Transplant medicine: rejection and graft-versus-host disease

• Transplantation replaces a failing organ or rescues marrow, but the recipient's immune system recognises the donor tissue as foreign and attacks it. Everything on this page is about that attack and how we stop it.
• Rejection is traditionally divided by timing and mechanism: hyperacute (minutes to hours, pre-existing antibodies), acute (most often within the first year, T-cell or antibody mediated and usually reversible), and chronic (months to years, progressive fibrosis and vasculopathy).
• The strongest predictor of long-term success is how well donor and recipient HLA match, together with whether the recipient already has donor-specific antibodies.
• Immunosuppression uses a combination of drugs at the lowest effective doses; the cost of preventing rejection is infection, cancer and drug toxicity, so regimens are individualised.
• A different process, graft-versus-host disease, occurs when donor immune cells attack the recipient. It is the mirror image of rejection and is best known after allogeneic stem cell transplantation, but it can also follow transfusion or solid organ transplant.

By the end of this page you should be able to:

1. Contrast hyperacute, accelerated, acute cellular, acute antibody-mediated and chronic rejection by timing, mechanism, pathology and treatment.
2. Explain how HLA matching, panel-reactive antibody testing and crossmatching (CDC, flow cytometry and virtual) decide transplant compatibility.
3. Describe the major maintenance and induction immunosuppressants, why each is used, and the toxicity that limits each.
4. Recognise the infection and malignancy complications of immunosuppression, including CMV, EBV and post-transplant lymphoproliferative disorder, and skin cancer, with their monitoring.
5. Outline acute and chronic graft-versus-host disease, prevention and treatment, including the role of corticosteroids and ruxolitinib.
6. Describe transfusion-associated graft-versus-host disease and its prevention.
7. Summarise KDIGO transplant-recipient guidance and how transplant care is adapted in low-resource settings.

Transplant rejection is the immune-mediated destruction of a grafted organ or tissue by the recipient. In solid organ transplantation the attack runs from the host immune system against the donor. Graft-versus-host disease (GVHD) is the reverse: immunocompetent donor (or transfused) T cells recognise recipient tissues as foreign and attack them.

Rejection is classified in two useful ways: by time (hyperacute, accelerated, acute, chronic) and by mechanism (T-cell mediated versus antibody mediated). A helpful clinical shorthand is: pre-sensitised antibodies cause hyperacute rejection; T cells drive acute cellular rejection; donor-specific antibodies drive acute antibody-mediated rejection; and immune-mediated scarring drives chronic rejection.

GVHD is classified by timing and organs involved: acute GVHD classically appears in the first 100 days after allogeneic haematopoietic stem cell transplant and affects skin, liver and gut; chronic GVHD appears later and can involve almost any organ. ^{[5] [11]}

• Rejection remains a major barrier despite modern immunosuppression. Acute (T-cell and antibody-mediated) rejection affects an estimated 10% to 20% of patients within the first year after transplant. ^[1]
• Hyperacute rejection is now rare because of rigorous pre-transplant crossmatching, but it is catastrophic when pre-existing antibodies are missed. ^[1]
• Chronic rejection, emerging months to years later, is the dominant cause of late graft loss, with progressive fibrosis and transplant vasculopathy. ^[1]
• GVHD follows a substantial minority of allogeneic stem cell transplants: in pooled cohorts grade II to IV acute GVHD occurs in about 10.4% of patients and grade III to IV in about 2.9%, while chronic GVHD develops in about 26.8%. Overall survival at 1 year is about 86.6% and at 2 years about 81.2%. ^[5]
• Post-transplant lymphoproliferative disorder (PTLD), an EBV-driven malignancy of B cells, has an incidence of 1% to 20% depending on the transplanted organ, with an early peak at 12 to 24 months and a late peak at 5 to 10 years. ^[9]
• Non-melanoma skin cancer is the most common post-transplant malignancy in fair-skinned populations, with a 65- to 250-fold risk of squamous cell carcinoma and a 10- to 16-fold risk of basal cell carcinoma compared with the general population. ^[3]

Rejection arises when recipient lymphocytes or antibodies recognise donor HLA and other antigens. Risk is set before the operation and reinforced by events afterwards.

