Infliximab effect on the levels of TNF-α and TGF-β in blood of irradiated patients
DOI:
https://doi.org/10.12923/Keywords:
radiation fibrosis, monoclonal antibody, TNF-α, TGF-β, cytokinesAbstract
TGF-β is supposed to be the major cytokine responsible for post-radiation fibrosis of healthy tissues and actively modifies post-radiation changes. The growth of TGF-β level induces the expression of collagen synthesis gene which triggers off the production of fibrosis of hyaline membranes. The main purpose of this study was to discover the way and methods of reducing post-radiation damage of normal tissues and provide an adequate scientific justification for using Infliximab as an effective radio protector in the neoplasm radiotherapy. A group of 98 patients were subjected to the experiment. Randomly selected patients were assigned to 3 groups according to the radiation exposure. The samples of whole blood were suspended in RPMI 1640 growth medium standardized according to the number of leukocytes.
Two milliliters of whole blood was taken from each patient immediately before irradiation and 100μl sample of the blood was placed in wells with 0.8mg/ml of Infliximab or without the preparation. TGF-β levels in blood culture without cA2 before irradiation showed continuous rise from 3978 to 8950 pg/ml at the 96th hour. In the post‑irradiated group without cA2, a continuous growth was recorded till the 48th hour (from 4758 to 13324 pg/ml at the 24th hour) and then a slight decline to 11950 pg/ml at 96th hour, respectively. In the cultures with cA2, TGF-β levels before irradiation showed also the peak value at the 48th h (from 4050 to 7340 pg/ml at the 48th hour) and then started to go down (6500 pg/ml at the 72nd hour and 5720 pg/ml at the 96th hour). In the post-irradiated group, during the first 6 hours, there was a growth from 4717 pg/ml to 7462 pg/ml, and then a paradoxical increase to 16885 pg/ml at the 12th hour. From the 12th hour the values started to decrease to 6895 pg/ml at the 96th h. The obtained results confirmed the hypothesis of decreasing the TGF-β expression by inactivating TNF-α with a monoclonal antibody (Infliximab) in the patients’ whole blood culture in vitro. These observations are a good starting point for further experiments in vitro and in vivo, whose main objective is to reduce post radiation fibrosis.
References
1. Aggarwal B.B., Kohr W.J., Hass P.E. et al: Human tumor necrosis factor. J Biol Chem. 260(4), 2345, 1985.
2. Anscher M.S., Crocker I.R., Jirtle R.L. : Transforming growth factor-β, expression in irradiated liver. Radiat Res. 122, 77, 1990.
3. Bauer K.A., ten Cate H., Barzegar S. et al: Tumor necrosis factor infusions have a procoagulant effect on the hemostatic mechanism in humans. Blood. 74, 165, 1989.
4. Broekelmann T.J., Limper A.H., Colby T.V., et al: Transforming growth factor β is present at sites of extracellular matrix gene expression in human pulmonary fibrosis. Proc Natl Acad Sci USA. 88, 6642, 1991.
5. Burger A., Löffler H., Bamberg M. et al: Molecular and cellular basis of radiation fibrosis. Int J Radiat Biol. 73(4), 401, 1998.
6. Canney P.A., Dean S.: Transforming growth factor β: A promotor of late connective tissue injury following radiotherapy? The British Journal of Radiology. 63, 620, 1990.
7. Finkelstein J.N., Johnston C.J., Baggs R. et al: Early alterations in extracellular matrix and transforming growth factor β gene expression in mouse lung indicative of late radiation fibrosis. Int J Radiation Oncology Biol Phys. 28(3), 621, 1994.
8. Fuks Z., Weichselbaum R.R.: Radiation tolerance and the new biology: Growth factor involvement in radiation injury to the lung. Int J Radiation Oncology Biol Phys. 24, 183, 1992.
9. Hallahan D.E., Spriggs D.R., Beckett M.A. et al: Increased tumor necrosis factor a mRNA after cellular exposure to ionizing radiation. Proc Nat Acad Sci USA. 10104, 1986.
10. Khalil N. : TGF-β: From latent to active. Microbes and Infection. 1, 1255, 1999.
11. Knight D.M., Trinh H., Le J. et al: Construction an initial characterization of mouse-human chimeric Anti TNF antibody. Mol Immunol. 30, 1443, 1993.
12. McBride W.H. : Cytokine cascades in late normal tissue radiation responses. Int J Radiation OncoIogy Biol Phys. 33(1), 233, 1995.
13. Pelton R.W., Moses H.L.: The β-type transforming growth factor. Am Rev Respir Dis. 42, 31, 1990.
14. Ritzenthaler J.D., Goldstein R.H., Fine A.: Regulation of the α 1 (I) collagen promoter via a transforming growth fac¬tor-β activation element. J Biol Chem. 268, 13625, 1993.
15. Roberts A.B., Sporn M.B., Assoian R.K. et al: Transforming growth factor type β: Rapid induction of fibrosis and angio¬genesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci USA. 83, 4167, 1986.
16. Rodemann H.P., Bamberg M.: Cellular basis of radiation-induced fibrosis. Radiation Oncol. 35, 83, 1995.
17. Rodemann H.P., Binder A., Burger A. et al: The underlying cellular mechanism of fibrosis. Kidney Int. 49, 32, 1996.
18. Rube C.E., Uthe D., Schmid K.W. et al: Dose dependent induction of transforming growth factor beta in the lung tissue of fibrosis prone mice after thoracic radiation. Int J Radiat Oncol Biol Phys. 47, 1033, 2000.
19. Rubin P., Johnston C.J., Williams J.P. et al: A perpetual cascade of cytokines post-radiation leads to pulmonary fibrosis. Int. J Radiat Oncol Biol Phys. 33, 99, 1995.
20. Sherman M.L., Datta R., Hallahan D.E. et al: Regulation of tumor necrosis factor gene expression by ionizing radiation in human myeloid leukemia cells and peripheral blood monocytes. J Clin Invest. 87, 1794, 1991.
21. Sime P.J., Xing Z., Graham F.L. et al: Adenovirus-mediated gene transfer of active transforming growth factor-β induces prolonged severe fibrosis in rat lungs. J Clin Invest. 100, 768, 1997.
22. Warshamana G.S., Corti M., Brody A.R.: TNF-α, PDGF,and TGF-β1 expression by primary mouse bronchiolar-alveolar epithelial and mesenchymal cells: TNF-α induces TGF-β1. Experimental and Molecular Pathology. 71, 13, 2001.
23. Zhang K., Flanders K.C., Phan S.H.: Cellular localization of transforming growth factor-β expression in bleomycin-induced pulmonary fibrosis. Am J Pathol. 147, 352, 1995.
Downloads
Published
Issue
Section
License
Copyright (c) 2011 Authors
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 Unported License.
