The Role of Foxp3+ Regulatory T Cells in Liver Transplant Tolerance
ABSTRACT The liver has long been considered a tolerogenic organ that favors the induction of peripheral tolerance. The mechanisms underlying liver tolerogenicity remain largely undefined. In this study, we characterized Foxp3-expressing CD4+CD25+ regulatory T cells (Treg) in liver allograft recipients and examined the role of Treg in inherent liver tolerogenicity by employing the mouse spontaneous liver transplant tolerance model. Orthotopic liver transplantation was performed from C57BL/10 (H2b) to C3H/HeJ (H2k) mice. The percentage of CD4+CD25+ Treg was expanded in the liver grafts and recipient spleens from day 5 up to day 100 posttransplantation, associated with high intracellular Foxp3 and CTLA4 expression. Immunohistochemistry further demonstrated significant numbers of Foxp3+ cells in the liver grafts and recipient spleens and increased transforming growth factor β expression in the recipient spleens throughout the time courses. Adoptive transfer of spleen cells from the long-term liver allograft survivors significantly prolonged donor heart graft survival. Depletion of recipient CD4+CD25+ Treg using anti-CD25 monoclonal antibody (250 μg/d) induced acute liver allograft rejection, associated with elevated anti-donor T-cell proliferative responses, CTL and natural killer activities, enhanced interleukin (IL)-2, interferon-γ, IL-10, and decreased IL-4 production, and decreased T-cell apoptotic activity in anti-CD25-treated recipients. Moreover, CTLA4 blockade by anti-CTLA4 monoclonal antibody administration exacerbated liver graft rejection when combined with anti-CD25 monoclonal antibody. Thus, Foxp3+CD4+CD25+ Treg appear to underpin spontaneous acceptance of major histocompatability complex– mismatched liver allografts in mice. CTLA4, IL-4, and apoptosis of alloreactive T cells appear to contribute to the function of Treg and regulation of graft outcome.
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ABSTRACT: This study aims to investigate the effects of anti-CD25 monoclonal antibody (mAb) on the effector T cells (Teff) and CD4+CD25+ regulatory T cells (CD4+CD25+Treg) in corneal allograft rejection. Wistar rats were used as donors and SD rats were used as recipients. Routine penetrating keratoplasty (PKP) was performed. 90 SD rats were randomly divided into 5 groups: A -E. Group A (n = 6) was normal group and rats in Groups B (n = 24), C (n = 18), D (n = 18) and E (n = 24) were transplanted and subconjunctivally treated with normal saline, 100 µg anti-CD25 mAb, 100 µg anti-CD25 mAb plus 50 µg dexamethasone and 100 µg dexamethasone, respectively, on day 0, 2, 4, 6 and 8 following transplantation. The average transplant survival time in the Group B was significantly shorter than that of Groups C, D and E (P < 0.05). The mRNA expression of IFN-γ, CD25 or FOXP3 was not detected in the Group A. Compared to the Groups C, D and E, the mRNA expression of IFN-γ and CD25 in the grafts of Group B was markedly increased (P < 0.05) on day 11 following PKP. Compared with the Groups D and E, the mRNA expression of FOXP3 in the grafts of Group C was markedly decreased (P < 0.05). When compared with Group B, the mean IFN-γ level in the aqueous humour was remarkably decreased in Groups C, D and E (P < 0.05) on day 6 and 11 following PKP 11 days after PKP, the mean IFN-γ level in the aqueous humour of Groups D and E was profoundly decreased compared to the Group C (P < 0.05). No significant difference was observed in Groups D and E. But high-dose dexamethasone monotherapy have a high risk of side effects. The results suggest Teff and CD4+CD25+Treg play important roles in the corneal allograft rejection.
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ABSTRACT: NO is an important bioactive molecule involved in a variety of physio- and pathological processes, including apoptosis induction. The proapoptotic activity of NO involves the rise in the tumor suppressor p53 and the accumulation and targeting of proapoptotic members of the Bcl-2 family, in particular Bax and the release of cytochrome c from the mitochondria. However, the exact mechanism by which NO induces p53 activation has not been fully elucidated. In this study, we describe that NO induces p19(ARF) through a transcriptional mechanism. This up-regulation of p19(ARF) activates p53, leading to apoptosis. The importance of p19(ARF) on NO-dependent apoptosis was revealed by the finding that various cell types from alternate reading frame-knockout mice exhibit a diminished response to NO-mediated apoptosis when compared with normal mice. Moreover, the biological relevance of alternative reading frame to p53 apoptosis was confirmed in in vivo models of apoptosis. Together, these results demonstrate that NO-dependent apoptosis requires, in part, the activation of p19(ARF).The Journal of Immunology 10/2006; 177(5):3327-36. DOI:10.4049/jimmunol.179.2.1389 · 5.36 Impact Factor