Etiology

Graft versus host disease (GHVD) is a serious and potentially life-threatening complication following allogeneic hematopoietic cell transplantation (HCT). GVHD occurs when donor T cells respond to histoincompatible antigens on the host tissues.

Several risk factors determine the development of GVHD, which may be acute or chronic.

Risk factors for the development of acute GVHD include:[18][23]​​[24][25][26][27][28][29][30][31]​​[32][33][34][35][36]​[37][38]​​​[39][40][41]

  • Human leukocyte antigen (HLA) mismatch

  • Oder recipient or donor age

  • Donor and recipient gender disparity (particularly a female donor with a male recipient)

  • Parous female donor

  • Type and stage of the underlying malignant condition

  • Transplant conditioning regimen intensity

  • ABO compatibility

  • Performance score

  • White/black race

  • Cytomegalovirus serostatus

  • Absent or suboptimal GVHD prophylaxis

  • Splenectomy

  • Low socioeconomic status

Risk factors for the development of chronic GVHD include:[7]​[8][21][39]​​​​​​​​[42][43][44]​​[45][38][46]

  • Prior acute GVHD

  • Older recipient age

  • Female donor with male recipient

  • Parous female donor

  • Mismatched or unrelated donors

  • Donor lymphocyte infusion (post-HCT)

  • Use of peripheral blood stem cells

  • Low socioeconomic status

Pathophysiology

Acute GVHD

The pathophysiology of acute GVHD is complex, but can be conceptualized in three sequential steps or phases:

  • Phase I: host activation of the antigen presenting cells (APCs). Initiated subsequent to the the profound damage caused by the underlying disease and consequent infections, exacerbated by the allogeneic HCT conditioning regimens (involving total body irradiation and/or chemotherapy) administered prior to the infusion of donor hematopoietic cells.

  • Phase II: donor T-cell activation. Activated APCs interact with the infused donor T cells, leading to activation, proliferation, differentiation, and migration of alloreactive donor T cells.

  • Phase III: cascade of multiple cellular and inflammatory effectors. Further modulate each other's responses, ultimately leading to the acute GVHD target organ damage. Effector mechanisms can be grouped into cellular effectors (e.g., cytotoxic T lymphocytes) and inflammatory effectors such as cytokines.

[Figure caption and citation for the preceding image starts]: GVHD pathophysiologyCourtesy of Dr James L.M. Ferrara, Professor, Blood and Marrow Transplantation Program, University of Michigan; used with permission [Citation ends].com.bmj.content.model.Caption@43143c6c

Chronic GVHD

In contrast to acute GVHD, the pathophysiology of chronic GVHD remains poorly understood.[47] Alloreactive T cells have been implicated in the pathogenesis; however, the precise role of specific T-cell subsets, autoantigens, alloantigens, and B cells, as well as interactions of chemokines and cytokines has not been fully elucidated. The clinical manifestations of chronic GVHD are similar to an autoimmune process, suggesting similar pathophysiology.

Classification

National Institutes of Health (NIH) working group GVHD classification[1]

Acute GVHD

  • Classic acute GVHD

    • Clinical manifestations include: maculopapular rash, anorexia, profuse diarrhea, nausea, vomiting, ileus, and cholestatic hepatitis

    • Occurs within 100 days post-allogeneic HCT or donor lymphocyte infusion

  • Late onset acute GVHD

    • Clinical manifestations of classic acute GVHD occurring beyond 100 days post-allogeneic HCT or donor lymphocyte infusion

    • Often occurs during taper, or following withdrawal, of immunosuppressive drugs

Chronic GVHD

  • Classic chronic GVHD

    • Clinical manifestations: variable and can involve any organ, including the mouth (e.g., oral lichen planus-like features), skin (e.g., poikiloderma), eyes (e.g., dry, gritty, painful), genitalia (e.g., lichen planus-like features), gastrointestinal tract (e.g., esophageal web), lungs (e.g., bronchiolitis obliterans), and muscle, fascia, or joints (e.g., fasciitis)

    • No characteristic features of acute GVHD

    • No temporal relationship to allogeneic HCT or donor lymphocyte infusion

  • Overlap syndrome

    • One or more features of acute GVHD in a patient with chronic GVHD

    • No temporal relationship to allogeneic HCT or donor lymphocyte infusion

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