Testosterone replacement effectively inhibits the development of experimental autoimmune orchitis in rats: Evidence for a direct role of testosterone on regulatory T cell expansion

Journal of Immunology

Volumn 186, Issue 9, 2011, Pages 5162-5172

  Fijak, Monika ^a   Schneider, Eva ^a   Klug, Jörg ^a   Bhushan, Sudhanshu ^a   Hackstein, Holger ^a   Schuler, Gerhard ^a   Wygrecka, Malgorzata ^a   Gromoll, Jörg ^b   Meinhardt, Andreas ^a  

^a JUSTUS LIEBIG UNIVERSITY   (Germany)

^b UNIVERSITY OF MÜNSTER   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

GAMMA INTERFERON; HYPOXANTHINE PHOSPHORIBOSYLTRANSFERASE; INTERLEUKIN 10; INTERLEUKIN 2; INTERLEUKIN 6; MESSENGER RNA; MONOCYTE CHEMOTACTIC PROTEIN 1; TESTOSTERONE; TRANSCRIPTION FACTOR FOXP3; TRANSFORMING GROWTH FACTOR BETA1; TUMOR NECROSIS FACTOR ALPHA;

ANDROGEN THERAPY; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; AUTOIMMUNE DISEASE; CD4+ CD25+ T LYMPHOCYTE; CD4+ T LYMPHOCYTE; CELL ISOLATION; CELL MIGRATION; CHEMOTAXIS; CONTROLLED STUDY; CYTOKINE RELEASE; DOWN REGULATION; FLUORESCENCE IN SITU HYBRIDIZATION; HISTOPATHOLOGY; IMMUNOMODULATION; LYMPH NODE; LYMPHOCYTIC INFILTRATION; MACROPHAGE; MALE; MONONUCLEAR CELL; NONHUMAN; ORCHITIS; PRIORITY JOURNAL; PROTEIN EXPRESSION; RAT; REGULATORY T LYMPHOCYTE; TESTIS WEIGHT; TESTOSTERONE BLOOD LEVEL; TH1 CELL; UPREGULATION;

ANDROGENS; ANIMALS; CELL SEPARATION; CYTOKINES; DISEASE MODELS, ANIMAL; ENZYME-LINKED IMMUNOSORBENT ASSAY; FLOW CYTOMETRY; LYMPHOCYTE ACTIVATION; MALE; MICROSCOPY, FLUORESCENCE; ORCHITIS; RATS; RATS, INBRED WKY; REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION; T-LYMPHOCYTES, REGULATORY; TESTOSTERONE;

EID: 79955540987     PISSN: 00221767     EISSN: 15506606     Source Type: Journal    
DOI: 10.4049/jimmunol.1001958     Document Type: Article

References (52)

