Definition and Pathogenesis

• Graft-versus-host disease (GVHD) represents 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.
• Donor T-cell activation is directed against either the recipient's major histocompatibility complex (MHC) antigens or minor histocompatibility antigens.

Prerequisites for GVHD

• Three specific conditions, known as the Billingham criteria, 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 must not reject the graft.
  • The recipient must express transplant antigens, such as MHC proteins, which are absent in the graft.

Classification

• GVHD is primarily subdivided into two distinct clinical forms based on the time of onset and clinical features.
  • Acute GVHD classically occurs within 3 months post-transplantation.
  • Chronic GVHD occurs later, persisting or developing greater than 3 months after transplantation.
• Chronic GVHD displays clinical and pathologic features that resemble autoimmune disorders, such as systemic sclerosis and Sjögren syndrome.

Acute Graft-Versus-Host Disease

Pathophysiology

• Acute GVHD develops via a complex, three-step pathophysiologic process.
• 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.
  • APCs secrete cytokines, such as interleukin (IL)-12, which favor the polarization of the T-cell response in the type 1 direction.
• Second step:
  • Donor T cells become activated in response to recipient antigens.
  • Activated donor T cells proliferate, expand, and generate high levels of cytokines.
  • This cytokine storm notably includes tumor necrosis factor (TNF)-alpha, IL-2, and interferon (IFN)-gamma.
• Third step:
  • The cytokine storm causes direct tissue damage.
  • It promotes the differentiation of cytotoxic CD8+ T cells, which, alongside macrophages, destroy recipient cells and disrupt target tissues.

Risk Factors

• 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 include a primary diagnosis of a malignant disease.
• Older donor and recipient age independently increase the risk.
• The use of an unmanipulated allograft significantly heightens the probability of acute GVHD.

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 target organ involvement.
• Skin involvement frequently presents as an erythematous maculopapular rash, commonly affecting the scalp, ears, palms, and soles.
• Gastrointestinal involvement includes persistent anorexia, vomiting, and severe diarrhea.
• Hepatic involvement is characterized by increased serum levels of bilirubin, alanine transaminase, aspartate transaminase, and alkaline phosphatase.
• Histologic examination reveals characteristic endothelial damage and lymphocytic infiltrates across affected tissues.
• Specific histologic hallmarks include damage to the epidermis and hair follicles.
• The liver exhibits segmental disruption of small bile ducts.
• The gastrointestinal tract demonstrates destruction of mucosal crypts accompanied by ulceration.

Staging and Grading

• The severity of acute GVHD is determined by standard staging of three target organs: the skin, liver, and lower gastrointestinal tract.

• The overall clinical grade (I to IV) is established based on the most severely involved target organ.
• Grade I GVHD carries a highly favorable prognosis and often requires only topical treatment.
• Grade IV is a life-threatening and frequently fatal condition.

Prophylaxis and Management

• Standard prophylaxis incorporates immunosuppressive drugs like cyclosporine or tacrolimus, combined with methotrexate, prednisone, or mycophenolate mofetil.
• Pre-transplantation infusion of antithymocyte globulin or alemtuzumab is utilized to modulate donor T cell alloreactivity.
• Infusion of post-transplant cyclophosphamide on days +3 and +4 effectively depletes alloreactive donor T lymphocytes.
• First-line therapy for established acute GVHD relies on systemic glucocorticoids.
• Pharmacologic treatments for steroid-resistant disease include ruxolitinib (JAK inhibitor), infliximab and etanercept (TNF targets), vedolizumab (alpha-4-beta-7-integrin target), and tocilizumab (IL-6 target).
• Extracorporeal photopheresis and mesenchymal stromal cells are also utilized as second-line treatments.

Chronic Graft-Versus-Host Disease

Pathophysiology

• Chronic GVHD is defined as disease developing or persisting greater than 3 months after transplantation.
• It functions as a profound disorder of immune regulation.
• Pathologically, it is characterized by autoantibody production, increased collagen deposition, and extensive tissue fibrosis.
• The pathophysiology is driven by type II cytokines, such as IL-4, IL-5, and IL-13.
• These cytokines promote eosinophilia and B-cell hyperactivity, leading to elevated IgM, IgG, and IgE titers.
• The condition relies on the persistence of donor T cells that have failed to achieve tolerance to the recipient.

Risk Factors

• The presence of prior acute GVHD is recognized as the most critical predictive risk factor for its development.
• Additional risk factors include the use of matched unrelated volunteer donors and unmanipulated peripheral blood stem cells.
• Older donor and recipient ages, female donors for male recipients, and the use of total body irradiation also increase the risk.

Clinical Manifestations

• Chronic GVHD exhibits pleomorphic clinical symptoms that closely mimic classical autoimmune diseases.

Management

• Single-agent prednisone remains the standard initial treatment.
• For steroid-dependent or refractory cases, targeted therapies such as ruxolitinib and ibrutinib (a Bruton tyrosine kinase inhibitor) are utilized.
• Imatinib mesylate, an inhibitor of collagen synthesis, demonstrates efficacy in patients with profound sclerotic features.
• Continuous immunosuppressive therapy is typically required for 1 to 3 years before successful withdrawal.
• Because affected patients are exceptionally susceptible to infections, appropriate antimicrobial prophylaxis, including trimethoprim-sulfamethoxazole, is strictly required.

Special Forms of GVHD

Transfusion-Associated GVHD

• GVHD can be iatrogenically induced when profoundly immunodeficient patients, such as infants with severe combined immunodeficiency (SCID), receive unirradiated blood transfusions.
• It is triggered by the contamination of fresh blood products with viable, immunocompetent donor T-lymphocytes.
• The patient's defective immune system is unable to reject these cells.
• Transfusion-associated GVHD manifests aggressively with fever, splenomegaly, thrombocytopenia, Coombs-positive hemolytic anemia, and a prominent maculopapular rash on volar surfaces.
• Intractable diarrhea and protein-losing enteropathy quickly follow.
• The outcome is exceedingly poor, with death typically occurring within 10 to 14 days after symptom onset.
• This fatal complication can be prevented by strictly utilizing only frozen or appropriately irradiated blood products for all transfusions in immunocompromised hosts.

Maternal Engraftment GVHD

• A naturally occurring analog to transfusion GVHD is maternal engraftment GVHD.
• It is frequently seen in infants with SCID, where maternal T cells cross the placenta during pregnancy.
• The engrafted maternal cells mount a fatal immune attack against the defenseless infant, manifesting with erythroderma, hepatosplenomegaly, and diarrhea.