The path for tolerance permissive immunomodulation in islet transplantation.
The path for tolerance permissive immunomodulation in islet transplantation.
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DOI：
10.1097/tp.0000000000000400
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发表时间：
2014-12-27
期刊：
影响因子：
6.2
通讯作者：
Ricordi C
中科院分区：
文献类型：
--
作者：
Ricordi C
Clinical islet transplantation has progressed significantly over the past three decades (1, 2). Major collaborative efforts have contributed to a progressive improvement of both immunosuppressive strategies and the complex sequential procedural steps required for the manufacturing of human islet cell products (2, 3, Fig. 1). Islet allotransplantation has been approved in selected countries for treatment of the most severe forms of type 1 diabetes mellitus (T1DM), such as those associated with hypoglycemia unawareness and an increased risk for severe hypoglycemic episodes. A multicenter Food and Drug Administration Phase III trial, which included centers in North America and Europe, has been completed and may lead to approval and eventual reimbursement of the procedure also in the United States. However, for islet transplantation to become applicable to most patients with T1DM and possibly also to other forms of insulin-requiring diabetes, it is now critically important to refocus collective efforts on the development of successful strategies for transplantation of insulin-producing cells in the absence of continuous recipient immunosuppression toward what has been for decades the Holy Grail of transplantation: immune tolerance. Unfortunately, traditional immunosuppressive protocols, although successful at controlling the effector phase of the immune response and early autoimmune recurrence, may not be highly conducive to tolerance induction. To achieve this goal, it is important to develop novel approaches of immunosuppression or immunomodulation that are compatible with the survival, function, and posttransplant expansion of regulatory cell subsets. The recent article by Maffi and collaborators (4) represents an excellent step in this direction. The protocol was in fact designed to avoid immunosuppressive agents with a mechanism of action that can affect T cell receptor signaling and calcineurin pathways, which could be detrimental to the survival, expansion, and function of regulatory cells (4).In contrast, rapamycin has been associated with both expansion of human regulatory cells in vitro and promotion of their immunomodulatory function in vivo, without affecting interleukin-10Ymediated regulatory pathways (4). However, some of the challenges associated with the requirement of balancing an adequate T-cellYdirected induction immunosuppression with a regulatory permissive overall immunomodulatory strategy have also been highlighted. In fact, it was of interest that all early graft losses (median graft survival of 37 days) were observed in recipients treated with lower doses of antithymocyte globulin (ATG) in the induction phase of immunosuppression. In these subjects, a less efficient depletion of CD3-CD8 T lymphocytes (in particular memory subset) was also observed (4), and none of them reached the primary endpoint of insulin independence at 3 years. In addition, a de novo, post-islet infusion expression of autoantibodies and alloantibodies was more often observed in these patients. In striking contrast, the total median islet graft survival in islet transplant recipients treated with higher-dose ATG induction was longer than 1,616 days and four of five of them reached the 3-year primary endpoint of insulin independence. Other variables that may have contributed to the success of this protocol in subjects receiving higher-dose ATG induction treatment could include the selected peritransplant antiinflammatory strategy and recipient treatment with granulocyte colony stimulating factor (GCSF), whose administration has been associated with tolerance-permissive, regulatory cellpromoting effects. Interestingly, the association of low-dose ATG (2.5 …
