Costimulatory blockade of CD154-CD40 in combination with T-cell lymphodepletion results in prevention of allogeneic sensitization.
Costimulatory blockade of CD154-CD40 in combination with T-cell lymphodepletion results in prevention of allogeneic sensitization.
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DOI：
10.1182/blood-2006-10-053801
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发表时间：
2008-03
期刊：
影响因子：
20.3
通讯作者：
Hong-lin Xu;Jun Yan;Yiming Huang;P. Chilton;C. Ding;Carrie L. Schanie;Li Wang;S. Ildstad
中科院分区：
文献类型：
--
作者：
Hong-lin Xu;Jun Yan;Yiming Huang;P. Chilton;C. Ding;Carrie L. Schanie;Li Wang;S. Ildstad
致敏是移植中一个关键的未解决的挑战。我们第一次表明，单独阻断CD 154或与T细胞耗竭相结合可防止致敏。同种异体皮肤移植物被单独用抗α T细胞受体（TCR）、抗CD 154、抗OX 40 L或抗诱导型共刺激通路（ICOS）mAb处理的受体排斥，其动力学与未处理的受体相似。然而，在仅用抗CD 154 mAb处理的小鼠中，抗供体MHC抗体的产生被阻止，表明CD 154-CD 40途径在B细胞活化中的特定作用。通过阻断CD 154而损害T细胞依赖性B细胞应答是通过抑制T和B细胞的活化以及IFN-γ和IL-10的分泌而发生的。联合治疗与抗CD 154和抗α TCR废除抗供体抗体的产生，并导致皮肤移植物的存活时间延长，这表明诱导T细胞和B细胞的耐受性与预防同种异体致敏。此外，我们表明，联合治疗诱导的耐受性是非缺失的。此外，这些预防致敏的策略促进了先前暴露于供体同种异体抗原的受者的骨髓植入。这些发现可能是临床相关的，以防止同种异体致敏与最小的毒性，并指出体液免疫在致敏受体的同种异体反应中发挥主导作用。
Sensitization is a critical unresolved challenge in transplantation. We show for the first time that blockade of CD154 alone or combined with T-cell depletion prevents sensitization. Allogeneic skin grafts were rejected by recipients treated with anti-alphabeta T-cell receptor (TCR), anti-CD154, anti-OX40L, or anti-inducible costimulatory pathway (ICOS) mAb alone with a kinetic similar to untreated recipients. However, the production of anti-donor MHC antibody was prevented in mice treated with anti-CD154 mAb only, suggesting a specific role for the CD154-CD40 pathway in B-cell activation. The impairment of T cell-dependent B-cell responses by blocking CD154 occurs through inhibiting activation of T and B cells and secretion of IFN-gamma and IL-10. Combined treatment with both anti-CD154 and anti-alphabeta TCR abrogated antidonor antibody production and resulted in prolonged skin graft survival, suggesting the induction of both T- and B-cell tolerance with prevention of allogeneic sensitization. In addition, we show that the tolerance induced by combined treatment was nondeletional. Moreover, these sensitization-preventive strategies promote bone marrow engraftment in recipients previously exposed to donor alloantigen. These findings may be clinically relevant to prevent allosensitization with minimal toxicity and point to humoral immunity as playing a dominant role in alloreactivity in sensitized recipients.