The testis in immune privilege

Immunological Reviews

Volumn 213, Issue 1, 2006, Pages 66-81

  Fijak, Monika ^a   Meinhardt, Andreas ^a  

^a JUSTUS LIEBIG UNIVERSITY   (Germany)

Author keywords

Dendritic cells; Immune privilege; Immunosuppression; Male infertility; Testis

Indexed keywords

ANDROGEN; CYTOKINE;

ANTIGEN SPECIFICITY; AUTOIMMUNITY; BLOOD TESTIS BARRIER; CELL ACTIVATION; CELL DIFFERENTIATION; CELL POPULATION; CYTOKINE PRODUCTION; DENDRITIC CELL; ENDOCRINE FUNCTION; EXPERIMENTAL MODEL; GAMETOGENESIS; GERM CELL; HORMONAL REGULATION; HUMAN; IMMUNE RESPONSE; IMMUNE STATUS; IMMUNE SYSTEM; IMMUNITY; IMMUNOLOGICAL TOLERANCE; IMMUNOREGULATION; IMMUNOSUPPRESSIVE TREATMENT; INFLAMMATION; LEUKOCYTE FUNCTION; MACROPHAGE; MALE INFERTILITY; MAST CELL; NONHUMAN; PRIORITY JOURNAL; REVIEW; SOMATIC CELL; T LYMPHOCYTE ACTIVATION; TESTIS; TESTIS DEVELOPMENT; TESTIS FUNCTION; TISSUE STRUCTURE;

ANIMALS; HUMANS; IMMUNE TOLERANCE; MALE; TESTIS;

EID: 33748748036     PISSN: 01052896     EISSN: 1600065X     Source Type: Journal    
DOI: 10.1111/j.1600-065X.2006.00438.x     Document Type: Review

References (235)

1. Tung KS, Teuscher C, Meng AL. Autoimmunity to spermatozoa and the testis. Immunol Rev 1981;55:217-255.
2. Suescun MO, Calandra RS, Lustig L. Alterations of testicular function after induced autoimmune orchitis in rats. J Androl 1994;15:442-448.
3. Tung KS, Unanue ER, Dixon FJ. Immunological events associated with immunization by sperm in incomplete Freund's adjuvant. Int Arch Allergy Appl Immunol 1971;41:565-574.
4. Head JR, Billingham RE. Immunologically privileged sites in transplantation immunology and oncology. Perspect Biol Med 1985;29:115-131.
5. Bobzien B, Yasunami Y, Majercik M, Lacy PE, Davie JM. Intratesticular transplants of islet xenografts (rat to mouse). Diabetes 1983;32:213-216.
6. Head JR, Neaves WB, Billingham RE. Immune privilege in the testis. I. Basic parameters of allograft survival. Transplantation 1983;36:423-431.
7. Setchell BP. The testis and tissue transplantation: historical aspects. J Reprod Immunol 1990;18:1-8.
8. Selawry HP, Cameron DF. Sertoli cell-enriched fractions in successful islet cell transplantation. Cell Transplant 1993;2:123-129.
9. Korbutt GS, Ao Z, Warnock GL, Flashner M, Rajotte RV. Successful reversal of diabetes in nude mice by transplantation of microencapsulated porcine neonatal islet cell aggregates. Transplant Proc 1995;27:3212.
10. Schlatt S, Rosiepen G, Weinbauer GF, Rolf C, Brook PF, Nieschlag E. Germ cell transfer into rat, bovine, monkey and human testes. Hum Reprod 1999;14:144-150.
11. Brinster RL. Germline stem cell transplantation and transgenesis. Science 2002;296:2174-2176.
12. Filippini A, et al. Control and impairment of immune privilege in the testis and in semen. Hum Reprod Update 2001;7:444-449.
13. Maddocks S, Setchell BP. Recent evidence for immune privilege in the testis. J Reprod Immunol 1990;18:9-18.
14. Setchell BP, Uksila J, Maddocks S, Pollanen P. Testis physiology relevant to immunoregulation. J Reprod Immunol 1990;18:19-32.
15. Setchell BP, Granholm T, Ritzen EM. Failure of thyroid allografts to function in the testes of cynomolgous monkeys. J Reprod Immunol 1995;28:75-80.
16. Kimmel SG, Ohbatake M, Kushida M, Merguerian P, Clarke ID, Kim PC. Murine xenogeneic immune responses to the human testis: a presumed immune-privileged tissue. Transplantation 2000;69:1075-1084.
17. McLachlan RI. Basis, diagnosis and treatment of immunological infertility in men. J Reprod Immunol 2002;57:35-45.
18. Mahmoud A, Comhaire FH. Immunological causes. In: Schill W-B, Comhaire FH, Hargreave TB, eds. Andrology for the Clinician. Berlin: Springer, 2006:47-52.
19. Naz RK. Modalities for treatment of antisperm antibody mediated infertility: novel perspectives. Am J Reprod Immunol 2004;51:390-397.
20. Nieschlag E, Behre HM. Andrology. Male Reproductive Health and Dysfunction, 2nd edn. Berlin: Springer, 2000:91-97.
21. WHO. Towards more objectivity in diagnosis and management of male infertility. Int J Androl 1987; (Suppl. 7).
22. Schuppe HC, Meinhardt A. Immune privilege and inflammation of the testis. Chem Immunol Allergy 2005;88:1-14.
23. Hedger MP, Meinhardt A. Cytokines and the immune-testicular axis. J Reprod Immunol 2003;58:1-26.
24. Marin-Briggiler CI, Vazquez-Levin MH, Gonzalez-Echeverria F, Blaquier JA, Miranda PV, Tezon JG. Effect of antisperm antibodies present in human follicular fluid upon the acrosome reaction and sperm-zona pellucida interaction. Am J Reprod Immunol 2003;50:209-219.
