Abstract
A single injection of αβ-interferon (αβ-IFN) (30 000 units/mouse), a major biological modifier of natural killer (NK) cytolytic activity, strongly stimulated NK activity in normal mice, as expected, while the same treatment did not statistically alter the NK response in cyclophosphamide (CY)-suppressed animals.
We investigated the possibility of thymosin α1 cooperating with αβ-IFN in boosting NK activity in CY-suppressed animals.
The results show that treatment with thymosin α1 (200 μg/kg) for 4 days, followed by a single injection of αβ-IFN 24 h before testing, strongly restored NK activity in CY-suppressed mice. Thymosin α1 was, moreover, able to accelerate the recovery rate of NK activity in bone marrow reconstituted murine chimeras.
Taken together the data support the concept that the synergic effect between thymosin α1 and αβ-IFN could be the result of effects on differentiation of the NK lineage at different levels.
Keywords: Bone Marrow, Cancer Research, Natural Killer, Interferon, Cyclophosphamide
References
- 1.Bardos P, Bach JF. Modulation of mouse natural killer cell activity by serum thymic factor. Scand J Immunol. 1982;15:321. doi: 10.1111/j.1365-3083.1982.tb00730.x. [DOI] [PubMed] [Google Scholar]
- 2.Bash JA, Woody JN, Neefe JR. NK Cells and other natural effector cells. New York: Academic Press; 1982. Phase I trial of immunomodulatory activities of human leukocyte interferon in advanced cancer patients; p. 1273. [Google Scholar]
- 3.Bloom BR. Interferons and the immune system. Nature. 1980;284:593. doi: 10.1038/284593a0. [DOI] [PubMed] [Google Scholar]
- 4.Djeu JY, Heinbaugh A, Holden HT, Herberman RB. Augmentation of mouse natural killer cell activity by interferon and interferon inducers. J Immunol. 1979;122:175. [PubMed] [Google Scholar]
- 5.Einhorn S, Blomgren H, Strander H. Interferon and spontaneous cytotoxicity in man. V. Enhancement of spontaneous cytotoxicity in patients receiving human leukocyte interferon. Int J Cancer. 1980;26:419. doi: 10.1002/ijc.2910260406. [DOI] [PubMed] [Google Scholar]
- 6.Flexman JP, Holt PG, Mayrhofer G, Latham BI, Shellam GR. The role of the thymus in the maintenance of natural killer cells in vivo. Cell Immunol. 1985;90:366. doi: 10.1016/0008-8749(85)90201-1. [DOI] [PubMed] [Google Scholar]
- 7.Gidlund M, Orn A, Wigzell H, Senik A, Gresser I. Enhanced NK cell activity in mice injected with intereron and interferon inducers. Nature. 1978;223:259. doi: 10.1038/273759a0. [DOI] [PubMed] [Google Scholar]
- 8.Goldstein AL, Low TLK, Mac Adoo M, McClure J, Thurman GB, Rossio J, Lai CJ, Chang D, Wang SS, Harvey C, Ramael AH, Meienhofer J. Thymosin α 1: isolation and sequence analysis of immunologically active polypeptide. Proc Nat Acad Sci. 1977;74:725. doi: 10.1073/pnas.74.2.725. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Herberman RB, Nunn ME, Lavrin DH. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. I. Distribution of reactivity. Int J Cancer. 1975;16:216. doi: 10.1002/ijc.2910160204. [DOI] [PubMed] [Google Scholar]
- 10.Herberman RB, Djeu JY, Kay HD, Ortaldo JR, Riccardi C, Bonnard GD, Holden HT, Fagnani R, Santoni A, Puccetti P. Natural Killer cells: charachteristics and regulation of activity. Immunol Rev. 1979;44:43. doi: 10.1111/j.1600-065x.1979.tb00267.x. [DOI] [PubMed] [Google Scholar]
