Etiology and clinical presentation
GVHD is an iatrogenic complication, meaning it is a consequence of medical procedures. Bone marrow transplantation is the most common triggering factor. The reaction may also develop following the infusion of lymphoid cell suspensions in patients who have undergone therapeutic irradiation (or victims of radiation accidents), as well as during the transplantation of organs rich in lymphoid tissue (e.g., intestinal or lung fragments).
The classic clinical presentation involves damage to three main target organs:
- Skin: epidermal damage clinically manifested by a rash.
- Liver: the immune attack targets the epithelium of the bile ducts (while hepatocytes themselves remain unaffected), leading to jaundice.
- Gastrointestinal tract: mucosal damage causes profuse diarrhea and intestinal bleeding.
Acute and chronic forms
The disease is typically divided into two main forms depending on the time of manifestation and predominant pathomorphological processes.
- Acute GVHD. Occurs within the first 100 days after irradiation and bone marrow transplantation (symptoms most frequently appear in the second decade). Clinically, the disease is usually caused by the reaction of donor cells to minor histocompatibility antigens, as donors are carefully matched for the major histocompatibility complex (MHC). Severe cases may be accompanied by massive desquamation of the intestinal mucosal epithelium and extensive necrosis. Previously, this condition was termed secondary radiation sickness.
- Chronic GVHD. Develops 100 days post-transplantation. Affected tissues are dominated by atrophy and fibrosis, with necrosis being atypical. The cytokine TGFβ plays an obligatory role in the development of fibrosis. In the chronic form, the lungs are added to the classic target organs (skin, liver, GI tract).
Mechanisms of cell damage
GVHD is based on the same immunological principles as allograft rejection. The key participants are donor T lymphocytes (CD4+ and CD8+). During the activation phase, they recognize antigens on dendritic cells via MHC-II and MHC-I molecules.
The generated pool of activated T cells destroys tissues through two pathways leading to apoptosis:
- Cytotoxic pathway (direct). Mediated by cytotoxic lymphocytes. It involves the release of perforin and granzymes, as well as the triggering of receptor-mediated apoptosis via the Fas-FasL mechanism.
- Inflammatory pathway (indirect). Activated T cells secrete inflammatory cytokines, recruiting macrophages and T helper 1 (Th1) cells. A vascular reaction occurs, impairing tissue trophism (nutrition), which also leads to cell death.
Epithelial damage and the development of cachexia in the acute form are directly mediated by cytokine action (this process is prevented by antibodies to IL-1 and TNFα). Characteristic enlargement of lymph nodes and the liver occurs not only due to the proliferation of donor lymphocytes, but also as a result of the recipient's own cells reacting to released cytokines.
Prevention and engraftment challenges
The generally accepted approach to preventing GVHD is the depletion of T cells from the transplanted bone marrow. However, this method impairs graft engraftment: colony-stimulating factors, which are secreted specifically by T cells, are necessary for engraftment.
Modern approaches to prevention include:
- Adding regulatory T lymphocytes to the graft to suppress the activity of effector cells.
- Replacing bone marrow transplantation with leukapheresis product transfusion. Stem cells are mobilized into the blood beforehand by administering G-CSF (however, mature T cells from this blood still need to be removed).
Post-transplantation, physicians frequently encounter the problem of restoring the CD4+ T helper pool. This is due to insufficient thymic activity in adults and attenuated expression of MHC-II molecules, which reduces the volume of 'niches' for these cells.
Experimental models
Historically, GVHD was studied by applying parental lymphocytes to the chorioallantoic membrane of chicken embryos. The modern standard model is the administration of parental mouse lymphoid cells to first-generation hybrids (F1).
Pathogenesis of the model: the F1 hybrid does not reject parental cells (no foreign antigens), but donor lymphocytes recognize the histocompatibility antigens of the second parent and initiate an attack. The administration of parental cells to newborn hybrids causes growth retardation disease (runt syndrome / wasting syndrome), which manifests as alopecia, cachexia, and mucosal lesions with diarrhea. Systemic administration to adult specimens leads to splenomegaly and hepatomegaly.
Briefly: answers to topical questions
What drugs are used for immunosuppressive therapy in the treatment of established acute GVHD?
- Methylprednisolone — 2 mg/kg/day.
- Cyclosporine — 1–3 mg/kg/day.
- Tacrolimus — 0.03 mg/kg/day.
- Mycophenolate mofetil — 190–1600 mg/m²/day.
- Ruxolitinib — 2.5–10 mg/m² twice daily.
- Etanercept — 0.4 mg/kg twice weekly.
- Infliximab — 10 mg/kg once weekly.
To memorize the classic target organs of acute GVHD, use the acronym SLI: Skin (rash), Liver (jaundice), Intestines/GI tract (diarrhea).
Class and exam questions
Why does jaundice occur in GVHD if liver cells themselves are not damaged?
Donor T lymphocytes selectively attack the epithelium of the bile ducts rather than hepatocytes themselves. Damage to the ducts disrupts normal bile outflow, which leads to the development of jaundice.
Why remove T cells from the donor material if it impairs engraftment?
T-cell depletion is a necessary compromise. Although their absence reduces the production of colony-stimulating factors and delays engraftment, the presence of mature donor T lymphocytes carries an enormous risk of developing severe and potentially lethal GVHD.
Which antigens are most important when selecting a donor for transplantation?
Compatibility for HLA class II genes (especially the polymorphic DRB locus) is of decisive importance for success. Among HLA class I gene products, antigens of the HLA-B locus are of the greatest importance.
What else to study on this topic
- Mechanisms of cellular apoptosis: perforin-granzyme and Fas-FasL pathways
- Genetic compatibility: HLA locus polymorphism and typing rules
- Mechanisms of allograft rejection
- The role of cytokines (IL-1, TNFα, TGFβ, G-CSF) in transplantology
- Principles of immunosuppressive therapy in organ transplantation
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