• HLA mismatch. The degree of HLA mismatch is consistently the strongest predictor of long-term graft survival. ^[1] HLA plays a central role, particularly in kidney and heart grafts. ^[7]
• Sensitisation. Previous blood transfusion, pregnancy, or a previous transplant can generate donor-specific antibodies (DSAs), so immunological screening before transplant is essential. ^[1][7]
• Ischaemia-reperfusion injury. Prolonged cold ischaemia time and warm ischaemia trigger innate immunity and worsen graft injury. ^[1]
• Non-immune factors such as recipient diabetes, hypertension and older age reduce graft function and increase rejection risk. ^[1]
• GVHD is driven by donor T cells recognising recipient minor and major histocompatibility antigens; risk factors include HLA disparity (especially haploidentical or unrelated donors), older recipient age, intense conditioning, and peripheral blood stem cells rather than marrow. ^[5][10]

Everything the clinician sees follows from one sequence: donor antigen is detected, lymphocytes activate, effector cells and antibodies injure the vessel, and the graft loses function.

1. Antigen presentation. Donor HLA molecules are presented to recipient T cells directly (on donor antigen-presenting cells) or indirectly (processed and presented by recipient cells). ^[1]
2. T-cell activation. T-cell receptors engage donor HLA, with co-stimulation; calcineurin and IL-2 drive proliferation and cytokine release (IFN-gamma, TNF-alpha, IL-17). These cytokines injure tubular and endothelial cells. ^[1]
3. B-cell and antibody injury. B cells become plasma cells and produce DSAs, which bind donor endothelium, activate complement (C4d deposition) and recruit NK cells and macrophages, producing microvascular inflammation and, later, chronic allograft vasculopathy. ^[1][7]
4. Innate and tissue injury. Ischaemia-reperfusion adds innate immune activation; late injury remodels into fibrosis and obliterative vasculopathy. ^[1]
5. Organ differences. The liver is relatively tolerogenic, so liver rejection is mostly acute cellular rejection (10% to 30% of recipients in the first weeks to months) and chronic liver rejection is uncommon. ^[1] Kidney, heart and lung are less forgiving, and vascular rejection leading to cardiac allograft vasculopathy accounts for roughly 60% of mortality after heart transplant. ^[1]

• Hyperacute rejection. Widespread thrombosis of the microvasculature; fibrinoid necrosis; neutrophil infiltration; the organ becomes cyanotic and non-functional within minutes. ^[1]
• Acute cellular rejection. Interstitial (and tubular in the kidney) inflammation, endothelial injury and, in arteries, intimal arteritis; in the heart, lymphocytic interstitial infiltration and myocyte necrosis. ^[1]
• Acute antibody-mediated rejection. Microvascular inflammation (glomerulitis, peritubular capillaritis in kidney), C4d deposition along peritubular capillaries, and donor-specific antibodies in serum. ^[1][7]
• Chronic rejection. Progressive interstitial fibrosis, tubular atrophy, obliterative (transplant) vasculopathy and glomerulosclerosis; a scarred, functionally failing graft. ^[1]

History and examination vary by organ, but the pattern is the same: the graft is losing function.

History (in the recipient's words):

• Fever, malaise, graft-site tenderness or swelling, reduced urine output after kidney transplant, rising serum creatinine, proteinuria.
• Breathlessness, reduced exercise tolerance, or new rhythm problems after heart transplant.
• Rising bilirubin and transaminases, or jaundice, after liver transplant.
• Cough, dyspnoea, wheeze or a falling FEV1 after lung transplant.

Examination:

• Kidney: graft tenderness over the iliac fossa, oedema, hypertension; signs of fluid overload.
• Heart: gallop, raised jugular venous pressure, pulmonary congestion.
• Liver: jaundice, hepatomegaly, ascites, worsening synthetic function.
• Lung: widespread crackles, wheeze, prolonged expiration.

