Ben Nasr Moufida, D'Addio Francesca, Malvandi Amir Mohammad, Faravelli Silvia, Castillo-Leon Eduardo, Usuelli Vera, Rocchio Francesca, Letizia Teresa, El Essawy Abdel Basset, Assi Emma, Mameli Chiara, Giani Elisa, Macedoni Maddalena, Maestroni Anna, Dassano Alice, Loretelli Cristian, Paroni Moira, Cannalire Giuseppe, Biasucci Giacomo, Sala Marco, Biffi Alessandra, Zuccotti Gian Vincenzo, Fiorina Paolo
Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States.
International Center for T1D, Pediatric Clinical Research Center Fondazione Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy.
Front Immunol. 2018 Jun 19;9:1387. doi: 10.3389/fimmu.2018.01387. eCollection 2018.
Hematopoietic stem and progenitor cells (HSPCs) are multipotent stem cells that have been harnessed as a curative therapy for patients with hematological malignancies. Notably, the discovery that HSPCs are endowed with immunoregulatory properties suggests that HSPC-based therapeutic approaches may be used to treat autoimmune diseases. Indeed, infusion with HSPCs has shown promising results in the treatment of type 1 diabetes (T1D) and remains the only "experimental therapy" that has achieved a satisfactory rate of remission (nearly 60%) in T1D. Patients with newly diagnosed T1D have been successfully reverted to normoglycemia by administration of autologous HSPCs in association with a non-myeloablative immunosuppressive regimen. However, this approach is hampered by a high incidence of adverse effects linked to immunosuppression. Herein, we report that while the use of autologous HSPCs is capable of improving C-peptide production in patients with T1D, modulation of HSPCs with prostaglandins (PGs) increases their immunoregulatory properties by upregulating expression of the immune checkpoint-signaling molecule PD-L1. Surprisingly, CXCR4 was upregulated as well, which could enhance HSPC trafficking toward the inflamed pancreatic zone. When tested in murine and human autoimmune assays, PG-modulated HSPCs were shown to abrogate the autoreactive T cell response. The use of PG-modulated HSPCs may thus provide an attractive and novel treatment of autoimmune diabetes.
造血干细胞和祖细胞（HSPCs）是多能干细胞，已被用作治疗血液系统恶性肿瘤患者的有效疗法。值得注意的是，HSPCs具有免疫调节特性这一发现表明，基于HSPCs的治疗方法可能用于治疗自身免疫性疾病。事实上，输注HSPCs在1型糖尿病（T1D）治疗中已显示出有前景的结果，并且仍然是唯一在T1D中实现了令人满意的缓解率（近60%）的“实验性疗法”。新诊断的T1D患者通过联合非清髓性免疫抑制方案给予自体HSPCs已成功恢复至正常血糖水平。然而，这种方法受到与免疫抑制相关的高不良反应发生率的阻碍。在此，我们报告，虽然使用自体HSPCs能够改善T1D患者的C肽产生，但用前列腺素（PGs）调节HSPCs可通过上调免疫检查点信号分子PD-L1的表达来增强其免疫调节特性。令人惊讶的是，CXCR4也被上调，这可增强HSPCs向炎症胰腺区域的迁移。在小鼠和人类自身免疫试验中进行测试时，PG调节的HSPCs被证明可消除自身反应性T细胞反应。因此，使用PG调节的HSPCs可能为自身免疫性糖尿病提供一种有吸引力的新型治疗方法。
