Murine xenogeneic immune responses to the human testis: a presumed immune-privileged tissue.

INTRODUCTION: Immune privilege provides a natural paradigm for potentially down-regulating allogeneic and xenogeneic inflammatory immune responses. Fas ligand has been suggested as a general underlying mechanism of immune privilege; the human Fas ligand has been shown to ligate murine Fas in vitro. METHODS: In this study, we examined whether the human testicular xenograft, a presumed immune-privileged tissue would have prolonged survival in mice. In addition, in vitro and in vivo murine xenogeneic immune responses to the human testicular xenografts were characterized using MHC class I, MHC class II, CD4, CD8, CD4/8 knockout mice. RESULTS: Unlike in rodent testis, Fas ligand mRNA is not expressed and Fas is highly expressed in human testis. Human testicular xenografts are immunogenic, and do not induce any preferential pattern of recipient systemic Th1 or Th2 cytokine bias. Interestingly, an indefinite survival of the human testicular xenografts is observed in murine MHC class II knockout mice, whereas the human skin xenografts were rejected without a delay. In vivo murine immune responses to human testicular xenografts require a recipient MHC class II-dependent CD4 T cell-mediated process that appears to depend on B7-1/B7-2 costimulatory signals. CONCLUSIONS: Our results demonstrate that the concept of immune privilege, as defined by the expression of Fas ligand and prolonged survival after transplantation, cannot be extended to human testis. The stringent restriction of murine xenogeneic immune responses to discordant human testicular xenografts to the indirect MHC class II-dependent CD4 T cell-mediated pathway suggests a potential venue for immune modulation to induce tolerance across a discordant species barrier.

New mouse models of congenital anorectal malformations.

BACKGROUND/PURPOSE: The genetic, embryological, and pathogenetic aspects of hindgut development remain poorly understood. Recently, the morphogenetic pathway involving the Sonic hedgehog (Shh) gene has been shown essential to the normal development of many midaxial organs, including the foregut. This study reports genetically based murine models of congenital anorectal malformations (CAM) involving the Shh-responsive transcription factors, Gli2 and Gli3. Its purpose is to show the necessity of these 2 factors to normal hindgut development. METHODS: Gli2-/- mutants were generated by a targeted deletion. Gli3-/- mutants are spontaneous mutants involving the Gli3 gene. Gli2-/- Gli3+/- mutants were generated by intercrossing double heterozygotes. Whole-mount midsagittal sections of the embryos were analyzed on embryonic days (E) 11.5 and E13.5. RESULTS: Gli3-/- mutants had anal stenosis and ectopic anus, and Gli2-/- mutants showed imperforate anus and rectourethral fistula. Gli2-/- Gli3+/- mutants had a cloacal abnormality. CONCLUSIONS: The phenotypic abnormalities observed in these mutant mice are identical to the spectrum of human CAM. The severity of the phenotype appears to reflect the gene dose. Gli2 and Gli3 play an important role in the normal development of murine hindgut. The results of this study provide, for the first time, a molecular basis for CAM.