25. Barratt CL, Havelock LM, Harrison PE, Cooke ID. Antisperm antibodies are more prevalent in men with low sperm motility. Int J Androl 1989;12:110-116.
26. Zouari R, De Almeida M, Rodrigues D, Jouannet P. Localization of antibodies on spermatozoa and sperm movement characteristics are good predictors of in vitro fertilization success in cases of male autoimmune infertility. Fertil Steril 1993;59:606-612.
27. Tasdemir I, Tasdemir M, Fukuda J, Kodama H, Matsui T, Tanaka T. Sperm immobilization antibodies in infertile male sera decrease the acrosome reaction: a possible mechanism for immunologic infertility. J Assist Reprod Genet 1996;13:413-416.
28. Kremer J, Jager S. The significance of antisperm antibodies for sperm-cervical mucus interaction. Hum Reprod 1992;7:781-784.
29. Francavilla F, Romano R, Santucci R, Marrone V, Properzi G, Ruvolo G. Interference of antisperm antibodies with the induction of the acrosome reaction by zona pellucida (ZP) and its relationship with the inhibition of ZP binding. Fertil Steril 1997;67:1128-1133.
30. Bronson RA, Cooper GW, Phillips DM. Effects of anti-sperm antibodies on human sperm ultrastructure and function. Hum Reprod 1989;4:653-657.
31. Clarke GN, Stojanoff A, Cauchi MN, Johnston WI. The immunoglobulin class of antispermatozoal antibodies in serum. Am J Reprod Immunol Microbiol 1985;7:143-147.
32. Eggert-Kruse W, Hofsass A, Haury E, Tilgen W, Gerhard I, Runnebaum B. Relationship between local anti-sperm antibodies and sperm-mucus interaction in vitro and in vivo. Hum Reprod 1991;6:267-276.
33. Crosignani PG, Rubin BL. Optimal use of infertility diagnostic tests and treatments. The ESHRE Capri Workshop Group. Hum Reprod 2000;15:723-732.
34. Lenzi A, Gandini L, Lombardo F, Rago R, Paoli D, Dondero F. Antisperm antibody detection: 2. Clinical, biological, and statistical correlation between methods. Am J Reprod Immunol 1997;38:224-230.
35. Turek PJ, Lipshultz LI. Immunologic infertility. Urol Clin North Am 1994;21:447-468.
36. Tung KS, Teuscher C. Mechanisms of autoimmune disease in the testis and ovary. Hum Reprod Update 1995;1:35-50.
37. Weidner W, Krause W, Ludwig M. Relevance of male accessory gland infection for subsequent fertility with special focus on prostatitis. Hum Reprod Update 1999;5:421-432.
38. Jenkin GA, Choo M, Hosking P, Johnson PD. Candidal epididymo-orchitis: case report and review. Clin Infect Dis 1998;26:942-945.
39. Andrada JA, von der Walde F, Hoschoian JC, Comini E, Mancini E. Immunological studies in patients with mumps orchitis. Andrologia 1977;9:207-215.
40. Casella R, Leibundgut B, Lehmann K, Gasser TC. Mumps orchitis: report of a miniepidemic. J Urol 1997;158:2158-2161.
41. Manson AL. Mumps orchitis. Urology 1990;36:355-358.
42. de Kretser DM, Loveland KL, Meinhardt A, Simorangkir D, Wreford N. Spermatogenesis. Hum Reprod 1998;13(Suppl. 1):1-8.
43. de Kretser DM, Kerr JB. The cytology of the testis. In: Knobil E, Neill J, eds. Physiology of Reproduction. 2nd edn. New York: Raven Press, 1994:1177-1300.
44. Fawcett DW. The mammalian spermatozoon. Dev Biol 1975;44:394-436.
45. Hedger MP. Testicular leukocytes: what are they doing? Rev Reprod 1997;2:38-47.
46. Holstein AF, Davidoff M. Compartmentalization of the intertubular space in the human testis. Adv Exp Med Biol 1997;424:161-162.
47. Ungefroren H, Ergun S, Krull NB, Holstein AF. Expression of the small proteoglycans biglycan and decorin in the adult human testis. Biol Reprod 1995;52:1095-1105.
48. Dym M. Basement membrane regulation of Sertoli cells. Endocr Rev 1994;15:102-115.
49. Vukicevic S, Kleinman HK, Luyten FP, Roberts AB, Roche NS, Reddi AH. Identification of multiple active growth factors in basement membrane Matrigel suggests caution in interpretation of cellular activity related to extracellular matrix components. Exp Cell Res 1992;202:1-8.
50. Schlatt S, Meinhardt A, Nieschlag E. Paracrine regulation of cellular interactions in the testis: factors in search of a function. Eur J Endocrinol 1997;137:107-117.
51. Hermo L, Dworkin J. Transitional cells at the junction of seminiferous tubules with the rete testis of the rat: their fine structure, endocytic activity, and basement membrane. Am J Anat 1988;181:111-131.
52. Itoh M, Terayama H, Naito M, Ogawa Y, Tainosho S. Tissue microcircumstances for leukocytic infiltration into the testis and epididymis in mice. J Reprod Immunol 2005;67:57-67.
53. Itoh M, Xie Q, Miyamoto K, Takeuchi Y. F4/80-positive cells rapidly accumulate around tubuli recti and rete testis between 3 and 4 weeks of age in the mouse: an immunohistochemical study. Am J Reprod Immunol 1999;42:321-326.
54. Itoh M, Takeuchi Y, De Rooij D. Histopathology of the seminiferous tubules in mice injected with syngeneic testicular germ cells alone. Arch Androl 1995;35:93-103.
55. Levy S, Robaire B. Segment-specific changes with age in the expression of junctional proteins and the permeability of the blood-epididymis barrier in rats. Biol Reprod 1999;60:1392-1401.
