The online version of this article (doi:10.1186/1476-9255-7-43) contains supplementary material, which is available to authorized users.
HE is President and a shareholder of Molecules for Health (MFH) and thereby has a financial interest in Didox or Trimidox therapeutic potential. All other authors declare that they have no competing interests.
MI participated in the design of the experiments, carried out the T-cell isolation, T-cell proliferation, cytokine analysis and MLR and analysis of the data. IE participated in the T-cell proliferation assays and statistical analysis. MB participated in the T-cell proliferation assays. HE supplied the compounds Trimidox and Didox and participated in the determination of the in vitro dosing. VG assisted in drafting the manuscript. OO conceived the study, directed its design and coordination and drafted the manuscript. All authors read and approved the final manuscript.
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-γ, TNF-α, 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.
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- Inhibition of allogeneic inflammatory responses by the Ribonucleotide Reductase Inhibitors, Didox and Trimidox
Mohammed S Inayat
Ismail S El-Amouri
Howard L Elford
Vincent S Gallicchio
Oliver R Oakley
- BioMed Central
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