Immune Privilege of the Testis for Islet Xenotransplantation (Rat to Mouse)

Abstract

The testis has been suggested as an immune privileged site for islet transplantation. The present study evaluated this hypothesis by transplanting islets from Wistar Furth rats into (a) the testes; (b) the subcapsular space of the kidneys; or (c) the cryptorchid abdominal testes of streptozotocin-induced diabetic Swiss ND4 mice. Transplantation of 800 rat islets into the cryptorchid testes normalized blood glucose for 9.3 ± 1.4 (Mean ± SD) days, not significantly different from that of the scrotal testis site (12.4 ± 1.3), or when the subcapsular space of the kidneys was used (11.5 ± 1.2). When mouse islets were isotransplanted into the cryptorchid testes of diabetic mice, normoglycemia was maintained for the entire 3 month study period. Histologic examination of the islet xenograft-bearing cryptorchid testes at day 7 post transplantation and 2 days after returning to hyperglycemia revealed lymphocyte infiltration surrounding and inside the graft. No lymphocyte infiltration was seen in the isograft bearing-testes at 3 mo after transplantation. Cyclosporine A (CsA, 15 mg/kg/day) administration to the islet xenograft recipient slightly prolonged the normoglycemic period to 13.7 ± 1.8 days (p < 0.01). Increasing CsA dose to 25 mg/kg induced a 66% (4/6) mortality, and did not further prolong the normoglycemic period. Using a lower number of rat islets (200 or 400 islets), prolonged graft survival was achieved in some (4 out of 20) animals when the cryptorchid testis was used. In contrast, transplantation of 400 rat islets into the subcapsular space of the kidneys was not associated with prolonged graft survival. When a second rat islet xenograft was transplanted into the subcapsular space of the kidneys of diabetic mice, subsequent to a rejected first intratesticular xenograft, the normoglycemic period was markedly shortened to 3.2 ± 0.5 days (p < 0.01). It is concluded that the testis may act as an immune privileged site for islet xenotransplantation, however, only when a small number of islets is transplanted. A large number of islets will override the immune privilege status of the testis. CsA slightly but significantly delays islet xenograft rejection. Finally, islets transplanted in the testes do sensitize the host against a second islet graft.