56. Flickinger CJ, Bush LA, Howards SS, Herr JC. Distribution of leukocytes in the epithelium and interstitium of four regions of the Lewis rat epididymis. Anat Rec 1997;248:380-390.
57. Nashan D, Cooper TG, Knuth UA, Schubeus P, Sorg C, Nieschlag E. Presence and distribution of leucocyte subsets in the murine epididymis after vasectomy. Int J Androl 1990;13:39-49.
58. Nashan D, Malorny U, Sorg C, Cooper T, Nieschlag E. Immuno-competent cells in the murine epididymis. Int J Androl 1989;12:85-94.
59. Setchell BP. The blood-testicular fluid barrier in sheep. J Physiol 1967;189:63P-65P.
60. Vitale R, Fawcett DW, Dym M. The normal development of the blood-testis barrier and the effects of clomiphene and estrogen treatment. Anat Rec 1973;176:331-344.
61. Dym M, Fawcett DW. The blood-testis barrier in the rat and the physiological compartmentation of the seminiferous epithelium. Biol Reprod 1970;3:308-326.
62. Fawcett DW, Leak LV, Heidger PM Jr. Electron microscopic observations on the structural components of the blood-testis barrier. J Reprod Fertil Suppl 1970;10:105-122.
63. Evans RW, Setchell BP. The effect of rete testis fluid on the metabolism of testicular spermatozoa. J Reprod Fertil 1978;52:15-20.
64. Tuck RR, Setchell BP, Waites GM, Young JA. The composition of fluid collected by micropuncture and catheterization from the seminiferous tubules and rete testis of rats. Pflugers Arch 1970;318:225-243.
65. Setchell BP. Local control of testicular fluids. Reprod Fertil Dev 1990;2:291-309.
66. Mruk DD, Cheng CY. Sertoli-Sertoli and Sertoli-germ cell interactions and their significance in germ cell movement in the seminiferous epithelium during spermatogenesis. Endocr Rev 2004;25:747-806.
67. Turksen K, Troy TC. Barriers built on claudins. J Cell Sci 2004;117:2435-2447.
68. Heiskala M, Peterson PA, Yang Y. The roles of claudin superfamily proteins in paracellular transport. Traffic 2001;2:93-98.
69. Xia W, Mruk DD, Lee WM, Cheng CY. Cytokines and junction restructuring during spermatogenesis-a lesson to learn from the testis. Cytokine Growth Factor Rev 2005;16:469-493.
70. Lui WY, Lee WM, Cheng CY. Transforming growth factor-beta3 perturbs the inter-Sertoli tight junction permeability barrier in vitro possibly mediated via its effects on occludin, zonula occludens-1, and claudin-11. Endocrinology 2001;142:1865-1877.
71. Wong CH, Mruk DD, Lui WY, Cheng CY. Regulation of blood-testis barrier dynamics: an in vivo study. J Cell Sci 2004;117:783-798.
72. Siu MK, Lee WM, Cheng CY. The interplay of collagen IV, tumor necrosis factor-alpha, gelatinase B (matrix metalloprotease-9), and tissue inhibitor of metalloproteases-1 in the basal lamina regulates Sertoli cell-tight junction dynamics in the rat testis. Endocrinology 2003;144:371-387.
73. Cheng CY, Mruk DD. Cell junction dynamics in the testis: Sertoli-germ cell interactions and male contraceptive development. Physiol Rev 2002;82:825-874.
74. Pelletier R. The tight junctions of the testis, epididymis and vas deferens, 2nd edn. Boca Raton: CRC Press, 2001.
75. Ebnet K, Suzuki A, Ohno S, Vestweber D. Junctional adhesion molecules (JAMs): more molecules with dual functions? J Cell Sci 2004;117:19-29.
76. Lewis-Jones DI, Richards RC, Lynch RV, Joughin EC. Immunocytochemical localisation of the antibody which breaches the blood-testis barrier in sympathetic orchiopathia. Br J Urol 1987;59:452-457.
77. Johnson MH. Changes in the blood-testis barrier of the guinea-pig in relation to histological damage following iso-immunization with testis. J Reprod Fertil 1970;22:119-127.
78. Slavis SA, et al. The effects of testicular trauma on fertility in the Lewis rat and comparisons to isoimmunized recipients of syngeneic sperm. J Urol 1990;143:638-641.
79. Comhaire FH, Mahmoud AM, Depuydt CE, Zalata AA, Christophe AB. Mechanisms and effects of male genital tract infection on sperm quality and fertilizing potential: the andrologist's viewpoint. Hum Reprod Update 1999;5:393-398.
80. Hales DB, Diemer T, Hales KH. Role of cytokines in testicular function. Endocrine 1999;10:201-217.
81. Iosub R, et al. Development of testicular inflammation in the rat involves activation of proteinase-activated receptor-2. J Pathol 2006;208:686-698.
82. Huleihel M, Lunenfeld E. Regulation of spermatogenesis by paracrine/autocrine testicular factors. Asian J Androl 2004;6:259-268.
83. Mankertz J, et al. Expression from the human occludin promoter is affected by tumor necrosis factor alpha and interferon gamma. J Cell Sci 2000;113:2085-2090.
84. Yule TD, Montoya GD, Russell LD, Williams TM, Tung KS. Autoantigenic germ cells exist outside the blood testis barrier. J Immunol 1988;141:1161-1167.
85. Saari T, Jahnukainen K, Pollanen P. Autoantigenicity of the basal compartment of seminiferous tubules in the rat. J Reprod Immunol 1996;31:65-79.
86. Mallidis C, Baker HW. Fine needle tissue aspiration biopsy of the testis. Fertil Steril 1994;61:367-375.
87. Lombardo F, et al. Androgens and fertility. J Endocrinol Invest 2005;28:51-55.
88. Nieschlag E, Behre HM. Testosterone: Action, Deficiency, Substitution, 3rd edn. Cambridge, UK: Cambridge University Press, 2004.
