2.
Suppressive effect of FK-506 on contralateral experimental
autoimmune orchitis (EAO) and infertility induced by unilateral testicular injury.
Yasuki SAKAMOT0 1, Joichi KUMAZAWA 2 and Tetsuro MATSUMOTO 3 Department of Urology, JR Kyushu Hospital, Kyushu Railway Co.1,
Faculty of Medicine, Kyushu University 2 and School of Medicine, University of Occupational and Environmental Health 3
EAO has been studied as an animal model for human male
immunological infertility. A delayed type hypersensitivity (DTH)
response has been detected in animals showing FAO and is thought to play a pivotal role in the development of the lesion (1, 2). We reported the induction of infertility as well as FAO by unilateral testicular injury at this meeting two years ago (3). Last year, we reported the
suppression of contralateral FAO and infertility by an
immunosuppressive drug, cyclosporin A (CsA). In the present study, we report a similar suppression of FAO and infertility by FK-506.
Three-month-old male mice of inbred C3H/HeN strain were utilized for the experiments. The left testis was injured in a following way. Ten to 20 needle punctures were made to the testis and the testis was crushed fully by a needle-holder (Injury-Group). In addition, FK-506- Group was treated with 1 mg/kg of FK-506 intraperitoneally every other day. A DTH response was measured by means of delayed footpad reaction (DFR). Anti-testis cells (TC) antibodies were assayed by ELISA. After 3 months, mice were mated with female ddY mice.
When the left testis was injured, the contralateral right testis showed moderate to severe mononuclear cell infiltration in the interstitium in 90% and hypospermatogenesis to several degrees in 100% on day 100, histologically. However, only 50% of mild cell infiltration and hypospermatogenesis was observed in FK-506-Group. A DTH response to syngeneic TC was significantly suppressed in the FK-506-Group compared to the Injury-Grooup. On the other hand, Anti-TC antibodies in the FK-506-Group were not suppressed at all. Fertility rate in the Injury-Group was 20%, whereas the rate was increased to 75% in the FK-506-Group.
We have already reported the induction of the contralateral FAO and infertility by unilateral testicular injury without immunization at all (3). This could be a very clinical model since our testicular injury mimics severe piercing testicular trauma. We have clearly shown that the contralateral testis is damaged and infertility is indeed induced by an immunological mechanism since a DTH response to autologous TC
-32-and anti-TC antibodies are significantly enhanced in such-treated mice. Even though "sympathetic orchitis" (contralateral EAO) is sometimes referred clinically, we could not find any detailed reports either in a laboratory study or clinically. In the present report, we have shown the suppressive effect of an immunosuppressive drug, FK-506, on the induction of contralateral orchitis and infertility in
a similar way as we reported on CsA last year. Administration of 1 mg/kg of FK-506 every other day significantly suppressed the DTH response to autologous TC as well as the induction of contralateral EAO
and infertility, but not anti-TC antibodies. Therefore, it seems that FK-506 might be effective on some male infertile patiens and that a DTH response plays a more direct role than anitbodies in the induction
and/or maintenance of EAO as has been suggested by many other studies on EAO (1, 3-6).
References
1. Sakamoto, Y et al. (19 85) Experimental allergic orchitis in mice. I. A new model induced by immunization without adjuvants. Clin.
Immunol. Immunopathol., 37, 360.
2. Sakamoto, Y et al. (1995) Testicular injury induces cell-mediated autoimmune response to testis. J. Urol., 153, 1316.
3. Sakamoto, Y et al. (1994) Unilateral testicular injury induces the contralateral autoimmune orchitis in mice. J. Urol., 151, 309A. 4. Kohno, S et al. (1983) Immunopathology of murine experimental
allergic orchitis. J. Immunol., 130, 2675.
5. Tung, KSK et al. (1977) Pathogenesis of experimental allergic orchitis. III. T lymphocyte requirement in local adoptive transfer by peritoneal exudate cells. J. Immunol., 118, 1774.
6. Mahi-Brown, CA et al. (19 87 ) Adoptive transfer of murine
autoimmune orchitis to naive recipients with immune lymphocytes. Cell. Immunol., 106, 408.
