Transplant Rejection and Graft-versus-Host Disease: Mechanisms and Emergency Care

Transplant Rejection and Graft-versus-Host Disease: Immunology, Types, Diagnosis and Emergency Care

Study level: Clinical medicine, emergency medicine and pathology | Topic: Immunopathology

Learning objectives

• Define autograft, isograft, allograft and xenograft and explain why histocompatibility matters.
• Describe direct, indirect and semi-direct allorecognition, antibody-mediated injury and the role of innate inflammation.
• Distinguish hyperacute, accelerated, acute and chronic rejection in solid-organ transplantation.
• Explain GVHD after allogeneic haematopoietic transplantation and distinguish acute from chronic disease.
• Recognise organ-specific warning signs, infection mimics and transplant emergencies.
• Describe the principles, monitoring and major adverse effects of anti-rejection immunosuppression.

1. Transplant terminology

Term	Definition	Relevance
Autograft	Tissue moved within the same person.	No alloimmune rejection; healing and ischemia remain concerns.
Isograft/syngeneic graft	Between genetically identical individuals, such as identical twins.	Very low alloreactivity; GVHD risk is minimal.
Allograft	Between genetically different members of the same species.	Most human solid-organ and donor stem-cell transplants; HLA mismatch drives rejection.
Xenograft	Between different species.	Pre-existing antibodies and innate barriers create major rejection risk.
Graft	Transplanted tissue or organ.	May be kidney, liver, heart, lung, pancreas, cornea, skin or stem cells.
Host	The recipient of the graft.	Host-versus-graft immunity causes ordinary rejection.
Donor lymphocyte chimerism	Persistence of donor immune cells in the recipient.	Required for GVHD, particularly after allogeneic haematopoietic cell transplantation.

2. Antigens and immune activation

2.1 What the recipient recognises

• Major histocompatibility complex (MHC/HLA): donor HLA class I and II molecules may be recognised as foreign directly by recipient T cells.
• Minor histocompatibility antigens: polymorphic peptides derived from otherwise similar proteins are presented by HLA and can activate alloreactive T cells even when major HLA loci are matched.
• ABO blood-group antigens: preformed anti-A or anti-B antibodies can trigger immediate vascular injury when incompatible organs are transplanted.
• Endothelial and tissue antigens: antibodies may target donor endothelium, activating complement, coagulation and leukocytes.

2.2 Ischemia–reperfusion as an alarm signal

Organ procurement, cold storage and revascularisation produce cellular stress, reactive oxygen species, endothelial activation and release of danger-associated molecular patterns. Complement, innate leukocytes and inflammasomes create a pro-inflammatory environment that lowers the threshold for adaptive alloreactivity.

2.3 Allorecognition pathways

Pathway	What happens	Clinical importance
Direct allorecognition	Recipient T cells recognise intact donor MHC on donor antigen-presenting cells that migrate from the graft.	Strong early response; important in acute cellular rejection.
Indirect allorecognition	Recipient APCs process donor proteins and present donor peptides on recipient MHC.	Persistent response; supports chronic rejection and donor-specific antibody formation.
Semi-direct allorecognition	Recipient APCs acquire intact donor MHC and display it to recipient T cells.	May combine features of direct and indirect activation.
Antibody-mediated recognition	Preformed or newly produced donor-specific antibodies bind graft endothelium.	Hyperacute and acute antibody-mediated rejection; microvascular injury.

3. Mechanisms of graft injury

• CD8 cytotoxicity: CTLs kill graft parenchymal and endothelial cells by perforin/granzyme and Fas pathways.
• CD4 cytokine injury: Th1 cells release IFN-gamma and activate macrophages; Th17 cells recruit neutrophils; helper cells provide B-cell support.
• Antibody/complement injury: donor-specific antibodies activate complement, injure endothelium, recruit neutrophils and promote thrombosis.
• Delayed-type inflammation: T-cell cytokines cause interstitial infiltrates, oedema and tissue dysfunction.
• Vascular remodelling: repeated endothelial injury produces intimal thickening, luminal narrowing and chronic ischemia.
• Innate amplification: NK cells, macrophages, complement, platelets and coagulation pathways intensify the adaptive response.

