ImmunologyTier 1Medical Sciences concept

Graft-versus-host disease - effector cells and mechanism

Core concept

Billingham's three requirements: immunocompetent graft, histoincompatible host, host unable to reject the graft
The effector cell is the DONOR mature T lymphocyte (helped by donor NK cells and monocytes)

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Conditioning -> tissue damage, gut mucosal breach

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HLA mismatch is the single strongest predictor - risk rises with each mismatched allele across HLA-A, -B, -C, -DRB1 (the "8/8" match)
- Matched siblings still develop GVHD because of minor histocompatibility antigens (HY antigens - hence female donor -> male recipient is the highest-risk sex mismatch)
Cord blood is the exception: T cells are naive and less alloreactive -> greater HLA mismatch is tolerated with less severe GVHD, at the cost of slower engraftment and slower immune reconstitution

	Acute	Chronic
Timing	Classically <100 days (but late-onset acute exists)	Usually >100 days; defined by features, not day count (NIH criteria)
Organs	Skin (maculopapular rash, palms/soles), gut (secretory diarrhoea, ileus), liver (cholestatic hyperbilirubinaemia)	Sclerodermatous skin, lichen planus-like oral/genital, sicca, fasciitis, bronchiolitis obliterans, cholestasis, cytopenias
Mechanism	Th1/Th17 alloreactive CTL	Fibrosis, autoantibodies, Th17/Tfh and B cells; thymic damage -> failed tolerance
Grading	Glucksberg / MAGIC I-IV on skin+gut+liver stage	NIH mild/moderate/severe

Risk factors: HLA mismatch > unrelated donor, peripheral blood stem cells > bone marrow > cord, older donor and recipient, sex mismatch (F->M), prior acute GVHD is the strongest risk factor for chronic GVHD, CMV serostatus, myeloablative conditioning
Graft-versus-leukaemia is the same alloreactivity - T-cell depletion reduces GVHD but increases relapse and graft failure; donor lymphocyte infusion exploits GVL and reintroduces GVHD risk
Transfusion-associated GVHD is a separate, near-uniformly fatal entity - prevented by irradiating cellular products for immunosuppressed recipients and for HLA-matched or directed-donor units

Prophylaxis
- Post-transplant cyclophosphamide (day +3/+4) with tacrolimus and mycophenolate is now the leading regimen - developed for haploidentical transplant, and superior to tacrolimus/methotrexate for GVHD-free relapse-free survival in matched reduced-intensity transplant (BMT CTN 1703)
- It works by selectively deleting proliferating alloreactive T cells while sparing regulatory T cells and haematopoietic stem cells (high aldehyde dehydrogenase)
- ATG is an alternative, mainly in unrelated-donor transplant
Treatment
- Systemic corticosteroids (1-2 mg/kg) are first-line for grade II-IV acute and for chronic GVHD
- Steroid-refractory acute or chronic GVHD -> ruxolitinib (REACH2, REACH3)
- Chronic, further lines: belumosudil (ROCK2), axatilimab (anti-CSF1R), ibrutinib, extracorporeal photopheresis
- Skin-limited grade I acute -> topical steroid alone
Infection dominates the outcome - prolonged steroids plus GVHD-induced immunodeficiency; keep PJP, antifungal, antiviral prophylaxis and immunoglobulin replacement in mind
Chronic GVHD -> functional asplenia: revaccinate, penicillin prophylaxis, encapsulated organism cover

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