89. Walker WH, Cheng J. FSH and testosterone signaling in Sertoli cells. Reproduction 2005;130:15-28.
90. Meinhardt A, Seitz J, Arslan M, Aumuller G, Weinbauer GF. Hormonal regulation and germ cell-specific expression of heat shock protein 60 (hsp60) in the testis of macaque monkeys (Macaca mulatta and M. fascicularis). Int J Androl 1998;21:301-307.
91. De Gendt K, et al. A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis. Proc Natl Acad Sci USA 2004;101:1327-1332.
92. McLachlan RI, et al. Identification of specific sites of hormonal regulation in spermatogenesis in rats, monkeys, and man. Recent Prog Horm Res 2002;57:149-179.
93. Holdcraft RW, Braun RE. Hormonal regulation of spermatogenesis. Int J Androl 2004;27:335-342.
94. Vornberger W, Prins G, Musto NA, Suarez-Quian CA. Androgen receptor distribution in rat testis: new implications for androgen regulation of spermatogenesis. Endocrinology 1994;134:2307-2316.
95. Bremner WJ, Millar MR, Sharpe RM, Saunders PT. Immunohistochemical localization of androgen receptors in the rat testis: evidence for stage-dependent expression and regulation by androgens. Endocrinology 1994;135:1227-1234.
96. Schlatt S, Arslan M, Weinbauer GF, Behre HM, Nieschlag E. Endocrine control of testicular somatic and premeiotic germ cell development in the immature testis of the primate Macaca mulatta. Eur J Endocrinol 1995;133:235-247.
97. Van Roijen JH, et al. Androgen receptor immunoexpression in the testes of subfertile men. J Androl 1995;16:510-516.
98. Muller R, Klug J, Rodewald M, Meinhardt A. Macrophage migration inhibitory factor suppresses transforming growth factor-beta2 secretion in cultured rat testicular peritubular cells. Reprod Fertil Dev 2005;17:435-438.
99. Verhoeven G, Hoeben E, De Gendt K. Peritubular cell-Sertoli cell interactions: factors involved in PmodS activity. Andrologia 2000;32:42-45.
100. Maekawa M, Kamimura K, Nagano T. Peritubular myoid cells in the testis: their structure and function. Arch Histol Cytol 1996;59:1-13.
101. Piquet-Pellorce C, Dorval-Coiffec I, Pham MD, Jegou B. Leukemia inhibitory factor expression and regulation within the testis. Endocrinology 2000;141:1136-1141.
102. Konrad L, Albrecht M, Renneberg H, Aumuller G. Transforming growth factor-beta2 mediates mesenchymal-epithelial interactions of testicular somatic cells. Endocrinology 2000;141:3679-3686.
103. Jarow JP, Zirkin BR. The androgen microenvironment of the human testis and hormonal control of spermatogenesis. Ann NY Acad Sci 2005;1061:208-220.
104. Jarow JP, Wright WW, Brown TR, Yan X, Zirkin BR. Bioactivity of androgens within the testes and serum of normal men. J Androl 2005;26:343-348.
105. Sharpe RM, Donachie K, Cooper I. Re-evaluation of the intratesticular level of testosterone required for quantitative maintenance of spermatogenesis in the rat. J Endocrinol 1988;117:19-26.
106. D'Agostino P, et al. Sex hormones modulate inflammatory mediators produced by macrophages. Ann NY Acad Sci 1999;876:426-429.
107. Li ZG, Danis VA, Brooks PM. Effect of gonadal steroids on the production of IL-1 and IL-6 by blood mononuclear cells in vitro. Clin Exp Rheumatol 1993;11:157-162.
108. Gornstein RA, Lapp CA, Bustos-Valdes SM, Zamorano P. Androgens modulate interleukin-6 production by gingival fibroblasts in vitro. J Periodontol 1999;70:604-609.
109. Liva SM, Voskuhl RR. Testosterone acts directly on CD4+ T lymphocytes to increase IL-10 production. J Immunol 2001;167:2060-2067.
110. Hatakeyama H, Nishizawa M, Nakagawa A, Nakano S, Kigoshi T, Uchida K. Testosterone inhibits tumor necrosis factor-alpha-induced vascular cell adhesion molecule-1 expression in human aortic endothelial cells. FEBS Lett 2002;530:129-132.
111. Cutolo M, Balleari E, Giusti M, Intra E, Accardo S. Androgen replacement therapy in male patients with rheumatoid arthritis. Arthritis Rheum 1991;34:1-5.
112. Bizzarro A, Valentini G, Di Martino G, DaPonte A, De Bellis A, Iacono G. Influence of testosterone therapy on clinical and immunological features of autoimmune diseases associated with Klinefelter's syndrome. J Clin Endocrinol Metab 1987;64:32-36.
113. Olsen NJ, Kovacs WJ. Case report: testosterone treatment of systemic lupus erythematosus in a patient with Klinefelter's syndrome. Am J Med Sci 1995;310:158-160.
114. Wunderlich F, et al. Testosterone responsiveness of spleen and liver in female lymphotoxin beta receptor-deficient mice resistant to blood-stage malaria. Microbes Infect 2005;7:399-409.
115. Krucken J, et al. Testosterone suppresses protective responses of the liver to blood-stage malaria. Infect Immun 2005;73:436-443.
116. do Prado JC Jr, Levy AM, Leal MP, Bernard E, Kloetzel JK. Influence of male gonadal hormones on the parasitemia and humoral response of male Calomys callosus infected with the Y strain of Trypanosoma cruzi. Parasitol Res 1999;85:826-829.
117. Rivero JC, Inoue Y, Murakami N, Horii Y. Androgen- and estrogen-dependent sex differences in host resistance to Strongyloides venezuelensis infection in Wistar rats. J Vet Med Sci 2002;64:457-461.