- 11.Herberman RB, Ortaldo JR, Mantovani A, Hobbs DS, Kung HF, Pestka S. Effect of human recobinant interferon on cytotoxic activity of natural killer (NK) cells and monocytes. Cell Immunol. 1982;67:160. doi: 10.1016/0008-8749(82)90208-8. [DOI] [PubMed] [Google Scholar]
- 12.Huddlestone JF, Marigan TC, Oldstone MB. Induction and kinetics of natural killer cells in humans following interferon therapy. Nature. 1979;282:417. doi: 10.1038/282417a0. [DOI] [PubMed] [Google Scholar]
- 13.Hurme M, Sihvola M. High expression of the Thy-1 antigen on natural killer cells recently derived from bone marrow. Cell Immunol. 1984;84:276. doi: 10.1016/0008-8749(84)90099-6. [DOI] [PubMed] [Google Scholar]
- 14.Karinieni AL, Timonen T, Kousa M. Effect of leukocyte interferon on natural killer cells in healthy volunteers. Scand J Immunol. 1980;12:371. doi: 10.1111/j.1365-3083.1980.tb00080.x. [DOI] [PubMed] [Google Scholar]
- 15.Kaiserlian D, Bardos P, Bach JF. In vitro modulation of mouse natural killer (NK) cell activity by the serum thymic factor (FTS) Cell Immunol. 1983;76:232. doi: 10.1016/0008-8749(83)90366-0. [DOI] [PubMed] [Google Scholar]
- 16.Koren HS, Anderson SJ, Fisher DG, Copeland CS, Jensen PJ. Regulation of human natural killing. I. The role of monocytes, interferon and prostaglandins. J Immunol. 1981;127:2007. [PubMed] [Google Scholar]
- 17.Low TLK, Thurman GB, McAdoo M, McClure J, Rossio JL, Naylor PH, Goldstein AL. The chemistry and biology of thymosin. I. Isolation, characterization, and biological activities of thymosin α 1 and polypeptide β 1 from calf thymus. J Biol Chem. 1979;254:981. [PubMed] [Google Scholar]
- 18.Maluish AE, Ortaldo JR, Herberman RB. NK cells and other natural effector cells. New York: Academic Press; 1982. Modulation of NK activity by recombinant leucocyte interferon in advanced cancer patients; p. 1279. [Google Scholar]
- 19.Otha J, Sueki K, Yomyama Y, Tezuka E, Yagi Y. Immunomodulating activity of thymosin F5 and thymosin α1 in immunosuppressed mice. Cancer Immunol Immunother. 1983;15:108. doi: 10.1007/BF00199700. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Riccardi C, Vose BM, Herberman RB. Modulation of IL-2 dependent growth of mouse NK cells by interferon and T-lymphocytes. J Immunol. 1983;130:228. [PubMed] [Google Scholar]
- 21.Saito T, Welker RD, Fukui H, Herberman RB, Chirigos MA. Development of hyporesponsivenes to augmentation of natural killer cell activity after multiple doses of maleic anhydride divinyl ether: association with decreased numbers of large granular lymphocytes. Cell Immunol. 1985;90:577. doi: 10.1016/0008-8749(85)90222-9. [DOI] [PubMed] [Google Scholar]
- 22.Timonen T, Ortaldo JR, Herberman RB. Analysis by a single cell cytotoxicity assay of natural killer (NK) cell frequencies among human large granular lymphocytes and the effects of interferon on their activity. J Immunol. 1982;128:2514. [PubMed] [Google Scholar]
- 23.Trinchieri G, Perussia B. NK cells and other natural effector cells. New York: Academic Press; 1982. Interferons and natural killer cells: interacting systems of non specific host defense; p. 369. [Google Scholar]
- 24.Umeda Y, Sakamoto A, Nakamura J, Ishitsuka H, Yagi Y. Thymosin α1 restores NK-cell activity and prevents tumor progression in mice immunosuppressed by cytostatics or X-rays. Cancer Immunol Immunother. 1983;15:78. doi: 10.1007/BF00199694. [DOI] [PMC free article] [PubMed] [Google Scholar]