Effects of combined therapy with thalidomide and glucantime on leishmaniasis induced by Leishmania major in BALB/c mice

  • SOLGI Ghassem (Department of Immunology, Faculty of Medicine, Tehran University of Medical Sciences) ;
  • KARIMINIA Amina (Department of Immunology, Pasteur Institute of Iran) ;
  • ABDI Khossro (Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences) ;
  • DARABI Majid (Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences) ;
  • GHAREGHOZLOO Behnaz (Immunology Laboratory, School of Para-Medical Sciences, Iran University of Medical Sciences)
  • Published : 2006.03.01

Abstract

For treating Leishmania major infection in BALB/c mice, we used thalidomide in conjunction with glucantime. Groups of mice were challenged with $5{\time}10^3$ metacyclic promastigotes of L. major subcutaneously. A week after the challenge, drug treatment was started and continued for 12 days. Thalidomide was orally administrated 30 mg/kg/day and glucantime was administrated intraperitoneally (200 mg/kg/day). It was shown that the combined therapy is more effective than single therapies with each one of the drugs since the foot pad swelling in the group of mice received thalidomide and glucantime was significantly decreased (0.9 :t 0.2 mm) compared to mice treated with either glucantime, thalidomide, or carrier alone (1.2 :t 0.25, 1.4 :t 0.3, and 1.7 :t 0.27 mm, respectively). Cytokine study showed that the effect of thalidomide was not dependent on IL-12; however, it up-regulated IFN-yand down-regulated IL-10 production. Conclusively, thalidomide seems promising as a conjunctive therapy with antimony in murine model of visceral leishmaniasis.