118. Rivero JC, Inoue Y, Murakami N, Horii Y. Age- and sex-related changes in susceptibility of Wistar rats to Strongyloides venezuelensis infection. J Vet Med Sci 2002;64:519-521.
119. McCollum WH, Little TV, Timoney PJ, Swerczek TW. Resistance of castrated male horses to attempted establishment of the carrier state with equine arteritis virus. J Comp Pathol 1994;111:383-388.
120. Zitzmann M, Erren M, Kamischke A, Simoni M, Nieschlag E. Endogenous progesterone and the exogenous progestin norethisterone enanthate are associated with a proinflammatory profile in healthy men. J Clin Endocrinol Metab 2005;90:6603-6608.
121. Head JR, Billingham RE. Immune privilege in the testis. II. Evaluation of potential local factors. Transplantation 1985;40:269-275.
122. Kovacs WJ, Olsen NJ. Androgen receptors in human thymocytes. J Immunol 1987;139:490-493.
123. Benten WP, Lieberherr M, Stamm O, Wrehlke C, Guo Z, Wunderlich F. Testosterone signaling through internalizable surface receptors in androgen receptor-free macrophages. Mol Biol Cell 1999;10:3113-3123.
124. Benten WP, Lieberherr M, Sekeris CE, Wunderlich F. Testosterone induces Ca2+ influx via non-genomic surface receptors in activated T cells. FEBS Lett 1997;407:211-214.
125. Benten WP, et al. Functional testosterone receptors in plasma membranes of T cells. FASEB J 1999;13:123-133.
126. Niemi M, Sharpe RM, Brown WR. Macrophages in the interstitial tissue of the rat testis. Cell Tissue Res 1986;243:337-344.
127. Hume DA, Halpin D, Charlton H, Gordon S. The mononuclear phagocyte system of the mouse defined by immunohistochemical localization of antigen F4/80: macrophages of endocrine organs. Proc Natl Acad Sci USA 1984;81:4174-4177.
128. Wang J, Wreford NG, Lan HY, Atkins R, Hedger MP. 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 1994;51:551-561.
129. Itoh M, De Rooij DG, Jansen A., Drexhage HA. Phenotypical heterogeneity of testicular macrophages/dendritic cells in normal adult mice: an immunohistochemical study. J Reprod Immunol 1995;28:217-232.
130. Hutson JC. Physiologic interactions between macrophages and Leydig cells. Exp Biol Med (Maywood) 2006;231:1-7.
131. Hutson JC. Testicular macrophages. Int Rev Cytol 1994;149:99-143.
132. Hedger MP. Macrophages and the immune responsiveness of the testis. J Reprod Immunol 2002;57:19-34.
133. Hedger MP, Hales DB. Immunophysiology of the male reproductive tract. In: Knobil E, Neill J, eds. Physiology of Reproduction, 3rd edn. Amsterdam: Academic Press, 2006:1195-1286.
134. Frungieri MB, et al. Number, distribution pattern, and identification of macrophages in the testes of infertile men. Fertil Steril 2002;78:298-306.
135. el-Demiry MI, Hargreave TB, Busuttil A, Elton R, James K, Chisholm GD. Immunocompetent cells in human testis in health and disease. Fertil Steril 1987;48:470-479.
136. Hoek A, Allaerts W, Leenen PJ, Schoemaker J, Drexhage HA. Dendritic cells and macrophages in the pituitary and the gonads. Evidence for their role in the fine regulation of the reproductive endocrine response. Eur J Endocrinol 1997;136:8-24.
137. Pollanen P, Niemi M. Immunohistochemical identification of macrophages, lymphoid cells and HLA antigens in the human testis. Int J Androl 1987;10:37-42.
138. Breucker H. Macrophages, a normal component in seasonally involuting testes of the swan, Cygnus olor. Cell Tissue Res 1978;193:463-471.
139. Hutson JC. Development of cytoplasmic digitations between Leydig cells and testicular macrophages of the rat. Cell Tissue Res 1992;267:385-389.
140. Gaytan F, Bellido C, Morales C, Reymundo C, Aguilar E, van Rooijen N. Selective depletion of testicular macrophages and prevention of Leydig cell repopulation after treatment with ethylene dimethane sulfonate in rats. J Reprod Fertil 1994;101:175-182.
141. Gaytan F, Bellido C, Romero JL, Morales C, Reymundo C, Aguilar E. Decreased number and size and the defective function of testicular macrophages in long-term hypophysectomized rats are reversed by treatment with human gonadotrophins. J Endocrinol 1994;140:399-407.
142. Bergh A, Damber JE, van Rooijen N. Liposome-mediated macrophage depletion: an experimental approach to study the role of testicular macrophages in the rat. J Endocrinol 1993;136:407-413.
143. Gaytan F, Bellido C, Morales C, Reymundo C, Aguilar E, Van Rooijen N. Effects of macrophage depletion at different times after treatment with ethylene dimethane sulfonate (EDS) on the regeneration of Leydig cells in the adult rat. J Androl 1994;15:558-564.
144. Gaytan F, Bellido C, Aguilar E, van Rooijen N. Requirement for testicular macrophages in Leydig cell proliferation and differentiation during prepubertal development in rats. J Reprod Fertil 1994;102:393-399.
145. Gaytan F, Bellido C, Morales C, Garcia M, van Rooijen N, Aguilar E. In vivo manipulation (depletion versus activation) of testicular macrophages: central and local effects. J Endocrinol 1996;150:57-65.
146. Cohen PE, Chisholm O, Arceci RJ, Stanley ER, Pollard JW. Absence of colony-stimulating factor-1 in osteopetrotic (csfmop/csfmop) mice results in male fertility defects. Biol Reprod 1996;55:310-317.