Red flags are a rising creatinine over days, falling urine output, fever with graft tenderness, a sudden drop in lung function, or new jaundice: these mandate same-day review. ^[1]

After transplant a deteriorating graft is not always rejection. The common confounders, with the feature that separates each, are listed below.

• Donor and recipient HLA typing and crossmatching before transplant, discussed below. ^[7]
• First-line monitoring after transplant: serum creatinine, urine protein, drug trough levels, and, where available, donor-specific antibody testing. ^[1][6]
• Donor-derived cell-free DNA (dd-cfDNA) is emerging as a non-invasive biomarker of graft injury and rejection. ^[1]
• Biopsy is the gold standard when the diagnosis is uncertain: it distinguishes cellular from antibody-mediated rejection and infection from rejection. ^[1]
• DSA testing uses Luminex single-antigen beads to identify specificities; MFI is semi-quantitative. ^[7]
• Complement-dependent cytotoxicity crossmatch (CDC-XM) detects complement-fixing cytotoxic antibodies with high specificity but low sensitivity. ^[7]
• Flow cytometric crossmatch (FC-XM) is more sensitive but may detect non-HLA or assay-related binding. ^[7]
• Virtual crossmatch integrates donor HLA typing, recipient antibody testing, exposure history and clinical context. ^[7]

There is no single blood test for rejection. The diagnosis combines timing, organ function, drug levels, imaging and biopsy.

• Hyperacute rejection (0 to 24 hours, usually minutes to hours): immediate graft failure with thrombosis and cyanosis in the operating theatre or shortly after. ^[1]
• Accelerated rejection (days 1 to 5, often 2 to 3): an unusually rapid acute rejection in a previously sensitised recipient. ^[1]
• Acute cellular rejection: typically within the first year, graded on biopsy (for kidney, Banff categories; for heart, ISHLT grades; for lung, A and B grades). ^[1]
• Acute antibody-mediated rejection: DSAs present with microvascular inflammation and, in the kidney, C4d deposition. ^[1]
• Chronic rejection: gradual loss of function over months to years with fibrosis and vasculopathy on biopsy. ^[1]

Regional guidance differs: KDIGO emphasises precise kidney-transplant management shaped by HLA mismatch, sensitisation, prior transplant, DSAs, diabetes, cardiovascular disease and infection. ^[1]

Management has three strands: treat the acute episode, protect and maintain the graft, and prevent recurrence.

• High-dose corticosteroids (such as methylprednisolone) are first-line for acute cellular rejection and for acute antibody-mediated rejection. ^[1]
• Antithymocyte globulin (ATG) is standard for steroid-resistant T-cell mediated rejection. ^[1]
• Plasmapheresis, IVIG and, in selected cases, rituximab or eculizumab treat antibody-mediated rejection and reduce donor-specific antibodies. ^[1][7]
• Always review and fix the trigger: inadequate maintenance immunosuppression, non-adherence, drug interactions and de novo DSAs. ^[1]

• Re-transplantation may be considered after graft loss; timing and desensitisation follow centre practice.
• ISHLT-, KDIGO- and organ-specific guidelines set surveillance intervals (for example, post-heart-transplant coronary angiography surveillance). ^[6]

Maintenance combines a calcineurin inhibitor, an antimetabolite and a corticosteroid, often with an induction antibody at the time of transplant. Doses are individualised by centre, drug levels, organ function, infection risk and drug interactions; check the local formulary.

Calcineurin inhibitors (cyclosporine, tacrolimus). Block calcineurin and stop T-cell activation and proliferation. Tacrolimus is often chosen over cyclosporine because it is more potent and causes less nephrotoxicity, but both can damage kidneys and nerves and increase infection risk. Both require dose adjustment based on measured drug levels. ^[1]

Antimetabolites (azathioprine, mycophenolate mofetil). Inhibit purine synthesis, suppressing T- and B-cell proliferation. Mycophenolate tends to have fewer side effects than azathioprine, but both can cause bone marrow suppression, gastrointestinal upset and an increased risk of infection and malignancy. ^[1]

