GVHD prevention (graft-versus-host disease)

GVHD is a complication in which donor immune cells attack recipient tissues, perceiving them as foreign. It develops after allogeneic haematopoietic stem cell transplantation (HSCT) in oncohaematological diseases (leukaemias, lymphomas), aplastic anaemia, severe immunodeficiencies, and a number of hereditary disorders. Acute GVHD (within 100 days post-HSCT) involves skin, liver, and GI tract; chronic GVHD (after 100 days) involves multiple organs. Clinically severe GVHD is the leading cause of mortality after HSCT (after primary disease relapse). Standard prophylaxis — immunosuppression with cyclosporine, methotrexate, antithymocyte globulin, post-transplant cyclophosphamide. Despite this, moderate and severe GVHD incidence reaches 30–50%. Mesenchymal cell therapy is considered as additional prophylaxis and as treatment of steroid-resistant GVHD — the most extensively studied and best-evidenced application of MSCs in clinical medicine.

Approximately 50,000 allogeneic HSCT procedures are performed worldwide each year. Indications include acute myeloid and lymphoblastic leukaemias (AML, ALL) after induction/consolidation, aplastic anaemia, myelodysplastic syndromes (MDS), Hodgkin and non-Hodgkin lymphomas, primary immunodeficiencies (SCID, Wiskott-Aldrich syndrome, X-linked chronic granulomatous disease), sickle cell anaemia, severe beta-thalassaemia, and selected inborn metabolic disorders. Donor type and conditioning intensity define the risk profile: HLA-matched sibling transplantation carries the lowest acute GVHD risk, unrelated donor (MUD) intermediate, haploidentical historically high but markedly reduced after introduction of post-transplant cyclophosphamide. Conditioning may be myeloablative (full ablation of recipient haematopoiesis) or reduced-intensity (RIC) — the latter in older patients and those with comorbidities.

The pathogenesis of GVHD is described by the classical three-phase model. Phase one — recipient tissue damage by conditioning therapy and antigen-presenting cell (APC) activation, with release of danger signals (DAMPs) and gut-microbiota products translocating across damaged epithelium. Phase two — activation and clonal expansion of donor T lymphocytes in draining lymph nodes against recipient antigens — predominantly at HLA mismatches but also at minor histocompatibility antigens even in fully HLA-matched pairs. Phase three — effector: a cytokine storm with TNF-α, IFN-γ, IL-1β, IL-6 and direct cytotoxicity of donor CD8+ T cells against skin, intestinal, and biliary epithelium. Acute GVHD severity is graded by the Glucksberg or MAGIC criteria (organ stages I–IV, overall grades I–IV). Chronic GVHD is autoimmune-like, involving skin (sclerodermoid), eyes (sicca syndrome), oral mucosa (lichenoid lesions), liver, lungs (bronchiolitis obliterans), and fasciae. Severity follows the NIH 2014 criteria.

Modern pharmacological GVHD prophylaxis is built on inhibiting donor T-cell activation. The standard regimen is a calcineurin inhibitor (cyclosporine or tacrolimus) plus methotrexate in the first weeks post-HSCT. In unrelated or mismatched donor transplants, antithymocyte globulin (ATG) is added, reducing GVHD frequency through ex vivo and in vivo donor T-cell depletion. The contemporary haploidentical standard is post-transplant cyclophosphamide (PTCy), selectively eliminating alloreactive T cells in the first days after infusion. First-line treatment of acute GVHD is methylprednisolone 2 mg/kg; for steroid-refractory cases (no response by 5–7 days or progression), options were limited until recently — the FDA has now approved ruxolitinib (a JAK1/2 inhibitor) as the second-line standard. Chronic GVHD treatment options include ibrutinib, ruxolitinib, belumosudil, extracorporeal photopheresis, rituximab, and MMF. Despite this armamentarium, overall moderate and severe GVHD incidence remains 30–50%, severe steroid-refractory acute GVHD has historical mortality of 50–90%, and chronic GVHD significantly impairs quality of life and increases late mortality.

Mesenchymal stem cell therapy is the most extensively studied and best-evidenced MSC application in clinical medicine. The unique immunomodulatory profile of MSCs includes: suppression of alloreactive T-cell proliferation through IDO, TGF-β, and prostaglandin E2 secretion; activation of regulatory T cells (Tregs) and expansion of their pool; reduction of pro-inflammatory cytokine production by donor lymphocytes; and protection of skin, intestinal, and biliary epithelium. Critically, MSCs selectively suppress responses against GVHD target tissues without diminishing the graft-versus-leukaemia effect — a finding confirmed across dozens of clinical studies. The multicentre RCT in JCO 2024 showed that sequential UC-MSC infusions over 3 months following haploidentical HSCT significantly reduce severe acute and chronic GVHD. The open-label JAMA Oncology 2024 RCT demonstrated efficacy of repeated MSC infusions in the early post-HSCT phase for severe chronic GVHD prophylaxis. The 2020 meta-analysis (PMC7027118) consolidated data from 654 patients on prophylaxis and 943 acute / 76 chronic GVHD patients on treatment; results support the use of allogeneic MSCs.

The Hanshi United programme for GVHD prevention and treatment is strictly coordinated with the transplant centre managing the patient. The prophylactic regimen is 2–3 intravenous infusions of UC-MSC or placenta-derived MSCs: the first 1–2 weeks before or immediately after HSCT, with subsequent infusions at 14–21 day intervals. The therapeutic regimen for steroid-refractory acute GVHD is weekly infusions over 4–8 weeks until response, in coordination with the treating transplantologist. Standard immunosuppression (cyclosporine, tacrolimus, methotrexate) and ruxolitinib in steroid-refractory patients are not discontinued. All procedures take place in a specialised haematology unit with around-the-clock monitoring. Follow-up at 30, 60, 100 days and beyond uses NIH criteria; in parallel, donor chimerism, cytopenias, and infectious complications are monitored. We emphasise that MSC therapy is an additional, not a replacing, modality — the decision to apply it is always made jointly with the treating transplant team.