147. Meinhardt A, et al. Local regulation of macrophage subsets in the adult rat testis: examination of the roles of the seminiferous tubules, testosterone, and macrophagemigration inhibitory factor. Biol Reprod 1998;59:371-378.
148. Cohen PE, Nishimura K, Zhu L, Pollard JW. Macrophages: important accessory cells for reproductive function. J Leukoc Biol 1999;66:765-772.
149. Benahmed M. Role of tumor necrosis factor in the male gonad. Contracept Fertil Sex 1997;25:569-571.
150. Kerr JB, Sharpe RM. Macrophage activation enhances the human chorionic gonadotrophin-induced disruption of spermatogenesis in the rat. J Endocrinol 1989;121:285-292.
151. Bergh A, Damber JE, Hjertkvist M. Human chorionic gonadotrophin-induced testicular inflammation may be related to increased sensitivity to interleukin-1. Int J Androl 1996;19:229-236.
152. Hayes R, Chalmers SA, Nikolic-Paterson DJ, Atkins RC, Hedger MP. Secretion of bioactive interleukin 1 by rat testicular macrophages in vitro. J Androl 1996;17:41-49.
153. Kern S, Maddocks S. Indomethacin blocks the immunosuppressive activity of rat testicular macrophages cultured in vitro. J Reprod Immunol 1995;28:189-201.
154. Kern S, Robertson SA, Mau VJ, Maddocks S. Cytokine secretion by macrophages in the rat testis. Biol Reprod 1995;53:1407-1416.
155. Bryniarski K, Szczepanik M, Maresz K, Ptak M, Ptak W. Subpopulations of mouse testicular macrophages and their immunoregulatory function. Am J Reprod Immunol 2004;52:27-35.
156. Jonsson CK, Setchell BP, Martinelle N, Svechnikov K, Soder O. Endotoxin-induced interleukin 1 expression in testicular macrophages is accompanied by downregulation of the constitutive expression in Sertoli cells. Cytokine 2001;14:283-288.
157. Elhija MA, et al. Testicular interleukin-6 response to systemic inflammation. Eur Cytokine Netw 2005;16:167-172.
158. O'Bryan MK, et al. Cytokine profiles in the testes of rats treated with lipopolysaccharide reveal localized suppression of inflammatory responses. Am J Physiol Regul Integr Comp Physiol 2005;288:R1744-R1755.
159. O'Bryan MK, Schlatt S, Phillips DJ, de Kretser DM, Hedger MP. Bacterial lipopolysaccharide-induced inflammation compromises testicular function at multiple levels in vivo. Endocrinology 2000;141:238-246.
160. Soder O, Sultana T, Jonsson C, Wahlgren A, Petersen C, Holst M. The interleukin-1 system in the testis. Andrologia 2000;32:52-55.
161. Soder O, et al. Production and secretion of an interleukin-1-like factor is stage-dependent and correlates with spermatogonial DNA synthesis in the rat seminiferous epithelium. Int J Androl 1991;14:223-231.
162. Meinhardt A, Bacher M, Wennemuth G, Eickhoff R, Hedger M. Macrophage migration inhibitory factor (MIF) as a paracrine mediator in the interaction of testicular somatic cells. Andrologia 2000;32:46-48.
163. Meinhardt A, et al. A switch in the cellular localization of macrophage migration inhibitory factor in the rat testis after ethane dimethane sulfonate treatment. J Cell Sci 1999;112:1337-1344.
164. Meinhardt A, et al. Macrophage migration inhibitory factor production by Leydig cells: evidence for a role in the regulation of testicular function. Endocrinology 1996;137:5090-5095.
165. Zeyse D, Lunenfeld E, Beck M, Prinsloo I, Huleihel M. Induction of interleukin-1alpha production in murine Sertoli cells by interleukin-1. Biol Reprod 2000;62:1291-1296.
166. Gerdprasert O, O'Bryan MK, Nikolic-Paterson DJ, Sebire K, de Kretser DM, Hedger MP. Expression of monocyte chemoattractant protein-1 and macrophage colony-stimulating factor in normal and inflamed rat testis. Mol Hum Reprod 2002;8:518-524.
167. Gerdprasert O, et al. The response of testicular leukocytes to lipopolysaccharideinduced inflammation: further evidence for heterogeneity of the testicular macrophage population. Cell Tissue Res 2002;308:277-285.
168. Suescun MO, Rival C, Theas MS, Calandra RS, Lustig L. Involvement of tumor necrosis factor-alpha in the pathogenesis of autoimmune orchitis in rats. Biol Reprod 2003;68:2114-2121.
169. Foulds LM, et al. Inhibition of T cells by gonadal fluids - a new explanation for immunological privilege of the testis. In: Gromoll J, Nieschlag E, eds. 14th European Testis Workshop, 2006, Bad Aibling, Germany, 2006:I-16.
170. Hedger MP, Meinhardt A. Local regulation of T cell numbers and lymphocyte-inhibiting activity in the interstitial tissue of the adult rat testis. J Reprod Immunol 2000;48:69-80.
171. Hedger MP, Wang J, Lan HY, Atkins RC, Wreford NG. Immunoregulatory activity in adult rat testicular interstitial fluid: relationship with intratesticular CD8+ lymphocytes following treatment with ethane dimethane sulfonate and testosterone implants. Biol Reprod 1998;58:935-942.
172. Sainio-Pollanen S, Pollanen P, Setchell BP. Testicular immunosuppressive activity in experimental hypogonadism and cryptorchidism. J Reprod Immunol 1991;20:59-72.
173. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998;392:245-252.
174. Banchereau J, et al. Immunobiology of dendritic cells. Annu Rev Immunol 2000;18:767-811.
175. Villadangos JA, Schnorrer P, Wilson NS. Control of MHC class II antigen presentation in dendritic cells: a balance between creative and destructive forces. Immunol Rev 2005;207:191-205.