4. Solid-organ rejection: timing and type

Type	Typical timing	Dominant mechanism	Pathology and examples
Hyperacute	Minutes to hours after reperfusion.	Preformed anti-ABO, anti-HLA or endothelial antibodies.	Complement activation, diffuse endothelial injury, platelet thrombi, cortical necrosis and immediate graft failure.
Accelerated	Several days in a previously sensitised recipient.	Memory T cells and pre-existing donor-specific antibodies.	Rapid vascular and cellular injury; more likely after prior transplant, transfusion or pregnancy.
Acute cellular (T-cell-mediated)	Usually weeks to months, but can occur any time after immunosuppression is reduced.	Recipient T-cell recognition of donor antigens.	Interstitial lymphocytes, tubulitis in kidney, bile-duct injury in liver, vascular inflammation and graft dysfunction.
Acute antibody-mediated	Days to months; may coexist with cellular rejection.	New donor-specific antibodies against graft endothelium.	Microvascular inflammation, complement deposition (e.g., C4d in selected organs), thrombosis and graft dysfunction.
Chronic	Months to years.	Persistent low-grade T-cell and antibody injury plus nonimmune stressors.	Transplant vasculopathy, interstitial fibrosis, tubular atrophy and progressive loss of function.

5. Organ-specific presentation

Graft	Possible rejection clues	Other urgent differentials
Kidney	Rising creatinine, reduced urine, proteinuria, hypertension, graft tenderness or weight gain.	Dehydration, obstruction, renal artery/vein thrombosis, calcineurin toxicity, infection and recurrent disease.
Liver	Rising AST/ALT, bilirubin, alkaline phosphatase, fever or graft dysfunction.	Biliary obstruction, vascular thrombosis, viral infection, drug injury and sepsis.
Heart	Fatigue, dyspnoea, reduced exercise tolerance, arrhythmia, hypotension or heart failure.	Acute coronary syndrome, infection, pulmonary embolism, graft vasculopathy and drug toxicity.
Lung	Falling FEV1, cough, dyspnoea, hypoxia, fever or new infiltrates.	Pneumonia, pulmonary embolism, anastomotic problems and chronic lung allograft dysfunction.
Pancreas/islet	Hyperglycaemia, recurrent insulin need or abnormal pancreatic enzymes.	Pancreatitis, infection, medication effect and metabolic disease.
Cornea	Pain, photophobia, redness, reduced vision, endothelial rejection line or graft oedema.	Infection, raised intraocular pressure, wound problems and trauma.

6. Diagnosis of solid-organ rejection

1. Establish the baseline: organ function, prior rejection, donor-specific antibodies, drug levels and usual vital signs.
2. Assess adherence and exposure: missed doses, vomiting/diarrhoea, new medicines, herbal products and grapefruit can alter immunosuppressant levels.
3. Exclude infection early: fever and graft dysfunction may be bacterial, viral, fungal or opportunistic infection; immunosuppression can blunt signs.
4. Perform organ-specific tests: creatinine/urinalysis, liver tests, echocardiography, spirometry, imaging or graft ultrasound as appropriate.
5. Measure donor-specific antibodies: useful for antibody-mediated rejection but must be interpreted with graft function and biopsy.
6. Biopsy when safe and indicated: histology often distinguishes cellular rejection, antibody-mediated injury, infection and drug toxicity. A biopsy can miss focal disease and is not always required before emergency treatment.

6.1 Common laboratory and monitoring tools

Tool	Information gained	Limitation
Drug trough levels	Exposure to tacrolimus, ciclosporin, sirolimus or everolimus.	Level does not prove adherence, efficacy or rejection; timing of sample matters.
Donor-specific antibody testing	Detects humoral sensitisation and supports antibody-mediated rejection.	Assay strength and clinical significance vary; absence does not exclude cellular rejection.
Complement-binding assays	May refine risk of antibody-mediated injury.	Not a stand-alone diagnostic test.
Viral PCR	Detects CMV, BK virus, EBV and other opportunistic infections.	Viral load must be linked to symptoms and organ findings.
Biopsy	Defines cellular infiltrate, vascular injury, fibrosis and infection.	Invasive; sampling error and bleeding risk require specialist assessment.

