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.
Authors’ original file for figure 112950_2010_162_MOESM1_ESM.pdf
Authors’ original file for figure 212950_2010_162_MOESM2_ESM.pdf
Authors’ original file for figure 312950_2010_162_MOESM3_ESM.pdf
Authors’ original file for figure 412950_2010_162_MOESM4_ESM.pdf
Authors’ original file for figure 512950_2010_162_MOESM5_ESM.pdf
Authors’ original file for figure 612950_2010_162_MOESM6_ESM.pdf
Authors’ original file for figure 712950_2010_162_MOESM7_ESM.pdf
Hong JC, Kahan BD: Immunosuppressive agents in organ transplantation: past, present, and future. Seminars in nephrology. 2000, 20: 108-25. PubMed
Yarbro JW: Mechanism of action of hydroxyurea. Seminars in oncology. 1992, 19: 1-10. PubMed
Kennedy BJ: The evolution of hydroxyurea therapy in chronic myelogenous leukemia. Seminars in oncology. 1992, 19: 21-6. PubMed
Kiladjian JJ, Rain JD, Bernard JF, Briere J, Chomienne C, Fenaux P: Long-term incidence of hematological evolution in three French prospective studies of hydroxyurea and pipobroman in polycythemia vera and essential thrombocythemia. Seminars in thrombosis and hemostasis. 2006, 32: 417-21. 10.1055/s-2006-942762. PubMedCrossRef
Anderson N: Hydroxyurea therapy: improving the lives of patients with sickle cell disease. Pediatric nursing. 2006, 32: 541-3. PubMed
Fathallah H, Atweh GF: Induction of fetal hemoglobin in the treatment of sickle cell disease. Hematology/the Education Program of the American Society of Hematology American Society of Hematology. 2006: 58-62.
Mayhew C, Oakley O, Piper J, Hughes NK, Phillips J, Birch NJ, Elford HL, Gallicchio VS: Effective use of ribonucleotide reductase inhibitors (Didox and Trimidox) alone or in combination with didanosine (ddI) to suppress disease progression and increase survival in murine acquired immunodeficiency syndrome (MAIDS). Cell Mol Biol (Noisy-le-grand). 1997, 43: 1019-29.
Mayhew CN, Sumpter R, Inayat M, Cibull M, Phillips JD, Elford HL, Gallicchio VS: Combination of inhibitors of lymphocyte activation (hydroxyurea, trimidox, and didox) and reverse transcriptase (didanosine) suppresses development of murine retrovirus-induced lymphoproliferative disease. Antiviral Res. 2005, 65: 13-22. 10.1016/j.antiviral.2004.09.003. PubMedCrossRef
Foli A, Lori F, Maserati R, Tinelli C, Minoli L, Lisziewicz J: Hydroxyurea and didanosine is a more potent combination than hydroxyurea and zidovudine. Antiviral therapy. 1997, 2: 31-8. PubMed
Gao WY, Cara A, Gallo RC, Lori F: Low levels of deoxynucleotides in peripheral blood lymphocytes: a strategy to inhibit human immunodeficiency virus type 1 replication. Proceedings of the National Academy of Sciences of the United States of America. 1993, 90: 8925-8. 10.1073/pnas.90.19.8925. PubMedPubMedCentralCrossRef
Lori F, Foli A, Groff A, Lova L, Whitman L, Bakare N, Pollard RB, Lisziewicz J: Optimal suppression of HIV replication by low-dose hydroxyurea through the combination of antiviral and cytostatic ('virostatic') mechanisms. AIDS. 2005, London, England, 19: 1173-81. 10.1097/01.aids.0000176217.02743.d1.
De Wit D, Van Mechelen M, Zanin C, Doutrelepont JM, Velu T, Gerard C, Abramowicz D, Scheerlinck JP, De Baetselier P, Urbain J: et al., Preferential activation of Th2 cells in chronic graft-versus-host reaction. J Immunol. 1993, 150: 361-6. PubMed
Schmaltz C, Alpdogan O, Muriglan SJ, Kappel BJ, Rotolo JA, Ricchetti ET, Greenberg AS, Willis LM, Murphy GF, Crawford JM, van den Brink MR: Donor T cell-derived TNF is required for graft-versus-host disease and graft-versus-tumor activity after bone marrow transplantation. Blood. 2003, 101: 2440-5. 10.1182/blood-2002-07-2109. PubMedCrossRef
Yang YG, Sykes M: The role of interleukin-12 in preserving the graft-versus-leukemia effect of allogeneic CD8 T cells independently of GVHD. Leukemia & lymphoma. 1999, 33: 409-20.
Lori F: Hydroxyurea and HIV: 5 years later--from antiviral to immune-modulating effects. AIDS. 1999, London, England, 13: 1433-42. 10.1097/00002030-199908200-00001.
Raje N, Kumar S, Hideshima T, Ishitsuka K, Yasui H, Chhetri S, Vallet S, Vonescu E, Shiraishi N, Kiziltepe T, Elford HL, Munshi NC, Anderson KC: Didox, a ribonucleotide reductase inhibitor, induces apoptosis and inhibits DNA repair in multiple myeloma cells. British journal of haematology. 2006, 135: 52-61. 10.1111/j.1365-2141.2006.06261.x. PubMedCrossRef
Obara H, Nagasaki K, Hsieh CL, Ogura Y, Esquivel CO, Martinez OM, Krams SM: IFN-gamma, produced by NK cells that infiltrate liver allografts early after transplantation, links the innate and adaptive immune responses. Am J Transplant. 2005, 5: 2094-103. 10.1111/j.1600-6143.2005.00995.x. PubMedPubMedCentralCrossRef
Ioannidou E, Kao D, Chang N, Burleson J, Dongari-Bagtzoglou A: Elevated serum interleukin-6 (IL-6) in solid-organ transplant recipients is positively associated with tissue destruction and IL-6 gene expression in the periodontium. Journal of periodontology. 2006, 77: 1871-8. 10.1902/jop.2006.060014. PubMedCrossRef
- 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
Neu im Fachgebiet Innere Medizin
Meistgelesene Bücher aus der Inneren Medizin
Sommerakademie-Visual, Mail Icon II