Graft Versus Host Disease (GVHD)

Learning Objectives

By the end of this lecture you should be able to:
- Define graft-versus-host disease (GVHD) and outline its immunological mechanism.
- Differentiate GVHD from graft rejection (direction of immune attack, cell types involved, clinical timing).
- Identify the three clinical temporal patterns (hyper-acute, acute, chronic) and their organ-specific manifestations.
- Stage acute GVHD using skin, liver and gut criteria; apply overall grading $0 \rightarrow 4$ .
- List laboratory, endoscopic and histological investigations used to confirm diagnosis and exclude differentials.
- Discuss prophylactic, first-line and steroid-refractory treatment options, including emerging biologics.
- Appraise future perspectives: HLA typing, selective donor-T-cell suppression, balance between GVHD control vs. graft-versus-leukemia effect.

Definition & Core Concept

GVHD = immune-mediated disease caused by immunologically competent donor T cells targeting immunocompromised recipient tissues after transplantation.
Critical conditions:
1. Graft contains viable T lymphocytes (or precursors).
2. Recipient immunity is inadequate to reject these cells.
3. Histoincompatibility exists (even minor HLA disparities suffice).
Incidence: $1!\text{–}!2\%$ of all transplants; mortality can reach $75\%$ in severe cases.
Two traditional temporal types:
- Acute: onset < $100$ days post-transplant.
- Chronic: onset > $100$ days (may evolve de novo or after acute episode).
Some authors recognise a hyper-acute form (day $7!\text{–}!14$ ) with explosive presentation.

Transplantation & Transfusion Settings at Risk

Allogeneic haemopoietic stem-cell transplantation (HSCT)
- Bone marrow transplant (BMT).
- Peripheral blood stem-cell transplant (PBSC).
- Umbilical cord blood transplant.
Solid-organ grafts rich in lymphoid tissue
- Liver (highest solid-organ risk).
- Heart, intestine, lung; kidney risk is rare.
Blood component therapy
- Transfusion of unirradiated whole blood or cellular components to SCID or other profoundly immunodeficient recipients.

Pathophysiology & Immunology

Sequential phases:
1. Host tissue damage & cytokine storm (conditioning chemo-/radiotherapy) primes antigen-presenting cells (APC).
2. Donor T-cell activation via allogenic recognition (direct) or autologous dys-recognition (indirect).
3. Expansion of CD4⁺ (helper) and CD8⁺ (cytotoxic) clones → effector cascade.
4. Release of pro-inflammatory cytokines: $\text{IL-1}, \text{IL-2}, \text{TNF-}\alpha, \text{IFN-}\gamma$ .
5. Target-organ damage: skin, liver, gut (classical triad) ± lung, bladder, marrow, neuromuscular tissue.
Future scope:
- HLA typing reduces but cannot eliminate risk (minor Ag disparities remain).
- Donor T-cell depletion/suppression ↓ GVHD but may also ↓ graft-versus-leukaemia (GVL) effect & engraftment.
- GVHD can paradoxically occur even after autologous PBSC (mechanism poorly understood).

Antigen Recognition Pathways (Kidney example applies to allografts)

Direct pathway: donor APCs present class I & II MHC to host T cells → CD8⁺ CTL killing & CD4⁺ DTH cytokine injury.
Indirect pathway: host APCs process donor peptides → activate CD4⁺ cells → macrophage activation & B-cell–derived antibodies (vascular endothelial injury).

Effector Cells & Cytokines Summary

Principal effector: donor T lymphocytes.
Cytokines: $\text{IL-1}, \text{IL-2}, \text{TNF-}\alpha, \text{IFN-}\gamma$ (pro-inflammatory, recruit macrophages & NK cells).
Resultant pathology: apoptosis, necrosis, fibrosis within skin, liver, intestines; secondary infection risk.

Clinical Features – Overview

Three temporal categories:
1. Hyper-acute (Day 7–14)
2. Acute (Day 5–100, median ≈ 19 d)
3. Chronic (> 100 d)
Severity hierarchy influenced by:
- Degree of HLA disparity.
- Stem-cell source: cord < marrow < PBSC (chronic ↑).
- Cryopreservation of graft ↓ risk.
- Immunosuppressive prophylaxis (post-transplant) ↓ incidence/severity.

