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Journal of Biomedical Science

, Volume 11, Issue 5, pp 623–630 | Cite as

Effect of thymosin alpha 1 on the antitumor activity of tumor-associated macrophage-derived dendritic cells

  • Pratima Shrivastava
  • Sukh Mahendra Singh
  • Nisha Singh
Original Paper

Abstract

We have previously suggested that thymosin α1 (thyα1), an immunomodulating thymic hormone, can activate tumor-associated macrophages to a tumoricidal state in a murine model bearing a transplantable T-cell lymphoma of spontaneous origin designated as Dalton's lymphoma (DL). Since tumor-infiltrating dendritic cells (DC) also play an important role in the host's antitumor response and are as such in an immunocompromised state in a tumor-bearing host, in the present investigation we studied if thyα1 is able to influence the differentiation of tumor-associated macrophages (TAM) into DC with granulocyte macrophage colony stimulating factor (GM-CSF), interleukin (IL)-4 and tumor necrosis factor (TNF) and whether these TAM-derived DC show enhanced antitumor activity. It was observed that DC generated from thyα1-administered tumor-bearing mice showed augmented antitumor activity in vitro. Adoptive immunotherapy using TAM-derived DC showed a significant delay in the tumor growth and a prolongation of the survival time in tumor-bearing mice. DC obtained from TAM of thyα1-administered mice also produced an enhanced amount of cytokines like IL-1 and TNF-α. This is the first study of its kind regarding the effect of thyα1 on the differentiation of DC from TAM and the role of TAM-derived DC in tumor progression.

Key Words

Adoptive transfer Cytotoxicity Dalton's lymphoma Dendritic cells Interleukin-1 Nitric oxide Thymosin α1 Tumor necrosis factor Tumor-associated macrophages 