7. Graft-versus-host disease (GVHD)

GVHD occurs when viable donor immunocompetent T cells in a graft recognise recipient antigens as foreign and attack host tissues. It is most important after allogeneic haematopoietic stem-cell or bone-marrow transplantation, but rare GVHD can follow solid-organ transplantation containing many donor lymphocytes.

7.1 The three essential requirements

1. The graft contains immunocompetent donor cells.
2. The recipient expresses tissue antigens that differ from the donor.
3. The recipient cannot effectively eliminate the donor immune cells.

7.2 Pathogenesis

• Conditioning chemotherapy/radiation damages host tissues and releases inflammatory cytokines.
• Donor T cells are activated by host APCs and alloantigens.
• Activated donor cells expand, migrate and attack skin, gastrointestinal epithelium, liver and other tissues.
• Microbiome disruption, barrier injury and infection amplify cytokine release and tissue damage.

Form	Typical timing	Main manifestations
Acute GVHD	Classically within the first 100 days, but timing-based definitions overlap with late acute disease.	Maculopapular rash that may progress to epidermal detachment, watery or bloody diarrhoea, abdominal pain, nausea, cholestatic hepatitis and fever.
Chronic GVHD	Usually later, often with persistent or new disease after day 100.	Sclerotic or lichenoid skin change, mouth/eye dryness, oesophageal narrowing, bronchiolitis obliterans, fasciitis, joint restriction, genital involvement and autoimmune-like features.
Overlap syndrome	Any time during transition.	Simultaneous acute gastrointestinal/liver/skin disease and chronic sclerotic or sicca manifestations.

8. Recognising and diagnosing GVHD

• Skin: diffuse erythematous maculopapular rash, palm/sole involvement, painful erythema, blistering or desquamation.
• Gastrointestinal: persistent nausea, anorexia, abdominal cramps, profuse watery diarrhoea, bleeding and dehydration.
• Liver: rising bilirubin and cholestatic enzymes; jaundice may be late.
• Chronic features: dry eyes/mouth, oral lichenoid lesions, skin tightening, dysphagia, cough, reduced lung function and contractures.

Diagnosis combines timing, transplant history, clinical pattern, medication review, blood tests, stool pathogen testing, imaging and biopsy of skin, gut or liver when appropriate. Drug toxicity, viral/bacterial infection, chemotherapy injury, inflammatory bowel disease and relapse must be considered. Treating presumed GVHD with more immunosuppression while missing infection can be fatal.

9. Prevention and immunosuppressive therapy

9.1 Prevention

• ABO/HLA matching and antibody screening reduce risk but cannot remove it.
• Crossmatch testing identifies preformed recipient antibodies against donor antigens.
• Induction therapy, maintenance immunosuppression and prophylaxis are individualised by organ, risk and local protocol.
• For stem-cell transplantation, graft selection, T-cell depletion and prophylactic combinations reduce GVHD while preserving graft-versus-leukaemia benefit.
• Adherence, therapeutic drug monitoring, vaccination planning and infection prevention are continuous, not one-time tasks.

