Dimethyl Fumarate Ameliorates Disease Severity in a Mouse Model of Chronic Graft-Versus-Host Disease.
Year: 2020
Type: article
Abstract: Introduction Chronic graft-versus host disease (cGvHD) is a major complication of allogeneic hematopoietic stem cell transplantation. Standard treatment mainly consists of corticosteroids but is limited by a high percentage of steroid-refractory cases. Alloreactive T cells are a major driver of the disease, infiltrating target organs such as the liver. However, global ablation of T cells interferes with the graft-versus-leukemia effect and bears the risk of increased infections. An increased use of glycolysis has been shown to drive T cell activation and its inhibition can blunt T cell effector functions. Dimethyl fumarate (DMF), an immunomodulatory drug already approved for the treatment of multiple sclerosis and psoriasis, has been shown to inhibit the activity of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a key glycolytic enzyme. Objective We hypothesized that metabolic targeting of T cells could specifically inhibit activated T cells while preserving other T cell populations in cGvHD. Methods Chronic GvHD was induced using the B10.D2 into BALB/c minor-mismatch mouse model. Daily oral treatment with 100 mg/kg DMF or vehicle was initiated on the day of the transplant and continued for a 42-day period. Weight and cGvHD severity were scored twice weekly and liver and spleen tissue was analyzed via flow cytometry on day 42. Results DMF treatment reduced weight loss and cGvHD severity over a 42-day period. In addition, DMF decreased the frequency of activated CD4/CD8 T cells in the liver while simultaneously increasing the frequency of naive T cells. Importantly, the frequency of regulatory T cells was not affected by the treatment. Conclusion DMF has already been shown to be safe and effective in autoimmune diseases. Our studies indicate that DMF could have therapeutic potential in the setting of cGvHD as a selective inhibitor of activated, alloreactive T cells.
Institution: National Cancer Institute
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,650
OpenAlex ID: W3001648260