Graft vs Host Disease

Pathogenesis and Prerequisites of Graft-Versus-Host Disease

• Graft-versus-host disease (GVHD) is a major cause of mortality and morbidity following allogeneic hematopoietic stem cell transplantation (HSCT).
• The disease is caused by the engraftment of immunocompetent donor T lymphocytes in an immunologically compromised host who exhibits histocompatibility differences with the donor.
• Three specific conditions must be met for a graft-versus-host reaction to occur: the donor graft must contain immunocompetent T-cells, the host must be immunocompromised and unable to reject the graft, and the recipient must express transplant antigens (such as major histocompatibility complex [MHC] proteins) that are absent in the graft.
• The donor T-cell activation is directed against either the recipient's MHC antigens or minor histocompatibility antigens.
• GVHD is primarily subdivided into two distinct clinical forms: acute GVHD, which classically occurs within 3 months post-transplantation, and chronic GVHD, which occurs later and displays clinical and pathologic features resembling autoimmune disorders.

Acute Graft-Versus-Host Disease

Pathophysiology

• Acute GVHD develops via a complex, three-step pathophysiologic process.
• In the first step, tissue damage induced by the preparative conditioning regimen activates recipient antigen-presenting cells (APCs).
• These activated APCs present recipient alloantigens to the donor T cells transferred with the graft and secrete cytokines, such as interleukin (IL)-12, which favor the polarization of the T-cell response in the type 1 direction.
• In the second step, donor T cells become activated in response to these recipient antigens, leading them to proliferate, expand, and generate high levels of cytokines, notably tumor necrosis factor (TNF)-$\alpha$, IL-2, and interferon (IFN)-$\gamma$.
• In the third step, this cytokine storm causes direct tissue damage and promotes the differentiation of cytotoxic CD8+ T cells, which, alongside macrophages, destroy recipient cells and further disrupt target tissues.

Risk Factors

• Despite standard prophylaxis, significant acute GVHD develops in approximately 30% of recipients receiving HSCT from matched siblings and in as many as 60% of recipients from unrelated donors.
• The most critical risk factor for the development of acute GVHD is the presence of disparities for human leukocyte antigen (HLA) molecules in the donor-recipient pair.
• Additional risk factors that heighten the probability of acute GVHD include a primary diagnosis of a malignant disease, older donor and recipient age, and the use of an unmanipulated allograft.

Clinical Manifestations and Histology

• Acute GVHD classically develops between 2 to 8 weeks following transplantation.
• The primary clinical manifestations depend heavily on the specific sites of organ involvement and frequently include an erythematous maculopapular rash, persistent anorexia, vomiting, severe diarrhea, and liver disease.
• Hepatic involvement is biochemically characterized by increased serum levels of bilirubin, alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP).
• Histologic examination of target organs is often utilized for confirmation and reveals characteristic endothelial damage and lymphocytic infiltrates across all affected tissues.
• Specific histologic hallmarks include damage to the epidermis and hair follicles in the skin, segmental disruption of hepatic small bile ducts, and the destruction of mucosal crypts accompanied by ulceration in the gastrointestinal (GI) tract.

Clinical Staging and Grading

• The severity of acute GVHD is determined by standard staging (0 to 4) of three target organs: the skin, the liver, and the GI tract,,.
• Skin staging: Stage 1 involves a maculopapular rash on <25% of the body surface area (BSA); Stage 2 involves 25–50% BSA; Stage 3 involves >50% BSA; and Stage 4 is characterized by generalized erythroderma (>50% BSA) plus bullous formation and desquamation (>5% BSA),.
• Liver staging (based on bilirubin): Stage 1 is 2–3 mg/dL; Stage 2 is 3.1–6 mg/dL; Stage 3 is 6.1–15 mg/dL; and Stage 4 is >15 mg/dL,.
• Lower GI staging (based on pediatric stool output): Stage 1 is 10–19.9 mL/kg/day; Stage 2 is 20–30 mL/kg/day; Stage 3 is >30 mL/kg/day; and Stage 4 is characterized by severe abdominal pain with or without ileus or grossly bloody stool regardless of output volume,.
• The overall clinical grade (I to IV) is established based on the most severely involved target organ.
• Grade I GVHD (skin rash alone) carries a highly favorable prognosis and often requires only topical treatment or no treatment at all.
• Grade II is a moderately severe multiorgan disease that mandates systemic immunosuppressive therapy.
• Grade III represents severe multiorgan disease, while Grade IV is a life-threatening and frequently fatal condition.

Prophylaxis

• Standard pharmacologic prophylaxis relies on posttransplant administration of immunosuppressive drugs, commonly incorporating cyclosporine or tacrolimus, often combined with methotrexate, prednisone, anti-T-cell antibodies, or mycophenolate mofetil (MMF).
• Pre-transplantation infusion of antithymocyte globulin (ATG) or monoclonal antibodies (such as alemtuzumab) is widely utilized to modulate the alloreactivity of donor T cells, particularly for patients receiving an allograft from an unrelated donor or a partially matched relative.
• The infusion of cyclophosphamide on days +3 and +4 post-transplant effectively depletes alloreactive donor T lymphocytes that activate upon exposure to recipient antigens; this is a cornerstone strategy in haploidentical transplantation,.
• Selective graft manipulation techniques are increasingly employed, specifically targeting the depletion of $\alpha /\beta$ T cells (which mediate GVHD) while preserving $\gamma /\delta$ T cells to maintain graft-versus-leukemia (GVL) effects and infectious immunity.