Hyper-acute GVHD (Early Accelerated Form)

Onset: $7!\text{–}!14$ d post-graft.
Presentation: high-grade fever, generalised erythroderma, early desquamation.
Rapidly merges into acute GVHD course.

Acute GVHD – Organ-Specific Details

Hallmark triad: Dermatitis, Hepatitis, Enteritis.

Skin

Timing: Day $5!\text{–}!50$ (mean $\approx19$ d).
Findings:
- Pruritic, painful maculo-papular rash.
- Colour spectrum: bright red → violaceous.
- Initial sites: palms, soles, cheeks, neck, ears → truncal spread.
- Severe: bullae, vesicles, eventual desquamation (resembles TEN).
- Chronic sequelae: lichenoid plaques, sclerodermatous thickening, joint contractures.

Liver

Manifestations:
- Jaundice, pruritus (→ scratch marks).
- Lab: ↑ bilirubin, ALT, AST, ALP.
- Rare: cirrhosis, portal hypertension, hepatic coma → death.

Gastro-intestinal

Upper: anorexia, dyspepsia.
Lower: voluminous secretory green watery diarrhoea, mucous, exfoliated cells; intestinal bleeding, cramps, ileus.

Pulmonary & Miscellaneous

Infectious / non-infectious pneumonia.
Sterile pleural effusions.
Haemorrhagic cystitis, thrombocytopenia, anaemia, haemolytic-uraemic syndrome.

Acute GVHD – Staging & Grading

Organ Staging Criteria

Skin:
- $+$ < $25\%$ rash.
- $++$ = $25!\text{–}!50\%$ .
- $+++$ = generalised erythroderma.
- $++++$ = erythroderma with desquamation/bullae.
Liver (bilirubin): $2!\text{–}!3$ , $3!\text{–}!6$ , $6!\text{–}!15$ , >15 mg/dL.
Gut (diarrhoea volume): <500 mL, $500!\text{–}!1000$ mL, $1000!\text{–}!1500$ mL, >1500 mL ± pain/ileus.

Overall Grade (Glucksberg/BSeattle)

Grade	Skin	Liver	Gut	Functional
0	0	0	0	0
1	+/++	0	0	0
2	+/+++	+	+	+
3	++/+++	++/+++	++/+++	++
4	++/++++	++/++++	++/++++	+++

Chronic GVHD – Multisystem Syndrome

May be continuation of acute or de novo after latent period.

Skin

Lichenoid plaques, sclerodermoid fibrosis, contractures, reduced joint mobility.

Eyes

Burning, irritation, photophobia, dryness.
Severe: haemorrhagic conjunctivitis, pseudomembranes, lagophthalmos, keratoconjunctivitis sicca, punctate keratopathy, corneal erosions.

Oral & GI

Dry mouth, mucosal atrophy, dysphagia, odynophagia → weight loss.

Lungs

Wheeze, dyspnoea, chronic cough, bronchiolitis obliterans (fixed airflow obstruction).

Neuromuscular

Proximal muscle weakness, neuropathic pain, muscle cramps.

Differential Diagnosis Highlights

Systemic sclerosis, SLE, lichen planus, Sjögren syndrome, eosinophilic fasciitis, rheumatoid arthritis, primary biliary cholangitis.
Infective: Viral hepatitis.
Cutaneous: Stevens–Johnson / erythema multiforme.
GI: Malabsorption syndromes.
Mixed connective-tissue disease.

Investigations

Baseline labs: CBC, serum electrolytes.
Liver function tests (bilirubin, ALT/AST, ALP).
Radiology/Ultrasound: USG abdomen – liver, gall-bladder; barium swallow for oesophageal strictures.
Pulmonary: PFT, ABG for bronchiolitis obliterans.
Ocular: Schirmer test.
Endoscopy/Histology:
- Skin punch biopsy.
- Upper GI endoscopy.
- Sigmoidoscopy / colonoscopy.
- Liver biopsy.
Biomarkers (prognostic research use):
- Soluble $\text{IL-2R}\alpha$ , $\text{TNF-R}1$ , $\text{IL-8}$ , Hepatocyte growth factor.