Corticosteroids (prednisone and others). Suppress T- and B-cell activation and control acute rejection. Prolonged use brings weight gain, osteoporosis, glucose intolerance, hypertension and infection, so doses are tapered once the immune response is controlled. ^[1]

mTOR inhibitors (sirolimus). Reduce rejection and preserve renal function; newer mTOR inhibitors aim to lessen metabolic complications. ^[1]

Costimulation blockade (belatacept). Blocks the CD28 pathway and prevents T-cell activation. It is less nephrotoxic than calcineurin inhibitors and useful for long-term use, but it carries more viral infections, particularly EBV, so it is generally restricted to EBV-positive recipients and is contraindicated in EBV-negative recipients because of PTLD risk. It is not approved for de novo liver transplantation. ^[1]

Induction agents such as basiliximab (anti-CD25) and depleting antibodies (for example, antithymocyte globulin) provide intense early immunosuppression and allow lower maintenance doses. ^[1]

Monitoring principles: measure CNI trough levels regularly; check renal function, blood pressure, glucose, lipids; monitor for myelosuppression with antimetabolites; screen for infection and malignancy on a schedule. ^[1][6]

Any suspected rejection, a rising creatinine, falling lung function, new jaundice, positive DSA, or an infective complication should be referred promptly to the transplant team; hyperacute rejection and severe AMR need same-day escalation. ^[1]

Lifelong immunosuppression reactivates and invites infection. Common viral threats include CMV, EBV, HBV, BK polyomavirus, norovirus and HEV; bacterial and opportunistic infections include Pneumocystis, fungi and tuberculosis. ^[1] CMV is the single most important pathogen after solid organ transplantation.

• CMV management. Two prevention strategies are used: universal prophylaxis (antivirals for all at-risk patients for 3 to 6 months, starting within 7 to 10 days of transplant) and preemptive therapy (weekly CMV PCR monitoring with treatment when DNAemia appears). Guidelines recommend 6 months (200 days) for D-positive/R-negative kidney recipients, because this reduces CMV disease compared with 100 days, and 100 days for seropositive recipients. CMV DNAemia is treated with ganciclovir or valganciclovir for at least 21 days, with reduction of immunosuppression; foscarnet, cidofovir and maribavir are reserved for resistant or refractory disease. Letermovir has different activity and is not for CMV treatment. ^[8]

• Post-transplant lymphoproliferative disorder (PTLD). PTLD is the most serious lymphoid complication, representing about 21% of post-transplant malignancies. Incidence is 1% to 20% by organ, highest per-procedure in intestinal and multiorgan transplants. It peaks early (12 to 24 months, EBV-driven, latency type III with LMP1 and EBNA2) and late (5 to 10 years, more often EBV-negative). Management is sequential: reduction of immunosuppression first, then rituximab, then R-CHOP for refractory or high-risk disease. EBV-seronegative recipients of high-risk transplants and EBV-positive donors are the key at-risk group; screening for EBV and pre-emptive immunosuppression reduction may help in selected populations. mTOR inhibitor conversion may be considered in high-risk patients. Checkpoint inhibitors are not recommended because of high rejection rates. ^[9]
• Skin cancer. In fair-skinned recipients, non-melanoma skin cancer is the most common post-transplant malignancy, with a 65- to 250-fold risk of squamous cell carcinoma and a 10- to 16-fold risk of basal cell carcinoma; melanoma risk ranges from comparable to about ten-fold higher. Ultraviolet radiation is the dominant risk factor, with fair skin, male sex and age over 60 adding risk. Squamous cell carcinoma is more aggressive, with more nodal spread, recurrence and mortality. Regular skin examination and sun protection are essential parts of post-transplant care. ^[3]
• Kaposi sarcoma and lymphoma are also increased in immunosuppressed patients. ^[1]

GVHD occurs when donor T cells recognise the recipient as foreign and attack skin, liver, gut and other targets. It is most often discussed after allogeneic stem cell transplantation, but GVHD has also been described after solid organ transplant and after transfusion.

