Graft-versus-Host Disease (GvHD)
Graft-versus-host disease (GvHD) is an immune-mediated disorder that occurs when immune cells from the donor (graft) recognize the recipient (host) as foreign and attack the host’s cells.
GvHD is a common complication after allogeneic bone marrow transplantation. Other procedures associated with high risk of GvHD include solid organs containing lymphoid cells transplantation and non-irradiated blood transfusion. Two forms of GvHD are classified based on the timing of manifestation using a cutoff of 100 days post-transplant: acute and chronic GvHD. Up to 50% of patients receiving hematopoietic stem cell transplantation from a HLA matched donor can develop acute GvHD, with the incidence of chronic GvHD ranging from 6-80%. More than 10% of patients eventually die from this complication.
The cause for GvHD is quite well-defined as immunologically competent cells in the graft attacking immunodeficient host due to histocompatibility differences. Donor allograft T cells (e.g cytotoxic CD8 cells) are believed to be the main effector cells for GvHD. Acute GvHD mainly has symptoms involving the skin ( e.g. skin rash and lesions), Gastrointestinal(GI) tract (e.g. nausea, vomit, abdominal pain and diarrhea), and liver (e.g. abnormal lab results). Chronic GvHD share some of acute GvHD symptoms, while a higher risk of infection is associated with chronic patients due to immunosuppressants.
The main objective of GvHD management is to balance immunosuppression of donor T cells and reduction/prevention of the clinical symptoms. As a prophylactic measure, immunosuppressants such as methotrexate and cyclosporine are given to all patients with HCT for several months post-procedure. Anti-infection (bacterial, viral and fungal) agents are commonly used together to reduce the risk of infection. To manage GvHD symptoms, the approach is often divided into first-line and second-line therapy. First-line therapy consists mainly of corticosteroids, such as methylprednisolone, which is proven to be effective in about 60% of GvHD patients; the remaining 40% who are resistant to steroid treatment are relegated to second-line therapy such as ibrutinib. There are significant demands for effective therapies for patients when neither therapies lead to satisfactory outcomes.
The Latest Research Progress of Stem Cell Therapy for GvHD
GvHD occurs when the immunocompetent T cells from donor attack recipient’s cells as foreign, causing severe organ damage due to the difference in histocompatibility. MSCs have shown inherent immunomodulatory functions as well as trophic capabilities modulating the function of the immune system. These characteristics support MSCs as a potential therapy for GvHD. The mechanism underlying MSCs’ effect in GvHD remains unclear, here are several possible explanations:
1. MSCs regulate the immune system by interacting with both innate and adaptive immune cells.
2. MSCs play an important role in local and distant immune regulation by secreting a series of cytokines, growth factors, chemokines and soluble receptors.
3. MSCs release extracellular vesicles (EVs) containing functional proteins and lipids, enabling their transfer between cells.
The first investigation of MSCs in treating a severe GvHD patient was conducted in Sweden in 2004 and the patient was reported to be very well one year after treatment. Since then, many preclinical and clinical studies of MSCs in GvHD have been conducted by which the application of MSCs in treating steroid refractory GvHD is proven to be feasible in clinical practice. However, due to variations in trial paradigms and treatment protocols, such as age of patients, stage of the disease, cell dosage, administration routes, and tissue origins among different studies, safety and efficacy results are somewhat inconsistent. Recently, Mesoblast filed a Biologics License Application (BLA) in the US to get its MSC investigational product, Remestemcel-L, for treatment of pediatric steroid resistant acute GvHD. Although the FDA issued a complete response letter in 2020, it underscores the feasibility of conducting late-stage clinical development to enable a BLA filing. More studies have to be conducted before MSCs become a standard off-the-shelf cell therapy for GvHD.