Management Strategies

Primary Prophylaxis

Calcineurin inhibitors (CNI):
- $\text{Cyclosporine A (CSA)}$ or Tacrolimus for $6$ months.
- Short-course Methotrexate (MTX) + Prednisolone.
Anti-thymocyte globulin (ATG): ↓ severity but no survival benefit.
Extracorporeal photopheresis (ECP): PBMCs incubated with $8$ -methoxy-psoralen + UVA → apoptosis of donor T cells.

Acute GVHD – Primary Therapy

Continue prophylactic CNI ± topical/systemic steroids.
Alternate mono-agents: ATG, CSA alone, Mycophenolate mofetil (MMF).

Steroid-Refractory / Secondary Therapy

High-dose methyl-prednisolone pulses ± repeat ATG.
MMF $2\,\text{g/day}$ .
Muromonab-CD3, Anti-IL-2R antibodies (Basiliximab, Daclizumab, Visilizumab).
Tacrolimus escalation.
Infliximab, Etanercept (TNF-α blockade).
PUVA (psoralen + UVA) for cutaneous disease.

Chronic GVHD Treatment

Prednisolone $1\,\text{mg/kg}$ ± Azathioprine.
CNI (CSA) ± Prednisolone.
Thalidomide (TNF modulator) – useful in mucocutaneous disease.
Clofazimine, PUVA, ECP as adjuncts.
Refractory: repeat ATG, MMF, newer biologics under trial.

Key Numerical / Statistical References

Incidence of GVHD: $1!\text{–}!2\%$ overall.
Mortality of severe GVHD: up to $75\%$ .
Acute GVHD timing: <100 days (median $≈19$ d post-HSCT).
Hyper-acute onset: $7!\text{–}!14$ d.
Chronic GVHD officially: >100 d.
Diarrhoea thresholds in staging: $500, 1000, 1500$ mL/day.

Ethical / Practical Considerations

Balancing GVHD prevention vs. preservation of graft-versus-leukaemia effect – over-immunosuppression may ↑ relapse.
Need for irradiating blood products for immunodeficient recipients to prevent transfusion-associated GVHD.
Long-term quality-of-life issues: chronic ocular, dermal and pulmonary sequelae demand multidisciplinary care.

Future Perspectives & Research Directions

Selective depletion (e.g., CD45RA⁺ naive T-cell removal) to spare memory T cells → maintain GVL, ↓ GVHD.
Regulatory T-cell (Treg) augmentation therapies under investigation.
Biomarker-driven risk stratification enabling pre-emptive intensification of prophylaxis.
Mesenchymal stromal cells, JAK inhibitors, IL-6 or IL-17 blockade in clinical trials.
Gene-edited universal donor grafts to reduce alloreactivity.

Connections to Foundational Immunology & Clinical Medicine

Illustrates principles of self vs. non-self recognition (central to adaptive immunity).
Provides clinical correlate to type IV hypersensitivity (T-cell mediated) vs. type II/III antibody-mediated rejection.
Reinforces importance of HLA genetics, immunogenetics and precision matching in transplantation.
Mirrors mechanisms seen in autoimmune diseases (e.g., scleroderma-like fibrosis in chronic GVHD), hence overlapping differential list.

High-Yield Take-Home Points

GVHD requires donor T cells + immunocompromised host + histoincompatibility.
Skin, liver, gut = primary targets; staging integrates rash %, bilirubin and diarrhoea volume.
Calcineurin inhibitors + MTX = cornerstone prophylaxis; high-dose steroids remain first-line therapy.
Steroid-refractory disease mandates biologics (ATG, anti-IL-2R, TNF-α inhibitors) or cellular therapies (ECP).
Chronic GVHD resembles systemic autoimmune disorders and demands prolonged immunomodulation and supportive care.