• Acute GVHD classically appears in the first 100 days after transplantation and affects skin (rash, sometimes bullous), liver (cholestatic jaundice, raised bilirubin) and gut (secretory diarrhoea, nausea, ileus, bleeding). It is graded by organ involvement and overall severity. ^[10][11]
• Chronic GVHD appears later, may persist, and can involve skin, mouth, eyes, gut, liver, lung (obstructive airways disease) and joints. It remains a major cause of late morbidity after transplant. ^[10]

Prevention (prophylaxis) usually combines a calcineurin inhibitor with methotrexate or mycophenolate, with post-transplant cyclophosphamide after haploidentical or mismatched transplants. ^[5] Ruxolitinib, a JAK1/2 inhibitor, has demonstrated efficacy in the treatment of steroid-refractory acute and chronic GVHD and is being studied as prophylaxis; pooled data show about 10.4% grade II to IV and 2.9% grade III to IV acute GVHD when used as prophylaxis, with about 26.8% chronic GVHD and about 30.6% CMV and 19.0% EBV reactivation. ^[5] Ruxolitinib is FDA approved for steroid-refractory acute GVHD (age 12 years and older) and for chronic GVHD after failure of one or two lines of systemic therapy. Its use requires vigilance for CMV and EBV reactivation. ^[5]

Treatment of acute GVHD is systemic corticosteroids first-line, with ruxolitinib for steroid-refractory disease and additional agents (for example, antithymocyte globulin, extracorporeal photopheresis, targeted monoclonal antibodies, or mesenchymal stromal cells) for refractory cases. ^[5][10] Chronic GVHD is treated with corticosteroids plus steroid-sparing agents (calcineurin inhibitors, sirolimus, ruxolitinib, belumosudil) and supportive care. ^[10]

Children, older adults and patients with the underlying disease each modify the balance between graft-versus-leukaemia and GVHD. In all cases the transplant team individualises conditioning, donor selection and prophylaxis.

TA-GVHD is a rare but usually fatal consequence of transfusing blood or blood products containing viable donor T cells to a recipient whose immune system cannot reject them, or to a recipient who is HLA-haploidentical with the donor.

• Timing and presentation. Typically 5 to 10 days after transfusion (range 3 to 30 days), with fever, skin rash, jaundice (liver involvement), diarrhoea (gut), pancytopenia (bone marrow) and infection. Mortality exceeds 90%. ^[4]
• Risk settings. Immunocompromised recipients; transfusion between first-degree relatives or within genetically homogeneous populations; fresh (non-irradiated) blood with viable lymphocytes; older age. ^[4]
• Prevention. Irradiated blood products (gamma or X-ray) for at-risk recipients are the standard of care. They are needed for cellular components (whole blood, red cells, platelets, granulocytes, non-frozen plasma); fresh frozen plasma and cryoprecipitate do not contain viable T cells. Leukoreduction filters and pathogen inactivation can help but do not reliably prevent TA-GVHD on their own. ^[4]
• Treatment. No specific therapy is effective; management is supportive with steroids, and emergency allogeneic stem cell transplantation is the treatment of last resort. ^[4]

The KDIGO 2009 Clinical Practice Guideline for the Care of Kidney Transplant Recipients, co-chaired by Bertram L. Kasiske and Martin G. Zeier, addresses immunosuppression, graft monitoring, and prevention and treatment of infection, cardiovascular disease, malignancy and other complications (including haematological and bone disorders) in adults and children after kidney transplantation, using GRADE methods. ^[6] Day-to-day translation means combining calcineurin inhibitors with an antimetabolite and steroids, the lowest effective doses, regular monitoring of renal function and drug levels, infection prophylaxis, and malignancy surveillance. ^[6][1]

Transplant programmes in low- and middle-income settings face budget limits, slow procurement and shortages of trained staff, which restrict access to comprehensive HLA typing, solid-phase antibody assays and sensitive crossmatching. ^[2]