1. Whiteford, L. M., and L. Gonzalez. 1995. Stigma: the hidden burden of infertility. Soc. Sci. Med. 40: 27-36.
2. WHO. 1987. Towards more objectivity in diagnosis and managment of male infertility. Int. J. Androl. 7(Suppl.): 1-53.
3. Nieschlag, E., and H. Behre. 2000. Andrology. Male Reproductive Health and Dysfunction. Springer, Berlin.
4. Schuppe, H. C., A. Meinhardt, J. P. Allam, M. Bergmann, W. Weidner, and G. Haidl. 2008. Chronic orchitis: a neglected cause of male infertility? Andrologia 40: 84-91.
5. Schuppe, H. C., and A. Meinhardt. 2005. Immune privilege and inflammation of the testis. Chem. Immunol. Allergy 88: 1-14.
6. Haidl, G., J. P. Allam, and H. C. Schuppe. 2008. Chronic epididymitis: impact on semen parameters and therapeutic options. Andrologia 40: 92-96.
7. Weidner, W., G. M. Colpi, T. B. Hargreave, G. K. Papp, J. M. Pomerol, C. Ghosh; EAU Working Group on Male Infertility. 2002. EAU guidelines on male infertility. Eur. Urol. 42: 313-322.
8. Osegbe, D. N. 1991. Testicular function after unilateral bacterial epididymoorchitis. Eur. Urol. 19: 204-208.
9. Fijak, M., and A. Meinhardt. 2006. The testis in immune privilege. Immunol. Rev. 213: 66-81.
10. Weidner, W., C. Garbe, L. Weissbach, J. Harbrecht, K. Kleinschmidt,H. G. Schiefer, and H. J. Friedrich. 1990. [Initial therapy of acute unilateral epididymitis using ofloxacin. II. Andrological findings]. Urologe A 29: 277-280.
11. Tung, K. S., and C. Teuscher. 1995. Mechanisms of autoimmune disease in the testis and ovary. Hum. Reprod. Update 1: 35-50.
12. Rival, C., M. S. Theas, M. O. Suescun, P. Jacobo, V. Guazzone, N. van Rooijen, and L. Lustig. 2008. Functional and phenotypic characteristics of testicular macrophages in experimental autoimmune orchitis. J. Pathol. 215: 108-117. (Pubitemid 351786029)
13. Iosub, R., J. Klug, M. Fijak, E. Schneider, S. Fröhlich, K. Blumbach, G. Wennemuth, C. P. Sommerhoff, M. Steinhoff, and A. Meinhardt. 2006. Development of testicular inflammation in the rat involves activation of proteinaseactivated receptor-2. J. Pathol. 208: 686-698.
14. Rival, C., L. Lustig, R. Iosub, V. A. Guazzone, E. Schneider, A. Meinhardt, and M. Fijak. 2006. Identification of a dendritic cell population in normal testis and in chronically inflamed testis of rats with autoimmune orchitis. Cell Tissue Res. 324: 311-318.
15. Guazzone, V. A., P. Jacobo, M. S. Theas, and L. Lustig. 2009. Cytokines and chemokines in testicular inflammation: A brief review. Microsc. Res. Tech. 72: 620-628.
16. Fijak, M., R. Iosub, E. Schneider, M. Linder, K. Respondek, J. Klug, and A. Meinhardt. 2005. Identification of immunodominant autoantigens in rat autoimmune orchitis. J. Pathol. 207: 127-138. (Pubitemid 41404143)
17. Guazzone, V. A., C. Rival, B. Denduchis, and L. Lustig. 2003. Monocyte chemoattractant protein-1 (MCP-1/CCL2) in experimental autoimmune orchitis. J. Reprod. Immunol. 60: 143-157.
18. Theas, M. S., C. Rival, S. Jarazo-Dietrich, P. Jacobo, V. A. Guazzone, and L. Lustig. 2008. Tumour necrosis factor-alpha released by testicular macrophages induces apoptosis of germ cells in autoimmune orchitis. Hum. Reprod. 23: 1865-1872.
19. Doncel, G. F., J. A. Di Paola, and L. Lustig. 1989. Sequential study of the histopathology and cellular and humoral immune response during the development of an autoimmune orchitis in Wistar rats. Am. J. Reprod. Immunol. 20: 44-51.
20. Lustig, L., L. Lourtau, R. Perez, and G. F. Doncel. 1993. Phenotypic characterization of lymphocytic cell infiltrates into the testes of rats undergoing autoimmune orchitis. Int. J. Androl. 16: 279-284.
21. Suescun, M. O., R. S. Calandra, and L. Lustig. 1994. Alterations of testicular function after induced autoimmune orchitis in rats. J. Androl. 15: 442-448. (Pubitemid 24338042)
22. Bouman, A., M. J. Heineman, and M. M. Faas. 2005. Sex hormones and the immune response in humans. Hum. Reprod. Update 11: 411-423.
23. Snider, H., C. Lezama-Davila, J. Alexander, and A. R. Satoskar. 2009. Sex hormones and modulation of immunity against leishmaniasis. Neuroimmunomodulation 16: 106-113.
24. Orton, S. M., B. M. Herrera, I. M. Yee, W. Valdar, S. V. Ramagopalan, A. D. Sadovnick, G. C. Ebers; Canadian Collaborative Study Group. 2006. Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol. 5: 932-936.
25. Duquette, P., J. Pleines, M. Girard, L. Charest, M. Senecal-Quevillon, and C. Masse. 1992. The increased susceptibility of women to multiple sclerosis. Can. J. Neurol. Sci. 19: 466-471.
26. Whitacre, C. C., S. C. Reingold, and P. A. O'Looney. 1999. A gender gap in autoimmunity. Science 283: 1277-1278.
27. Gold, S. M., and R. R. Voskuhl. 2009. Estrogen and testosterone therapies in multiple sclerosis. Prog. Brain Res. 175: 239-251.
28. Swerdloff, R. S., and C. Wang. 2004. Androgens and the ageing male. Best Pract. Res. Clin. Endocrinol. Metab. 18: 349-362.
29. Fitzpatrick, F., F. Lepault, F. Homo-Delarche, J. F. Bach, and M. Dardenne. 1991. Influence of castration, alone or combined with thymectomy, on the development of diabetes in the nonobese diabetic mouse. Endocrinology 129: 1382-1390.