176. Hackstein H, Thomson AW. Dendritic cells: emerging pharmacological targets of immunosuppressive drugs. Nat Rev Immunol 2004;4:24-34.
177. Pollanen P, Maddocks S. Macrophages, lymphocytes and MHC II antigen in the ram and the rat testis. J Reprod Fertil 1988;82:437-445.
178. Tung KS, Yule TD, Mahi-Brown CA, Listrom MB. Distribution of histopathology and Ia positive cells in actively induced and passively transferred experimental autoimmune orchitis. J Immunol 1987;138:752-759.
179. Hedger MP, Eddy EM. The heterogeneity of isolated adult rat Leydig cells separated on Percoll density gradients: an immunological, cytochemical, and functional analysis. Endocrinology 1987;121:1824-1838.
180. Lustig L, Lourtau L, Perez R, Doncel GF. Phenotypic characterization of lymphocytic cell infiltrates into the testes of rats undergoing autoimmune orchitis. Int J Androl 1993;16:279-284.
181. Pollanen P, Jahnukainen K, Punnonen J, Sainio-Pollanen S. Ontogeny of immunosuppressive activity, MHC antigens and leukocytes in the rat testis. J Reprod Immunol 1992;21:257-274.
182. Haas GG Jr, D'Cruz OJ, De Bault LE. Distribution of human leukocyte antigen-ABC and -D/DR antigens in the unfixed human testis. Am J Reprod Immunol Microbiol 1988;18:47-51.
183. Ohashi K, Saji F, Kato M, Wakimoto A, Tanizawa O. HLA expression on human ejaculated sperm. Am J Reprod Immunol 1990;23:29-32.
184. Fellous M, Dausset J. Probable heploid expression of HL-A antigens on human spermatozoon. Nature 1970;225:191-193.
185. Martin-Villa JM, et al. Diploid expression of human leukocyte antigen class I and class II molecules on spermatozoa and their cyclic inverse correlation with inhibin concentration. Biol Reprod 1996;55:620-629.
186. Bishara A, et al. Human leukocyte antigens (HLA) class I and class II on sperm cells studied at the serological, cellular, and genomic levels. Am J Reprod Immunol Microbiol 1987;13:97-103.
187. Zhou ZZ, Zheng Y, Steenstra R, Hickey WF, Teuscher C. Actively-induced experimental allergic orchitis (EAO) in Lewis/NCR rats: sequential histo- and immunopathologic analysis. Autoimmunity 1989;3:125-134.
188. Yule TD, Mahi-Brown CA, Tung KS. Role of testicular autoantigens and influence of lymphokines in testicular autoimmune disease. J Reprod Immunol 1990;18:89-103.
189. Pollanen P, Cooper TG. Immunology of the testicular excurrent ducts. J Reprod Immunol 1994;26:167-216.
190. Matzinger P. Tolerance, danger, and the extended family. Annu Rev Immunol 1994;12:991-1045.
191. Flores-Romo L. In vivo maturation and migration of dendritic cells. Immunology 2001;102:255-262.
192. Eriksson U, et al. Dendritic cell-induced autoimmune heart failure requires cooperation between adaptive and innate immunity. Nat Med 2003;9:1484-1490.
193. Turley S, Poirot L, Hattori M, Benoist C, Mathis D. Physiological beta cell death triggers priming of self-reactive T cells by dendritic cells in a type-1 diabetes model. J Exp Med 2003;198:1527-1537.
194. Colonna L, Dinnall JA, Shivers DK, Frisoni L, Caricchio R, Gallucci S. Abnormal costimulatory phenotype and function of dendritic cells before and after the onset of severe murine lupus. Arthritis Res Ther 2006;8:R49.
195. Suter T, et al. The brain as an immune privileged site: dendritic cells of the central nervous system inhibit T cell activation. Eur J Immunol 2003;33:2998-3006.
196. Derrick EK, Barker JN, Khan A, Price ML, Macdonald DM. The tissue distribution of factor XIIIa positive cells. Histopathology 1993;22:157-162.
197. Rival C, et al. Identification of a dendritic cell population in normal testis and in chronically inflamed testis of rats with autoimmune orchitis. Cell Tissue Res 2006;324:1-8.
198. Sainio-Pollanen S, Saari T, Simell O, Pollanen P. CD28-CD80/CD86 interactions in testicular immunoregulation. J Reprod Immunol 1996;31:145-163.
199. Wolf H, Muller Y, Salmen S, Wilmanns W, Jung G. Induction of anergy in resting human T lymphocytes by immobilized anti-CD3 antibodies. Eur J Immunol 1994;24:1410-1417.
200. Fijak M, et al. Identification of immunodominant autoantigens in rat autoimmune orchitis. J Pathol 2005;207:127-138.
201. Millar DG, et al. Hsp70 promotes antigen-presenting cell function and converts T-cell tolerance to autoimmunity in vivo. Nat Med 2003;9:1469-1476.
202. Serafini B, et al. Dendritic cells in multiple sclerosis lesions: maturation stage, myelin uptake, and interaction with proliferating T cells. J Neuropathol Exp Neurol 2006;65:124-141.
203. Iizasa H, et al. Exacerbation of granuloma formation in IL-1 receptor antagonist-deficient mice with impaired dendritic cell maturation associated with Th2 cytokine production. J Immunol 2005;174:3273-3280.
204. Frossi B, De Carli M, Pucillo C. The mast cell: an antenna of the microenvironment that directs the immune response. J Leukoc Biol 2004;75:579-585.
205. Benoist C, Mathis D. Mast cells in autoimmune disease. Nature 2002;420:875-878.
206. Bhattacharyya SP, Drucker I, Reshef T, Kirshenbaum AS, Metcalfe DD, Mekori YA. Activated T lymphocytes induce degranulation and cytokine production by human mast cells following cell-to-cell contact. J Leukoc Biol 1998;63:337-341.