• Rely on a minimum viable immunology package: donor and recipient HLA typing of acceptable quality, antibody screening (PRA), CDC crossmatch as the fallback where flow cytometry is unavailable, and careful donor-recipient selection. ^[2]
• Where typing is incomplete, virtual crossmatch should not be the sole decision tool; a negative CDC crossmatch and a "clean" antibody screen do not guarantee against accelerated injury. ^[2]
• Close post-transplant monitoring, pragmatic immunosuppression and biopsy capacity (with C4d) matter more than advanced molecular testing, which belongs to staged, affordable upgrades. ^[2]
• Prevent TA-GVHD with irradiated blood products where possible, and ensure access to second-line and supportive care for GVHD.
• Sun protection, skin examination and patient education remain cheap and high-yield for the enormous skin-cancer burden. ^[3] A staged roadmap, with workforce development, quality assurance and national coordination, is more realistic than importing high-cost technology. ^[2]

• Pregnancy. Transplant recipients who conceive need multidisciplinary care, with attention to medication changes; women of reproductive age should be counselled before transplant. Guidance differs by jurisdiction (who, nice, us). ^[6]
• Children. Paediatric recipients have specific immunology and growth considerations, and chronic GVHD and PTLD are major concerns in children. ^[9]
• Immunocompromised patients. Additional infection prophylaxis and careful reduction of immunosuppression are required for documented infection. ^[1][8]

• Rejection is classified by timing (hyperacute, accelerated, acute, chronic) and mechanism (cellular versus antibody mediated); hyperacute is driven by pre-existing antibodies and is now rare. ^[1]
• HLA mismatch is the strongest predictor of long-term graft survival; sensitisation from transfusion, pregnancy or prior transplant raises DSA risk. ^[1][7]
• Crossmatching spans CDC (specific, insensitive) and flow cytometry (sensitive), with virtual crossmatching integrating donor HLA and antibody data. ^[7]
• Maintenance immunosuppression is a three-drug backbone: calcineurin inhibitor, antimetabolite and steroid, with induction antibody support; doses are followed by drug levels and toxicity. ^[1]
• Calcineurin inhibitors cause nephrotoxicity, neurotoxicity and infection risk; tacrolimus is more potent and less nephrotoxic than cyclosporine. ^[1]
• Steroids work for acute rejection but bring weight gain, osteoporosis, hyperglycaemia, hypertension and infection; mycophenolate has fewer side effects than azathioprine. ^[1]
• Belatacept is less nephrotoxic but EBV-associated PTLD limits use in EBV-negative recipients; mTOR inhibitors (sirolimus) reduce rejection and preserve renal function. ^[1]
• Immunosuppression buys rejection control at the cost of infection (CMV, EBV, BK, Pneumocystis) and cancer (skin, PTLD, Kaposi sarcoma). ^[1][3][9]
• CMV prevention uses universal prophylaxis or preemptive therapy; 6 months for D+/R- and 100 days for R+ kidney recipients; treatment continues for at least 21 days. ^[8]
• PTLD peaks at 12 to 24 months (EBV-driven) and 5 to 10 years; reduction of immunosuppression is first, then rituximab, then R-CHOP. ^[9]
• Skin cancer risk is markedly raised: 65 to 250-fold SCC, 10 to 16-fold BCC. ^[3]
• Acute GVHD appears in the first 100 days after allogeneic stem cell transplant, affecting skin, liver and gut; chronic GVHD is a major late problem. ^[5][10]
• Ruxolitinib is approved for steroid-refractory acute and chronic GVHD; CMV and EBV reactivation must be watched. ^[5]
• TA-GVHD can follow transfusion: 5 to 10 day onset, greater than 90% mortality, prevention with irradiated blood products. ^[4]
• KDIGO 2009 guides kidney transplant recipient care (immunosuppression, graft monitoring, infection, malignancy, bone disease) in adults and children. ^[6]
• Low-resource programmes should build a minimum viable immunology package and strengthen prevention and surveillance. ^[2]

Transplant immunology overlaps with several areas of the MedGrasp library: immunology and host defence, infection in the immunocompromised host (including CMV and EBV), lymphoma and leukaemia, anaemias and red cell disorders, anticoagulant and antithrombotic drugs, and nephrology. In the absence of verified topic links, the reader should navigate via the discipline hubs.