Treatment

• First-line therapy for established acute GVHD relies on systemic glucocorticoids, which achieve a complete clinical response in approximately 40–50% of patients,.
• Patients who fail to respond to corticosteroids face a substantially higher risk of transplantation-related mortality.
• Pharmacologic treatments for steroid-resistant acute GVHD include ruxolitinib (targeting the JAK signaling pathway), infliximab and etanercept (targeting TNF), vedolizumab (targeting ${\alpha }_4{\beta }_7$-integrin), and tocilizumab (targeting IL-6).
• Extracorporeal photopheresis is an efficacious second-line treatment, particularly for cutaneous GVHD; it works by exposing peripheral blood to ultraviolet light in the presence of a photosensitive compound, thereby increasing apoptosis of alloreactive lymphocytes and upregulating regulatory T cells.
• Mesenchymal stromal cells have also demonstrated promising results in blunting the severe inflammatory response in children with steroid-refractory disease.

Chronic Graft-Versus-Host Disease

Pathophysiology and Risk Factors

• Chronic GVHD is defined as disease developing or persisting greater than 3 months after transplantation, and it stands as the major cause of nonrelapse mortality and morbidity in long-term HSCT survivors.
• The incidence in pediatric patients is approximately 25%, and the presence of prior acute GVHD is recognized as the most critical predictive risk factor for its development.
• Additional factors increasing the risk include the use of matched unrelated volunteer donors, unmanipulated peripheral blood stem cells, older donor and recipient ages, female donors for male recipients, a primary diagnosis of malignancy, and the use of TBI.
• Chronic GVHD functions as a profound disorder of immune regulation, pathologically characterized by autoantibody production, increased collagen deposition, and extensive tissue fibrosis.
• The pathophysiology is heavily driven by type II cytokines, such as IL-4, IL-5, and IL-13, which promote eosinophilia and B-cell hyperactivity, leading to elevated IgM, IgG, and IgE titers,.
• The condition is dependent on the persistence of donor T cells that have failed to achieve tolerance to the recipient; this may occur when stem cells mature within a conditioning-damaged thymus, leading to defective negative selection and the generation of recipient-reactive T cells.

Clinical Manifestations

• Chronic GVHD exhibits pleomorphic clinical symptoms that closely mimic classical autoimmune diseases, such as systemic sclerosis and Sjögren syndrome,.
• Dermatologic findings are prominent and include lichen planus, scleroderma, hyperpigmentation or hypopigmentation, profound ichthyosis, severe ulcerations, and flexion contractures secondary to skin tightening.
• Appendage involvement includes onycholysis, nail loss, and scarring or nonscarring alopecia.
• Mucosal and ocular manifestations present as severe sicca syndrome, oral lichen planus, depapillation of the tongue, xerostomia, decreased tearing, scarring conjunctivitis, and keratopathy,.
• Hepatic chronic GVHD mimics primary biliary cirrhosis, presenting with elevated transaminases, cholestasis, hepatomegaly, and progressive cirrhosis.
• Pulmonary involvement is life-threatening and typically presents as progressive bronchiolitis obliterans, chronic cough, dyspnea, wheezing, and pulmonary fibrosis.
• Gastrointestinal and systemic symptoms include failure to thrive, malabsorption, chronic diarrhea, esophageal strictures, and profound immunodeficiency predisposing to recurrent infections,.
• Hematologic manifestations may include thrombocytopenia, eosinophilia, and the presence of Howell-Jolly bodies indicative of splenic dysfunction.

Treatment and Complications

• Patients with chronic GVHD limited strictly to the skin and liver frequently experience a favorable clinical course.
• In contrast, extensive multiorgan chronic GVHD is associated with a high mortality rate, recurrent severe infections secondary to prolonged immunosuppression, and a severely diminished quality of life.
• Single-agent prednisone remains the standard initial treatment.
• For steroid-dependent or refractory cases, targeted therapies such as ruxolitinib (a Janus kinase inhibitor) and ibrutinib (a Bruton tyrosine kinase inhibitor) are utilized.
• Imatinib mesylate, an inhibitor of collagen synthesis, has demonstrated efficacy specifically in patients exhibiting profound sclerotic features.
• Because affected patients are exceptionally susceptible to infections, appropriate antimicrobial prophylaxis, including trimethoprim/sulfamethoxazole (TMP/SMX), is strictly required.
• While chronic GVHD resolves in most pediatric patients, continuous immunosuppressive therapy is typically required for 1 to 3 years before these agents can be successfully withdrawn without disease recurrence.
• A severe long-term complication of chronic GVHD and its prolonged immunosuppressive treatment is the promotion of secondary neoplasms, particularly in highly susceptible populations such as those with Fanconi anemia.

Transfusion-Associated Graft-Versus-Host Disease

• GVHD can be iatrogenically induced when profoundly immunodeficient patients, such as infants with severe combined immunodeficiency (SCID), receive unirradiated blood transfusions.
• The condition is triggered by the contamination of fresh blood products with viable, immunocompetent donor T-lymphocytes, which the patient's defective immune system is completely unable to reject.
• Transfusion-associated GVHD manifests aggressively with fever, splenomegaly, thrombocytopenia, Coombs-positive hemolytic anemia, a prominent maculopapular rash on volar surfaces, intractable diarrhea, and protein-losing enteropathy.
• The outcome of full-blown transfusion-associated GVHD is exceedingly poor, with the patient typically dying within 10 to 14 days after the onset of symptomatology.
• This fatal complication can be entirely prevented by strictly utilizing only frozen or appropriately irradiated blood products for all transfusions in immunocompromised hosts.
• A naturally occurring analog to this phenomenon is maternal engraftment GVHD, seen in infants with SCID, where maternal T cells cross the placenta during pregnancy and mount a fatal immune attack against the defenseless infant, manifesting with erythroderma, hepatosplenomegaly, and diarrhea.