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References

  1. 1.
    Ancell CD, Phipps J, Young L. Thymosin alpha-1. Am J Health Syst Pharm 15:879–885;2001.Google Scholar
  2. 2.
    Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, Pulendran B, Palucka K. Immunobiology of dendritic cells. Annu Rev Immunol 18:767–81;2000.Google Scholar
  3. 3.
    Baumann C, Badamachian M, Goldstein A. Preclinical studies of thymosin α1 and thymosin β4. In: Mauer HR, Goldstein AL, Hager ED, eds. Thymic Peptides in Preclinical and Clinical Medicine — An Update. Munich, Zuckschwerdt, 13–27;1998.Google Scholar
  4. 4.
    Bell D, Chomarat P, Broyles D, Netto G, Harb GM, Lebecque S, Valladeau J, Davoust J, Palucka KA, Banchereau J. In breast carcinoma tissue, immature dendritic cells reside within the tumor, whereas mature dendritic cells are located in peritumoral areas. J Exp Med 190:1417–1425;1999.Google Scholar
  5. 5.
    Beuth J, Schierholz JM, Mayer G. Thymosin alpha-1 application augments immune response and down-regulates tumor weight and organ colonization in BALB/c-mice. Cancer Lett 159:9–13;2000.Google Scholar
  6. 6.
    Bharti A, Singh SM. Inhibition of macrophage nitric oxide production by gangliosides derived from a spontaneous T cell lymphoma: the involved mechanisms. Nitric Oxide 8:75–82;2003.Google Scholar
  7. 7.
    Billich A. Thymosin alpha1. SciClone Pharmaceuticals (review). Curr Opin Investig Drugs 3:698–707;2002.Google Scholar
  8. 8.
    Biragyn A, Ruffini PA, Leifer CA, Klyushnenkova E, Shakhov A, Chertov O, Shirakawa AK, Farber JM, Segal DM, Oppenheim JJ, Kwak LW. Toll-like receptor 4-dependent activation of dendritic cells by beta-defensin 2. Science 298:1025–1029;2002.Google Scholar
  9. 9.
    Bodey B, Bodey B Jr, Sigel SE, Kaiser HE. Review of thymic hormones in cancer diagnosis and treatment. Int J Immunopharmacol 22:261–273;2000.Google Scholar
  10. 10.
    Boudaly S, Morin J, Berthier R, Marche P, Boitard C. Altered dendritic cells (DC) might be responsible for regulatory T cell imbalance and autoimmunity in nonobese diabetic (NOD) mice. Eur Cytokine Network 13:29–37;2002.Google Scholar
  11. 11.
    Bubenik J. Genetically engineered dendritic cell-based cancer vaccines. Int J Oncol 18:475–478;2000.Google Scholar
  12. 12.
    Candido KA, Shimizu K, McLaughlin JC, et al. Local administration of dendritic cells inhibits established breast tumor growth: implications for apoptosis-inducing agents. Cancer Res 61:228–236;2001.Google Scholar
  13. 13.
    Chu CS, Woo EY, Toll AJ, Rubin SC, June CH, Caroll RG, Schlienger K. Tumor-associated macrophages as a source of functional dendritic cells in ovarian cancer patients. Clin Immunol 102:291–301;2002.Google Scholar
  14. 14.
    Colaco CA. Why are dendritic cells central to cancer immunotherapy. Mol Med Today 5:14–17;1999.Google Scholar
  15. 15.
    Garaci E, Pica F, Rasi G, Favalli C. Thymosin α1 in the treatment of cancer: from basic research to clinical application (review). Int J Immunopharmacol 22:1067–1075;2000.Google Scholar
  16. 16.
    Garbin F, Eckert K, Buttner P, Garbe C, Maurer HR. The influence of thymic preparation thymex-L on deficient antitumor activity of monocytes from melanoma patients in vitro. Oncol Rep 2:469;1995.Google Scholar
  17. 17.
    Gunzer M, Grabbe S. Dendritic cells in cancer immunotherapy. Crit Rev Immunol 21:133–145;2001.Google Scholar
  18. 18.
    Sodhi A, Gupta P. Study on pinocytosis and antigen presentation by murine peritoneal macrophages to T cells in vitro after cisplatin treatment. Arch Immunol Ther Exp (Warsz) 36:315–323;1988.Google Scholar
  19. 19.
    Hajek R, Butch AW. Dendritic cell biology and the application of dendritic cells to immunotherapy of multiple myeloma. Med Oncol 17:2–15;2000.Google Scholar
  20. 20.
    Hart D. Dendritic cells: unique leukocyte populations which control the primary immune response (review). Blood 90:3245–3287;1997.Google Scholar
  21. 21.
    Hodge JW, Rad AN, Grosenbach DW, Sabzevari H, Yafal AG, Gritz L, Schlom J. Enhanced activation of T cells by dendritic cells engineered to hyperexpress a triad of costimulatory molecules. J Natl Cancer Inst 92:1228–1239;2000.Google Scholar
  22. 22.
    Jalali A, Stoklosa T, Giermasz A, Olszewska D, Wilczynski G, Jakobisiak M, Golab J. A single injection of immature dendritic cells is able to induce antitumour response against a murine colon adenocarcinoma with a low apoptotic index. Oncol Rep 9:991–994;2002.Google Scholar
  23. 23.
    Johanne MK, Queendy Yu, Susan TP, Sarah EP, Srinivas S, Lisa AW, Bruce LR. Induction of antitumor immunity with dendritic cells transduced with adenovirus vector-encoding endogenous tumor-associated antigens. J Immunol 163:699–707;1999.Google Scholar
