Use of Post-transplant Cyclophosphamide Treatment to Build a Tolerance Platform to Prevent Liquid and Solid Organ Allograft Rejection.
Use of Post-transplant Cyclophosphamide Treatment to Build a Tolerance Platform to Prevent Liquid and Solid Organ Allograft Rejection.
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使用移植后环磷酰胺治疗建立耐受平台以防止液体和固体器官移植排斥反应。
DOI：
10.3389/fimmu.2021.636789
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发表时间：
2021
影响因子：
7.3
通讯作者：
Levy RB
中科院分区：
文献类型：
--
作者：
Lightbourn CO;Wolf D;Copsel SN;Wang Y;Pfeiffer BJ;Barreras H;Bader CS;Komanduri KV;Perez VL;Levy RB
角膜移植(CT)是世界范围内最常见的实体器官移植(SOT)手术。不幸的是，免疫排斥是CT移植失败的主要原因，因此在诱导耐受的免疫调节方面的进展仍然是一个未得到满足的医学需求。最近，我们的工作和其他临床前研究发现，在(移植后，PTCy)造血干细胞移植(HSCT)后给予环磷酰胺(Cy)，即液体移植，对移植物和宿主疾病的预防有效，并提高总体存活率。重要的是，在过去的10年里，PTCy已被广泛应用于临床HSCT，许多中心的结果非常令人鼓舞。目前的研究发现Cy可以有效地延长SOT的存活时间，特别是小鼠同种异体角膜移植的存活时间。结果表明，PTCy给药的时机对这些CT是至关重要的，并且不同于同种异体HSCT后的动力学。PTCy被观察到干扰新生血管的形成，这一过程与角膜组织的免疫排斥反应密切相关，而角膜组织免疫排斥反应是眼睛失去“免疫豁免权”后的结果。PTCy具有删除或直接抑制同种反应性T细胞的潜力，这里的治疗被证明减少了T细胞的排斥反应。观察到这些PTCy剂量节省了大量的CD4+FoxP3+(Tregs)，这些Tregs被发现具有功能，并可以很容易地接收刺激信号，导致它们通过TNFRSF25和CD25激动剂在体内扩张。总而言之，我们假设未来的研究可以利用基于Cy的平台来生成长期耐受诱导的组合策略。
Corneal transplantation (CT) is the most frequent type of solid organ transplant (SOT) performed worldwide. Unfortunately, immunological rejection is the primary cause of graft failure for CT and therefore advances in immune regulation to induce tolerance remains an unmet medical need. Recently, our work and others in pre-clinical studies found that cyclophosphamide (Cy) administered after (“post-transplant,” PTCy) hematopoietic stem cell transplantation (HSCT), i.e., liquid transplants is effective for graft vs. host disease prophylaxis and enhances overall survival. Importantly, within the past 10 years, PTCy has been widely adopted for clinical HSCT and the results at many centers have been extremely encouraging. The present studies found that Cy can be effectively employed to prolong the survival of SOT, specifically mouse corneal allografts. The results demonstrated that the timing of PTCy administration is critical for these CT and distinct from the kinetics employed following allogeneic HSCT. PTCy was observed to interfere with neovascularization, a process critically associated with immune rejection of corneal tissue that ensues following the loss of ocular “immune privilege.” PTCy has the potential to delete or directly suppress allo-reactive T cells and treatment here was shown to diminish T cell rejection responses. These PTCy doses were observed to spare significant levels of CD4+ FoxP3+ (Tregs) which were found to be functional and could readily receive stimulating signals leading to their in vivo expansion via TNFRSF25 and CD25 agonists. In total, we posit future studies can take advantage of Cy based platforms to generate combinatorial strategies for long-term tolerance induction.
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影响因子：
5.4
作者：
Bayer, Allison L.;Chirinos, Jackeline;Cabello, Cecilia;Yang, Jing;Matsutani, Takaji;Malek, Thomas R.;Levy, Robert B.
通讯作者：
Levy, Robert B.
TNF受体超家族25（TNFRSF25）在过敏性肺部炎症发展中的重要作用。
影响因子：
15.3
作者：
Fang, Lei;Adkins, Becky;Deyev, Vadim;Podack, Eckhard R.
通讯作者：
Podack, Eckhard R.
影响因子：
6.2
作者：
Boisgérault F;Liu Y;Anosova N;Dana R;Benichou G
通讯作者：
Benichou G
影响因子：
2.8
作者：
Cursiefen, C;Chen, L;Streilein, JW
通讯作者：
Streilein, JW
影响因子：
20.3
作者：
Bayer, Allison L.;Jones, Monica;Levy, Robert B.
通讯作者：
Levy, Robert B.