9.2 Major anti-rejection drug classes

Class/examples	Mechanism	Uses	Important adverse effects/interactions and precautions
Glucocorticoids (prednisone, methylprednisolone)	Suppress transcription of inflammatory cytokines and lymphocyte activation.	Induction, acute cellular rejection and GVHD treatment.	Hyperglycaemia, hypertension, psychosis, osteoporosis, GI injury and infection; taper after prolonged use; interact with diabetes therapy and increase infection risk.
Calcineurin inhibitors (tacrolimus, ciclosporin)	Block calcineurin–NFAT signalling and IL-2 transcription, reducing T-cell activation.	Core maintenance therapy for many solid-organ and stem-cell regimens.	Nephrotoxicity, hypertension, tremor, seizures, diabetes, hyperkalaemia and thrombotic microangiopathy. CYP3A4 inhibitors/inducers, grapefruit and St John’s wort markedly alter levels; monitor troughs, renal function, BP and electrolytes.
Antimetabolites (mycophenolate, azathioprine)	Inhibit purine synthesis or lymphocyte proliferation.	Maintenance and steroid-sparing therapy.	Bone-marrow suppression, diarrhoea, infection and teratogenicity; check CBC/liver tests; azathioprine interacts with allopurinol/febuxostat and requires dose adjustment.
mTOR inhibitors (sirolimus, everolimus)	Block IL-2-driven cell-cycle progression.	Maintenance or calcineurin-sparing regimens.	Hyperlipidaemia, mouth ulcers, impaired wound healing, pneumonitis, cytopenias and proteinuria; interactions via CYP3A4; avoid early use when wound healing is critical unless specialist-directed.
Costimulation blockade (belatacept)	Blocks CD80/86–CD28 co-stimulation, promoting T-cell anergy.	Selected kidney transplant maintenance.	Infusion reactions, infection and post-transplant lymphoproliferative disorder; EBV status and specialist monitoring matter.
Monoclonal antibodies (basiliximab, anti-thymocyte globulin, rituximab)	Deplete or inhibit T cells, B cells or activation pathways.	Induction, steroid-resistant rejection or antibody-mediated disease.	Cytokine-release reactions, cytopenias, hypogammaglobulinaemia and opportunistic infection; screen for hepatitis/TB where appropriate.
Plasma exchange/IVIG	Remove pathogenic antibody and modulate Fc/complement pathways.	Severe antibody-mediated rejection, desensitisation and selected GVHD/autoantibody syndromes.	Bleeding, hypocalcaemia, hypotension, thrombosis, renal injury or aseptic reactions; use specialist protocols.

9.3 Universal safety principles

• Never adjust, stop or restart anti-rejection therapy without the transplant team unless directed during a documented emergency protocol.
• Check interactions before prescribing antibiotics, antifungals, anticonvulsants, anticoagulants, herbal products or over-the-counter medicines.
• Vaccination, cancer screening, skin protection, renal and metabolic monitoring reduce long-term harm; live vaccines are generally avoided during significant immunosuppression.
• Fever may be muted; obtain cultures and consider opportunistic pathogens early.

10. Transplant emergencies

Emergency	Clues	Immediate priorities
Hyperacute rejection	Immediate graft nonfunction, severe graft ischemia or vascular thrombosis after reperfusion.	Urgent transplant surgery/nephrology/critical-care review; confirm perfusion and antibodies; definitive graft management may be required.
Acute rejection with organ failure	Rapidly rising creatinine, liver failure, cardiac dysfunction or hypoxia.	ABCDE, organ support, urgent transplant centre contact, drug levels, infection evaluation and biopsy-directed treatment.
Severe GVHD	Profuse diarrhoea, GI bleeding, rash/desquamation, jaundice, shock or respiratory failure.	Fluid/electrolyte resuscitation, stool cultures/PCR, skin/gut/liver assessment and urgent transplant-haematology management.
Opportunistic sepsis	Fever or hypothermia, hypotension, confusion, focal symptoms or sudden graft dysfunction.	Sepsis bundle adapted to organ function, cultures, prompt antimicrobials, source control and review of immunosuppression.
Calcineurin toxicity	Acute kidney injury, tremor, seizures, hypertension, hyperkalaemia or microangiopathic haemolysis.	Check level and interactions, support organ function and involve transplant pharmacy/team before dose changes.
Drug withdrawal/nonadherence	Subtherapeutic trough, missed doses, vomiting or inability to access medicine.	Restore supervised therapy safely and assess for established rejection; never simply double doses without advice.

11. Rejection versus infection: a practical comparison

Feature	More suggestive of rejection	More suggestive of infection
Timing	After immunosuppression reduction, missed doses or rising donor-specific antibody.	After intensified immunosuppression, exposure or neutropenia.
Symptoms	Isolated graft dysfunction without a clear infectious focus.	Fever, focal symptoms, respiratory/GI/urinary signs or sepsis physiology.
Tests	Biopsy features of rejection, donor-specific antibodies, organ-specific functional decline.	Positive cultures/PCR, imaging focus, inflammatory markers (not specific).
Management risk	Under-treating rejection loses graft.	Increasing immunosuppression during occult infection may cause rapid deterioration.

Both may occur together. The safe approach is simultaneous stabilisation, infection evaluation and transplant-team consultation rather than an untested either/or assumption.

