Inhibition of allogeneic inflammatory responses by the Ribonucleotide Reductase Inhibitors, Didox and Trimidox

• Published in: Journal of inflammation (London, England) England), 2010-08, Vol.7 (1), p.43-43, Article 43
• Main Authors: Inayat, Mohammed S, El-Amouri, Ismail S, Bani-Ahmad, Mohammad, Elford, Howard L, Gallicchio, Vincent S, Oakley, Oliver R
• Format: Article
• Language: English
• Subjects: Bone marrow; Care and treatment; Cell activation; Cell cycle; Cyclosporins; Data processing; Enzyme inhibitors; gamma -Interferon; Graft versus host reaction; Health aspects; Health sciences; Immunosuppressive agents; Inflammation; Interleukin 10; Interleukin 13; Interleukin 2; Interleukin 4; Interleukin 6; Lymphocytes T; Mixed leukocyte reaction; Morbidity; Mortality; Ribonucleoside-triphosphate reductase; Ribonucleotide reductase; Risk factors; Spleen; Studies; Substance abuse treatment; Toxicity; Transplantation; trimidox; Tumor necrosis factor- alpha
• ISSN: 1476-9255; 1476-9255
• DOI: 10.1186/1476-9255-7-43

Graft-versus-host disease is the single most important obstacle facing successful allogeneic stem cell transplantation (SCT). Even with current immunosuppressive therapies, morbidity and mortality rates are high. Current therapies including cyclosporine A (CyA) and related compounds target IL-2 signaling. However, although these compounds offer great benefit, they are also associated with multiple toxicities. Therefore, new compounds with a greater efficacy and reduced toxicity are needed to enable us to overcome this hurdle. The allogeneic mixed lymphocyte reaction (MLR) is a unique ex vivo method to study a drug's action on the initial events resulting in T-cell activation and proliferation, synonymous to the initial stages of tissue and organ destruction by T-cell responses in organ rejection and Graft-versus-host disease. Using this approach, we examined the effectiveness of two ribonucleotide reductase inhibitors (RRI), Didox and Trimidox, to inhibit T-cell activation and proliferation. The compounds caused a marked reduction in the proliferative responses of T-cells, which is also accompanied by decreased secretion of cytokines IL-6, IFN-gamma, TNF-alpha, IL-2, IL-13, IL-10 and IL-4. In conclusion, these data provide critical information to justify further investigation into the potential use of these compounds post allogeneic bone marrow transplantation to alleviate graft-versus-host disease thereby achieving better outcomes.