30. Bebo, B. F., Jr., E. Zelinka-Vincent, G. Adamus, D. Amundson, A. A. Vandenbark, and H. Offner. 1998. Gonadal hormones influence the immune response to PLP 139-151 and the clinical course of relapsing experimental autoimmune encephalomyelitis. J. Neuroimmunol. 84: 122-130. (Pubitemid 28248396)
31. Fox, H. S. 1992. Androgen treatment prevents diabetes in nonobese diabetic mice. J. Exp. Med. 175: 1409-1412.
32. Dalal, M., S. Kim, and R. R. Voskuhl. 1997. Testosterone therapy ameliorates experimental autoimmune encephalomyelitis and induces a T helper 2 bias in the autoantigen-specific T lymphocyte response. J. Immunol. 159: 3-6.
33. Ansar Ahmed, S., P. R. Young, and W. J. Penhale. 1986. Beneficial effect of testosterone in the treatment of chronic autoimmune thyroiditis in rats. J. Immunol. 136: 143-147.
34. Harbuz, M. S., Z. Perveen-Gill, S. L. Lightman, and D. S. Jessop. 1995. A protective role for testosterone in adjuvant-induced arthritis. Br. J. Rheumatol. 34: 1117-1122.
35. Bebo, B. F., Jr., J. C. Schuster, A. A. Vandenbark, and H. Offner. 1999. Androgens alter the cytokine profile and reduce encephalitogenicity of myelinreactive T cells. J. Immunol. 162: 35-40. (Pubitemid 29018901)
36. Liva, S. M., and R. R. Voskuhl. 2001. Testosterone acts directly on CD4+ T lymphocytes to increase IL-10 production. J. Immunol. 167: 2060-2067.
37. Head, J. R., and R. E. Billingham. 1985. Immune privilege in the testis. II. Evaluation of potential local factors. Transplantation 40: 269-275.
38. Sun, Y. T., D. M. Robertson, G. Gonzales, G. P. Risbridger, and D. M. de Kretser. 1989. Effect of testosterone on serum immunoactive inhibin concentrations in intact and hypophysectomized male rats. J. Reprod. Fertil. 87: 795-801.
39. Sun, Y. T., N. G. Wreford, D. M. Robertson, and D. M. de Kretser. 1990. Quantitative cytological studies of spermatogenesis in intact and hypophysectomized rats: identification of androgen-dependent stages. Endocrinology 127: 1215-1223.
40. Wang, J., N. G. Wreford, H. Y. Lan, R. Atkins, and M. P. Hedger. 1994. Leukocyte populations of the adult rat testis following removal of the Leydig cells by treatment with ethane dimethane sulfonate and subcutaneous testosterone implants. Biol. Reprod. 51: 551-561.
41. Hoffmann, B., and A. Landeck. 1999. Testicular endocrine function, seasonality and semen quality of the stallion. Anim. Reprod. Sci. 57: 89-98.
42. Rival, C., V. A. Guazzone, W. von Wulffen, H. Hackstein, E. Schneider, L. Lustig, A. Meinhardt, and M. Fijak. 2007. Expression of co-stimulatory molecules, chemokine receptors and proinflammatory cytokines in dendritic cells from normal and chronically inflamed rat testis. Mol. Hum. Reprod. 13: 853-861.
43. Ahmed, S. A., and W. J. Penhale. 1982. The influence of testosterone on the development of autoimmune thyroiditis in thymectomized and irradiated rats. Clin. Exp. Immunol. 48: 367-374.
44. Sato, E. H., H. Ariga, and D. A. Sullivan. 1992. Impact of androgen therapy in Sjögren's syndrome: hormonal influence on lymphocyte populations and Ia expression in lacrimal glands of MRL/Mp-lpr/lpr mice. Invest. Ophthalmol. Vis. Sci. 33: 2537-2545.
45. McLachlan, R. I., N. G. Wreford, S. J. Meachem, D. M. De Kretser, and D. M. Robertson. 1994. Effects of testosterone on spermatogenic cell populations in the adult rat. Biol. Reprod. 51: 945-955.
46. Meinhardt, A., M. Bacher, C. Metz, R. Bucala, N. Wreford, H. Lan, R. Atkins, and M. Hedger. 1998. Local regulation of macrophage subsets in the adult rat testis: examination of the roles of the seminiferous tubules, testosterone, and macrophage-migration inhibitory factor. Biol. Reprod. 59: 371-378.
47. Macció, D. R., G. Calfa, and G. A. Roth. 2005. Oral testosterone in male rats and the development of experimental autoimmune encephalomyelitis. Neuroimmunomodulation 12: 246-254.
48. Sakaguchi, S., N. Sakaguchi, M. Asano, M. Itoh, and M. Toda. 1995. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155: 1151-1164.
49. Jacobo, P., V. A. Guazzone, S. Jarazo-Dietrich, M. S. Theas, and L. Lustig. 2009. Differential changes in CD4+ and CD8+ effector and regulatory T lymphocyte subsets in the testis of rats undergoing autoimmune orchitis. J. Reprod. Immunol. 81: 44-54.
50. Cao, D., V. Malmström, C. Baecher-Allan, D. Hafler, L. Klareskog, and C. Trollmo. 2003. Isolation and functional characterization of regulatory CD25brightCD4+ T cells from the target organ of patients with rheumatoid arthritis. Eur. J. Immunol. 33: 215-223.
51. Möttönen, M., J. Heikkinen, L. Mustonen, P. Isomäki, R. Luukkainen, and O. Lassila. 2005. CD4+ CD25+ T cells with the phenotypic and functional characteristics of regulatory T cells are enriched in the synovial fluid of patients with rheumatoid arthritis. Clin. Exp. Immunol. 140: 360-367.
52. Dejaco, C., C. Duftner, B. Grubeck-Loebenstein, and M. Schirmer. 2006. Imbalance of regulatory T cells in human autoimmune diseases. Immunology 117: 289-300.