12. Clinical cases

Case 1: kidney transplant dysfunction

A kidney recipient has a creatinine rise after diarrhoea and starting an antifungal. The differential includes dehydration, tacrolimus toxicity, drug interaction, infection and rejection. Check volume status, electrolytes, drug trough, viral PCR, urinalysis, ultrasound and donor-specific antibodies; urgent transplant assessment may require biopsy.

Case 2: acute GVHD

After allogeneic stem-cell transplant, a patient develops a widespread rash, watery diarrhoea and rising bilirubin. Acute GVHD is likely, but infection, drug rash and conditioning injury must be excluded. Resuscitate, quantify stool output, send pathogen testing, assess liver and skin/gut, and involve the transplant team urgently.

Case 3: chronic lung allograft dysfunction

A lung recipient has a gradual fall in FEV1 and exertional dyspnoea months after transplant. Chronic rejection is possible, but infection, airway stenosis, reflux and pulmonary embolism must be assessed. Serial spirometry and imaging guide specialist evaluation.

13. Exam-focused comparison

Question	Answer
What causes hyperacute rejection?	Preformed recipient antibodies against donor ABO/HLA/endothelial antigens causing immediate complement and vascular thrombosis.
Which cells dominate acute cellular rejection?	Recipient T cells, with CD4 cytokine and CD8 cytotoxic mechanisms.
What causes chronic rejection?	Persistent low-grade cellular and antibody injury causing graft vasculopathy, fibrosis and progressive loss of function.
Who attacks whom in GVHD?	Immunocompetent donor lymphocytes attack recipient tissues.
Which organs are classically injured in acute GVHD?	Skin, gastrointestinal tract and liver.
Why can tacrolimus cause toxicity even at a stable dose?	Absorption, diarrhoea, liver function and CYP3A4 drug/herbal interactions change exposure; monitor levels and organs.

14. Quick self-test

1. Differentiate direct from indirect allorecognition.
2. Explain why prior transfusion, pregnancy or transplant increases accelerated rejection risk.
3. List five causes of acute graft dysfunction other than rejection.
4. What three conditions are required for GVHD?
5. How do calcineurin inhibitors suppress T cells, and what toxicities must be monitored?
6. Why must infection be assessed before escalating immunosuppression?

Answers

1. Direct recognition is recipient T-cell recognition of intact donor MHC; indirect recognition is recipient APC presentation of processed donor peptides.
2. They can sensitise the recipient to donor or HLA antigens and leave memory cells or antibodies ready for a rapid response.
3. Infection, obstruction, ischemia/thrombosis, drug toxicity, dehydration, recurrence of disease, nonadherence and surgical complications.
4. Immunocompetent donor cells, recipient antigens that differ from the donor, and failure of the recipient to eliminate those donor cells.
5. They block calcineurin/NFAT signalling and IL-2 transcription; monitor renal function, BP, glucose, potassium, neurologic effects, tremor and trough levels.
6. Immunosuppression can worsen occult infection, while infection can mimic rejection and delay the correct therapy.

Key take-home points

• HLA, ABO, minor antigens and ischemia–reperfusion injury initiate transplant immunity.
• Hyperacute rejection is antibody-mediated and immediate; acute rejection is cellular and/or antibody-mediated; chronic rejection produces vasculopathy and fibrosis.
• Any graft dysfunction requires a simultaneous search for rejection, infection, drug toxicity, obstruction and nonadherence.
• GVHD is the reverse direction: donor immune cells attack the recipient, classically skin, gut and liver after allogeneic stem-cell transplant.
• Anti-rejection medicines prevent graft loss but cause nephrotoxicity, metabolic disease, malignancy and opportunistic infection; monitoring and interaction checks are essential.
• Early transplant-centre involvement saves grafts and lives; do not wait for a biopsy when the patient is unstable.

Selected references

• NCBI Bookshelf: Responses to alloantigens and transplant rejection
• NCBI Bookshelf: Acute Transplantation Rejection
• NCBI Bookshelf: Graft-versus-Host Disease
• MedlinePlus: Transplant rejection
• MedlinePlus: Organ transplantation
• NCBI: Engraftment, graft failure and rejection