - transfer of intact donor MHC to recipient APCs

Type	Timing	Mechanism	Treatment
Hyperacute	Minutes-hours	Pre-formed antibody (ABO or HLA) -> complement, thrombosis	None - prevented by crossmatch
Acute cellular	Days-months	T cell -> tubulitis, endarteritis	Pulse steroid; ATG if severe
Acute antibody-mediated	Days-years	DSA -> C4d deposition, peritubular capillaritis	PLEX, IVIg, rituximab
Chronic	Months-years	Indirect allorecognition, chronic DSA -> transplant glomerulopathy, vasculopathy	Largely irreversible

ABO blood group - the first compatibility barrier
HLA typing - now by high-resolution sequence-based typing (A, B, C, DRB1, DQB1, DPB1)
HLA antibody screening - solid phase (Luminex single antigen bead)
- Reported as calculated PRA (cPRA) - the proportion of donors against whom the recipient has antibody
- Defines unacceptable antigens entered into the allocation algorithm
Crossmatch
- Complement-dependent cytotoxicity (CDC) crossmatch - donor lymphocytes + recipient serum + complement; a positive T-cell CDC crossmatch is an absolute contraindication (hyperacute rejection)
- Flow crossmatch - more sensitive, detects non-complement-fixing antibody
- Virtual crossmatch - matching donor HLA type against known recipient antibody specificities; enables rapid deceased-donor allocation
Infection screen: CMV, EBV, HIV, hepatitis B/C, syphilis, TB, strongyloides
- CMV D+/R- is the highest-risk serostatus -> prophylactic valganciclovir
- EBV D+/R- drives PTLD risk

Graft function, drug levels (tacrolimus trough), de novo DSA surveillance
Biopsy is the diagnostic standard - Banff classification; C4d staining for antibody-mediated rejection
Donor-derived cell-free DNA as an emerging non-invasive marker

Induction - lymphocyte-depleting ATG (high immunological risk) or non-depleting basiliximab (anti-IL-2R, standard risk)
Maintenance - standard triple therapy
- Tacrolimus (calcineurin inhibitor) + mycophenolate + prednisolone
- Alternatives: ciclosporin, azathioprine (preferred in pregnancy), everolimus, belatacept (CTLA4-Ig; contraindicated if EBV-seronegative - PTLD)
Rejection treatment - as per the table above

Valganciclovir for CMV mismatch, cotrimoxazole for PJP and nocardia, nystatin/fluconazole, HBV antiviral if core antibody positive

Skin cancer - up to 50-100x SCC risk. Annual dermatology review and rigorous photoprotection
PTLD - EBV-driven; reduce immunosuppression first, then rituximab
Cardiovascular risk, post-transplant diabetes (tacrolimus, steroids), bone disease
Drug interactions: azoles, macrolides and diltiazem raise CNI levels; rifampicin and phenytoin drop them into rejection range

Desensitisation with plasma exchange, IVIg, rituximab enables selected incompatible transplants
Paired kidney exchange is preferred where available - better long-term outcome than desensitisation

Sensitising events: pregnancy, transfusion, prior transplant
HLA disease associations - B27 (ankylosing spondylitis), DQ2/DQ8 (coeliac), B57:01 (abacavir), B15:02 (carbamazepine SJS), DR15 (MS), DR3/DR4 (T1DM)
Post-transplant: PTLD, skin malignancy, CMV/BK/EBV, diabetes, CKD from CNI toxicity
Graft-versus-host disease in HSCT and after non-irradiated blood products

Kidney graft survival: ~95% at 1 year, ~80-90% at 5 years (living donor better than deceased)
Death with a functioning graft - cardiovascular disease, infection and malignancy - now outweighs immunological graft loss
Chronic antibody-mediated rejection and transplant glomerulopathy drive late loss; de novo DSA is the single strongest predictor, and non-adherence is its commonest cause
Adolescent and young adult transition periods carry the peak risk of non-adherence and graft loss

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