  24. 24.
    Kugler A, Stuhler G, Walden P, Zoller G, Zobywalski A, Brossart P, Trefzer U, Ullrich S, Muller CA, Becker B, Gross AJ, Hemmerleim B, Kanz L, Muller GA, Ringert RH. Regression of human metastatic renal cell carcinoma after vaccination with tumor cell-dendritic cell hybrids. Nat Med 6:332–336;2000.Google Scholar
  25. 25.
    Kullavanuaya P, Treeprasertsuk S, Thong-Ngam B, Chaermthai K, Gonlachanvit S, Suwanagool P. The combined treatment of interferon α2a and thymosin α1 for chronic hepatitis C: the 48 weeks of treatment results. J Med Assoc Thai 84(suppl 1):S462-S468;2001.Google Scholar
  26. 26.
    Kumar A, Singh SM, Parajuli P. Modulatory effects of Dalton's lymphoma cells on the production of reactive nitrogen intermediates, IL-1 and TNF by murine peritoneal macrophages. Neoplasma 44:363;1994.Google Scholar
  27. 27.
    Labeur MS, Roters B, Pers B, Mehling A, Luger TA, Schwarz T, Grabbe S. Generation of tumor immunity by bone marrow-derived dendritic cells correlates with dendritic cell maturation stage. J Immunol 162:168–175;1999.Google Scholar
  28. 28.
    Lotze MT. Getting to the source: dendritic cells as therapeutic reagents for the treatment of patients with cancer. Ann Surg 226:1–5;1997.Google Scholar
  29. 29.
    Ludewig B, Barchiesi F, Pericin M, Zinkernagel RM, Hengartner H, Schwendener RA. In vivo antigen loading and activation of dendritic cells via a liposomal peptide vaccine mediates protective antiviral and anti-tumour immunity. Vaccine 19:23–32;2000.Google Scholar
  30. 30.
    Mayer G, Pohlmeyer K, Caliebe A, Heimueller E, Behnke B, Steimann G, Lange C, Beuth J. Low molecular thymic peptides stimulate human blood dendritic cells. Anticancer Res 5:2873–2883;2000.Google Scholar
  31. 31.
    Melero I, Vile RG, Colombo MP. Feeding dendritic cells with tumor antigens: self-service buffet or a la carte? Gene Ther 7:1167–1170;2000.Google Scholar
  32. 32.
    Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63;1983.Google Scholar
  33. 33.
    Nestle FO, Alijagic S, Gilliet M, Sun Y, Grabbe S, Dummer R, Burg G, Schadendorf D. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med 4:328–332;1998.Google Scholar
  34. 34.
    Ohmori H, Kamo M, Yamakoshi K, Nitta MH, Hikida M, Kanayama N. Restoration of immunocyte functions by thymosin α1 in cyclophosphamide-induced immunodeficient mice. Immunopharmacol Immunotoxicol 23:75–82;2001.Google Scholar
  35. 35.
    Parajuli P, Singh SM. Ascitic growth of a T cell lymphoma in mice alters the humoral and cellular immune response to exogenous antigen. Tumor Biol 18:104–112;1997.Google Scholar
  36. 36.
    Parajuli P, Singh SM, Kumar A, Sodhi A. Alterations in the tumoricidal functions of murine tumor-associated macrophages during progressive growth of tumors in vivo. Cancer J 10:222–228;1997.Google Scholar
  37. 37.
    Sallusto F, Lanzavecchia A. Efficient presentation of soluble antigens by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor-α. J Exp Med 179:1109–1118;1994.Google Scholar
  38. 38.
    Schmitz M, Diestelkoetter P, Weigle B, Schmachtenberg F, Stevanovic S, Ockert D, Rammensee HG, Rieber EP. Generation of survivin-specific CD8+ T effector cells by dendritic cells pulsed with protein or selected peptides. Cancer Res 60:4845–4849;2000.Google Scholar
  39. 39.
    Shanker A, Singh SM. Immunopotentiation in mice bearing a transplantable T-cell lymphoma: role of thymic extract. Neoplasma 50:272–279;2003.Google Scholar
  40. 40.
    Shanker A, Singh SM, Sodhi A. Ascitic growth of a spontaneous T cell lymphoma induces thymic involution. 1. Alterations in the repertoire of CD4+/CD8+ thymocytes. Tumor Biol 21:288;2000.Google Scholar
  41. 41.
    Shanker A, Singh SM, Sodhi A. Ascitic growth of a spontaneous transplantable T cell lymphoma induces thymic involution. 2. Induction of apoptosis in thymocytes. Tumor Biol 21:315;2000.Google Scholar
  42. 42.
    Shanker A, Singh SM, Sodhi A. Impairment of T-cell functions with the progressive ascitic growth of a transplantable T-cell lymphoma of spontaneous origin. FEMS Immunol Med Microbiol 27:247–255;2000.Google Scholar
  43. 43.
    Shrivastava P, Singh SM, Singh N. Effect of thymosin-α1 on the production of nitric oxide by tumor-associated macrophages. Neoplasma 50:47–53;2003.Google Scholar

Copyright information

© National Science Council 2004

Authors and Affiliations

  • Pratima Shrivastava
    • 1
  • Sukh Mahendra Singh
    • 1
  • Nisha Singh
    • 1
  1. 1.School of BiotechnologyBanaras Hindu UniversityVaranasiIndia

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