Keywords

References

  1. Alimohammadian MH, Darabi H, Kariminia A, Rivier D, Bovay P, Mauel J, Ajdary S, and Kharazmi A (2002) Adjuvant Effect of Leishmania major promastigotes on the immune response of mice to ovalbumin. Iranian Biomed J 6: 123-128
  2. Arruda MS, Richini VB, Oliveira SM, Vilani-Moreno FR (2004) Experimental murine mycobacteriosis: evaluation of the functional activity of alveolar macrophages in Thalidomide-treated mice. Braz J Med Biol Res 37: 485-492 https://doi.org/10.1590/S0100-879X2004000400005
  3. Chatelain R, Mauze S, Coffman RL (1999) Experimental Leishmania major infection in mice: role of IL-10. Parasite Immunol 21: 211-218 https://doi.org/10.1046/j.1365-3024.1999.00224.x
  4. Elso C, Kumar B, Smyth G, Foote S, Handman E (2004) Dissociation of disease susceptibility, inflammation and cytokine profile in lmr1/2 congenic mice infected with Leishmania major. Genes Immun 5: 188-196 https://doi.org/10.1038/sj.gene.6364056
  5. Franks ME, Macpherson GR, Figg WD (2004) Thalidomide. Lancet 363: 1802-1811 https://doi.org/10.1016/S0140-6736(04)16308-3
  6. Fu LM, Fu-Liu CS (2002) Thalidomide and tuberculosis. Int J Tuberc Lung Dis 6: 569-572
  7. Hailu A, van der Poll T, Berhe N, Kager PA (2004) Elevated plasma levels of interferon (IFN)-gamma, IFN-gamma inducing cytokines, and IFN-gamma inducible CXC chemokines in visceral leishmaniasis. Am J Trop Med Hyg 71: 561-567
  8. Handman E (2001) Leishmaniasis: Current status of vaccine development. Clin Microbiol Rev 14: 229-243 https://doi.org/10.1128/CMR.14.2.229-243.2001
  9. Karrow NA, Guoa TL, Zhanga LX, McCay JA, Musgrovea DL, Peacheea VL, Germolecb DR, White KL Jr (2003) Thalidomide modulation of the immune response in female B6C3F1 mice: a host resistance study. Int Immunopharmacol 3: 1447-1456 https://doi.org/10.1016/S1567-5769(03)00143-7
  10. Karrow NA, McCay JA, Brown RD, Musgrove DL, Pettit DA, Munson AE, Germolec DR, White KL Jr (2000) Thalidomide stimulates splenic antibody response and cytotoxic T lymphocyte activity and alters leukocyte subpopulation numbers in female B6C3F1 mice. Toxicol Appl Pharmacol 165: 237-244 https://doi.org/10.1006/taap.2000.8939
  11. Lang T, Courret N, Colle JH, Milon G, Antoine JC (2003) The levels and patterns of cytokines produced by CD4 T lymphocytes of BALB / c mice infected with Leishmania major by inoculation into the ear dermis depend on the infectiousness and size of the inoculum. Infect Immun 71: 2674-2683 https://doi.org/10.1128/IAI.71.5.2674-2683.2003
  12. Marriott JB, Muller G, Dalgleish AG (1999) Thalidomide as an emerging immuno-therapeutic agent. Immunol Today 20: 538-540 https://doi.org/10.1016/S0167-5699(99)01531-5
  13. Murray HW (2000) Treatment of visceral leishmaniasis (kala-azar): a decade of progress and future approaches. Int J Infect Dis 4: 158-177 https://doi.org/10.1016/S1201-9712(00)90078-X
  14. Murray HW (2001) Clinical and experimental advances in treatment of visceral leishmaniasis. Antimicrob Agents Chemother 45: 2185-2197 https://doi.org/10.1128/AAC.45.8.2185-2197.2001
  15. Murray HW, Delph-Etienne S (2000) Role of endogenous gamma interferon and macrophage microbicidal mechanisms in host response to chemotherapy in experimental visceral leishmaniasis. Infect Immun 68: 288-293 https://doi.org/10.1128/IAI.68.1.288-293.2000
  16. Murray HW, Jungbluth A, Ritter E, Montelibano C, Marino MW (2000) Visceral leishmaniasis in mice devoid of tumor necrosis factor and response to treatment. Infect Immun 68: 6289-6293 https://doi.org/10.1128/IAI.68.11.6289-6293.2000
  17. Noben-Trauth N, Lira R, Nagase H, Paul WE, Sacks DL (2003) The relative contribution of IL-4 receptor signaling and IL-10 to susceptibility to Leishmania major. J Immunol 170: 5152-5158 https://doi.org/10.4049/jimmunol.170.10.5152
  18. Passos VM, Barreto SM, Romanha AJ, Krettli AU, Volpini AC, Lima e Costa MF (2000) American cutaneous leishmaniasis: use of a skin test as a predictor of relapse after treatment. Bull World Health Organ 78: 968-974
  19. Sommer F, Meixner M, Mannherz M, Ogilvie AL, Rollinghoff M, Lohoff M (1998) Analysis of cytokine patterns produced by individual CD4+ lymph node cells during experimental murine leishmaniasis in resistant and susceptible mice. Int Immunol 10: 1853-1861 https://doi.org/10.1093/intimm/10.12.1853
  20. Stenger S, Donhauser N, Thuring H, Rollinghoff M, Bogdan C (1996) Reactivation of latent leishmaniasis by inhibition of inducible nitric oxide synthase. J Exp Med 183: 1501-1514 https://doi.org/10.1084/jem.183.4.1501
  21. Sundar S, Singh VP, Sharma S, Makharia MK, Murray HW (1997) Response to interferon-gamma plus antimony in Indian visceral leishmaniasis. J Infect Dis 176: 1117-1119 https://doi.org/10.1086/516526
  22. Sundar S, Murray HW (1995) Effect of treatment with interferon-gamma alone in Indian visceral leishmaniasis. J Infect Dis 172: 1627-1629 https://doi.org/10.1093/infdis/172.6.1627
  23. Toledo VP, Mayrink W, Gollob KJ, Oliveira MA, Costa CA, Genaro O, Pinto JA, Afonso LC (2001) Immunochemotherapy in American cutaneous leishmaniasis: immunological aspects before and after treatment. Mem Inst Oswaldo Cruz 96: 89-98 https://doi.org/10.1590/S0074-02762001000100010