207. Bebo BF Jr, Yong T, Orr EL, Linthicum DS. Hypothesis: a possible role for mast cells and their inflammatory mediators in the pathogenesis of autoimmune encephalomyelitis. J Neurosci Res 1996;45:340-348.
208. Ibrahim MZ, Reder AT, Lawand R, Takash W, Sallouh-Khatib S. The mast cells of the multiple sclerosis brain. J Neuroimmunol 1996;70:131-138.
209. Johnson D, Seeldrayers PA, Weiner HL. The role of mast cells in demyelination. 1. Myelin proteins are degraded by mast cell proteases and myelin basic protein and P2 can stimulate mast cell degranulation. Brain Res 1988;444:195-198.
210. Secor VH, Secor WE, Gutekunst CA, Brown MA. Mast cells are essential for early onset and severe disease in a murine model of multiple sclerosis. J Exp Med 2000;191:813-822.
211. Brenner T, Soffer D, Shalit M, Levi-Schaffer F. Mast cells in experimental allergic encephalomyelitis: characterization, distribution in the CNS and in vitro activation by myelin basic protein and neuropeptides. J Neurol Sci 1994;122:210-213.
212. Brown MA, Tanzola MB, Robbie-Ryan M. Mechanisms underlying mast cell influence on EAE disease course. Mol Immunol 2002;38:1373-1378.
213. Rozniecki JJ, Hauser SL, Stein M, Lincoln R, Theoharides TC. Elevated mast cell tryptase in cerebrospinal fluid of multiple sclerosis patients. Ann Neurol 1995;37:63-66.
214. Rodewald HR, Dessing M, Dvorak AM, Galli SJ. Identification of a committed precursor for the mast cell lineage. Science 1996;271:818-822.
215. Galli SJ, Zsebo KM, Geissler EN. The kit ligand, stem cell factor. Adv Immunol 1994;55:1-96.
216. Galli SJ, Hammel I. Mast cell and basophil development. Curr Opin Hematol 1994;1:33-39.
217. Anton F, Morales C, Aguilar R, Bellido C, Aguilar E, Gaytan F. A comparative study of mast cells and eosinophil leukocytes in the mammalian testis. Zentralbl Veterinarmed A 1998;45:209-218.
218. Nistal M, Santamaria L, Paniagua R. Mast cells in the human testis and epididymis from birth to adulthood. Acta Anat (Basel) 1984;119:155-160.
219. Aguilar R, Anton F, Bellido C, Aguilar E, Gaytan F. Testicular serotonin is related to mast cells but not to Leydig cells in the rat. J Endocrinol 1995;146:15-21.
220. Temkin V, Kantor B, Weg V, Hartman ML, Levi-Schaffer F. Tryptase activates the mitogen-activated protein kinase/activator protein-1 pathway in human peripheral blood eosinophils, causing cytokine production and release. J Immunol 2002;169:2662-2669.
221. Abe M, Kurosawa M, Ishikawa O, Miyachi Y, Kido H. Mast cell tryptase stimulates both human dermal fibroblast proliferation and type I collagen production. Clin Exp Allergy 1998;28:1509-1517.
222. Frungieri MB, Weidinger S, Meineke V, Kohn FM, Mayerhofer A. Proliferative action of mast-cell tryptase is mediated by PAR2, COX2, prostaglandins, and PPARgamma: possible relevance to human fibrotic disorders. Proc Natl Acad Sci USA 2002;99:15072-15077.
223. Hussein MR, et al. Phenotypic characterization of the immune and mast cell infiltrates in the human testis shows normal and abnormal spermatogenesis. Fertil Steril 2005;83:1447-1453.
224. Apa DD, Cayan S, Polat A, Akbay E. Mast cells and fibrosis on testicular biopsies in male infertility. Arch Androl 2002;48:337-344.
225. Meineke V, Frungieri MB, Jessberger B, Vogt H, Mayerhofer A. Human testicular mast cells contain tryptase: increased mast cell number and altered distribution in the testes of infertile men. Fertil Steril 2000;74:239-244.
226. Hashimoto J, Nagai T, Takaba H, Yamamoto M, Miyake K. Increased mast cells in the limiting membrane of seminiferous tubules in testes of patients with idiopathic infertility. Urol Int 1988;43:129-132.
227. Agarwal S, Choudhury M, Banerjee A. Mast cells and idiopathic male infertility. Int J Fertil 1987;32:283-286.
228. Jezek D, Banek L, Hittmair A, Pezerovic-Panijan R, Goluza T, Schulze W. Mast cells in testicular biopsies of infertile men with 'mixed atrophy' of seminiferous tubules. Andrologia 1999;31:203-210.
229. Steinhoff M, et al. Proteinase-activated receptors: transducers of proteinase-mediated signaling in inflammation and immune response. Endocr Rev 2005;26:1-43.
230. Brosnan CF, Tansey FA. Delayed onset of experimental allergic neuritis in rats treated with reserpine. J Neuropathol Exp Neurol 1984;43:84-93.
231. Dietsch GN, Hinrichs DJ. The role of mast cells in the elicitation of experimental allergic encephalomyelitis. J Immunol 1989;142:1476-1481.
232. Seeldrayers PA, Yasui D, Weiner HL, Johnson D. Treatment of experimental allergic neuritis with nedocromil sodium. J Neuroimmunol 1989;25:221-226.
233. Yamamoto M, Hibi H, Miyake K. New treatment of idiopathic severe oligozoospermia with mast cell blocker: results of a single-blind study. Fertil Steril 1995;64:1221-1223.
234. Hibi H, et al. Treatment of oligoasthenozoospermia with tranilast, a mast cell blocker, after long-term administration. Arch Androl 2002;48:451-459.
235. Matsuki S, et al. The use of ebastine, a mast cell blocker, for treatment of oligozoospermia. Arch Androl 2000;44:129-132.