Abstract
Animal models for opportunistic infections were developed by using mice immunosuppressed by 5-FU. These mice were susceptible to various microorganisms, while normal mice had greater tolerance to such microbial infections. In these models, thymosin α1 was found to protect mice against lethal infections with Candida albicans, Listeria monocytogenes, Pseudomonas aeruginosa, and Serratia marcescens when it was administered during 5-FU treatment prior to the infections. Thymosin α1 was effective in some infections at 0.4–400 μg/kg/day IP, about 1/100 of the dose required for thymosin fraction 5. Activity was also demonstrated against L-monocytogenes and Ps. aeruginosa by counting the viable bacteria in the liver after infection. The protective activity against Candida, elimination of which macrophages were essential, was abrogated by anti-thymocyte serum and/or carrageenan, indicating that thymosin α1 serves to maintain the functions of macrophages by reducing the damage to T cells by 5-FU. On the other hand, the activity against Pseudomonas infection was not affected by anti-thymocyte serum or carrageenan. It is probable that thymosin α1 also exerts its effect on neutrophils without participation of T cells and macrophages.
Keywords: Animal Model, Cancer Research, Pseudomonas Aeruginosa, Candida Albicans, Opportunistic Infection
References
- 1.Ahmed A, Smith AH, Wong DM, Thurman GB, Goldstein AL. In vitro induction of Lyt surface markers on precursor cells incubated with thymosin polypeptides. Cancer Treat Reports. 1978;62:1739. [PubMed] [Google Scholar]
- 2.Bodey GP. Infections in cancer patients. Cancer Treat Rev. 1975;2:89. doi: 10.1016/s0305-7372(75)80005-3. [DOI] [PubMed] [Google Scholar]
- 3.Catanzaro PJ, Schwarts HJ, Graham RC. Spectrum and possible mechanism of carrageenan cytotoxicity. Am J Pathol. 1971;64:387. [PMC free article] [PubMed] [Google Scholar]
- 4.Dobias B. specific and nonspecific immunity in Candida infections. Acta Med Scand. 1964;176:79. [PubMed] [Google Scholar]
- 5.Goldschneider I, Ahmed A, Bollum FJ, Goldstein AL. Induction of terminal deoxynucleotidyl transferase and Lyt antigens with thymosin: Identification of multiple subsets of prothymocytes in mouse bone marrow and spleen. Proc Natl Acad Sci USA. 1981;78:2469. doi: 10.1073/pnas.78.4.2469. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Goldstein AL, Low TLK, McAdoo M, McClure J, Thurman G, Rossio J, Lai C, Chang D, Wang S, Marvey C, Ramel AH, Meienhofer J. Thymosin α1: Isolation and sequence analysis of an immunologically active thymic polypeptide. Proc Natl Acad Sci USA. 1977;74:725. doi: 10.1073/pnas.74.2.725. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Hartzman RJ, Bach ML, Bach FH, Thurman GB, Sell KW. Precipitation of radioactively labeled sample: A semiautomatic multiple processor. Cell Immunol. 1972;4:182. doi: 10.1016/0008-8749(72)90018-4. [DOI] [PubMed] [Google Scholar]
- 8.Haung K-Y, Kind PD, Jagoda EM, Goldstein AL. Thymosin treatment modulates production of interferon. J Int Res. 1981;1:411. doi: 10.1089/jir.1981.1.411. [DOI] [PubMed] [Google Scholar]
- 9.Heidelberger C, Griesbach L, Cruz O, Schnitzer RJ, Grunberg E. Fluorinated pyrimidines, VI. Effects of 5-fluorouridine and 5-fluoro-2′-deoxyuridine on transplanted tumors. Proc Soc Exp Biol Med. 1958;97:470. doi: 10.3181/00379727-97-23777. [DOI] [PubMed] [Google Scholar]
- 10.Hooper JA, MaDaniel MC, Thurman GB, Cohen GH, Schulof RS, Goldstein AL. The purification and properties of bovine thymosin. Ann NY Acad Sci. 1975;249:125. doi: 10.1111/j.1749-6632.1975.tb29063.x. [DOI] [PubMed] [Google Scholar]
- 11.Ketchel SJ, Rodriguez V. Acute infections in cancer patients. Semin Oncol. 1978;5:167. [PubMed] [Google Scholar]
- 12.Levey RH, Medawar RB. Nature and mode of action of antilymphocyte antiserum. Proc Natl Acad Sci USA. 1966;56:1130. doi: 10.1073/pnas.56.4.1130. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Ohta Y, Yagi Y (1982) Effect of thymosin α1 on growth and differentiation of hematopoietic stem cells. (Abstract) Proc Jap Can Assoc. The 41th Annu Meet 392
- 14.Pazmino NH, Ihle JN, Goldstein AL. Induction in vivo and in vitro of terminal deoxynucleotidyl transferase by thymosin in bone marrow cells from athymic mice. J Exp Med. 1978;147:708. doi: 10.1084/jem.147.3.708. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Reed LJ, Muench H. A simple method of estimating fifty per cent endpoint. Am J Hyg. 1938;27:493. [Google Scholar]
- 16.Singer C, Kaplan MH, Armstrong D. Bacteremia and fungemia complicating neoplastic disease. Am J Med. 1977;62:731. doi: 10.1016/0002-9343(77)90876-2. [DOI] [PubMed] [Google Scholar]
- 17.Tatsukawa K, Mitsuyama M, Takeya K, Nomoto K. Differing contribution of polymorphonuclear cells and macrophages to protection of mice against Listeria monocytogenes and Pseudomonas aeruginosa . J Gen Microbiol. 1979;115:161. doi: 10.1099/00221287-115-1-161. [DOI] [PubMed] [Google Scholar]
- 18.Umeda Y, Nakamura J, Ishitsuka H, Yagi Y. Protective mechanisms of thymosin α1 against opportunistic infections. Proc Jap Soc Immunol. 1981;11:222. [Google Scholar]
- 19.Wara DW, Goldstein AL, Doyle W, Ammann AJ. Thymosin activity in patients with cellular immunodeficiency. N Engl J Med. 1975;292:70. doi: 10.1056/NEJM197501092920204. [DOI] [PubMed] [Google Scholar]