Immunologically based clinical trials performed thus far have failed to cure type 1 diabetes (T1D), in part because these approaches were nonspecific. Because the disease is driven by autoreactive CD4 T cells, which destroy b cells, transplantation of hematopoietic stem and progenitor cells (HSPCs) has been recently offered as a therapy for T1D. Our transcriptomic profiling of HSPCs revealed that these cells are deficient in programmed death ligand 1 (PD-L1), an important immune checkpoint, in the T1D nonobese diabetic (NOD) mouse model. Notably, the immunoregulatory molecule PD-L1 plays a determinant role in controlling/inhibiting activated T cells and thus maintains immune tolerance. Furthermore, our genome-wide and bioinformatic analysis revealed the existence of a network of microRNAs (miRNAs) controlling PD-L1 expression, and silencing one of key altered miRNAs restored PD-L1 expression in HSPCs. We therefore sought to determine whether restoration of this defect would cure T1D as an alternative to immunosuppression. Genetically engineered or pharmacologically modulated HSPCs overexpressing PD-L1 inhibited the autoimmune response in vitro, reverted diabetes in newly hyperglycemic NOD mice in vivo, and homed to the pancreas of hyperglycemic NOD mice. The PD-L1 expression defect was confirmed in human HSPCs in T1D patients as well, and pharmacologically modulated human HSPCs also inhibited the autoimmune response in vitro. Targeting a specific immune checkpoint defect in HSPCs thus may contribute to establishing a cure for T1D.

PD-L1 genetic overexpression or pharmacological restoration in hematopoietic stem and progenitor cells reverses autoimmune diabetes / Nasr, Moufida Ben; Tezza, Sara; D'Addio, Francesca; Mameli, Chiara; Usuelli, Vera; Maestroni, Anna; Corradi, Domenico; Belletti, Silvana; Albarello, Luca; Becchi, Gabriella; Fadini, Gian Paolo; Schuetz, Christian; Markmann, James; Wasserfall, Clive; Zon, Leonard; Zuccotti, Gian Vincenzo; Fiorina, Paolo. - In: SCIENCE TRANSLATIONAL MEDICINE. - ISSN 1946-6234. - 9:416(2017), p. eaam7543. [10.1126/scitranslmed.aam7543]

PD-L1 genetic overexpression or pharmacological restoration in hematopoietic stem and progenitor cells reverses autoimmune diabetes

Corradi, Domenico;Belletti, Silvana;Becchi, Gabriella;Fadini, Gian Paolo;
2017

Abstract

Immunologically based clinical trials performed thus far have failed to cure type 1 diabetes (T1D), in part because these approaches were nonspecific. Because the disease is driven by autoreactive CD4 T cells, which destroy b cells, transplantation of hematopoietic stem and progenitor cells (HSPCs) has been recently offered as a therapy for T1D. Our transcriptomic profiling of HSPCs revealed that these cells are deficient in programmed death ligand 1 (PD-L1), an important immune checkpoint, in the T1D nonobese diabetic (NOD) mouse model. Notably, the immunoregulatory molecule PD-L1 plays a determinant role in controlling/inhibiting activated T cells and thus maintains immune tolerance. Furthermore, our genome-wide and bioinformatic analysis revealed the existence of a network of microRNAs (miRNAs) controlling PD-L1 expression, and silencing one of key altered miRNAs restored PD-L1 expression in HSPCs. We therefore sought to determine whether restoration of this defect would cure T1D as an alternative to immunosuppression. Genetically engineered or pharmacologically modulated HSPCs overexpressing PD-L1 inhibited the autoimmune response in vitro, reverted diabetes in newly hyperglycemic NOD mice in vivo, and homed to the pancreas of hyperglycemic NOD mice. The PD-L1 expression defect was confirmed in human HSPCs in T1D patients as well, and pharmacologically modulated human HSPCs also inhibited the autoimmune response in vitro. Targeting a specific immune checkpoint defect in HSPCs thus may contribute to establishing a cure for T1D.
PD-L1 genetic overexpression or pharmacological restoration in hematopoietic stem and progenitor cells reverses autoimmune diabetes / Nasr, Moufida Ben; Tezza, Sara; D'Addio, Francesca; Mameli, Chiara; Usuelli, Vera; Maestroni, Anna; Corradi, Domenico; Belletti, Silvana; Albarello, Luca; Becchi, Gabriella; Fadini, Gian Paolo; Schuetz, Christian; Markmann, James; Wasserfall, Clive; Zon, Leonard; Zuccotti, Gian Vincenzo; Fiorina, Paolo. - In: SCIENCE TRANSLATIONAL MEDICINE. - ISSN 1946-6234. - 9:416(2017), p. eaam7543. [10.1126/scitranslmed.aam7543]
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11381/2838396
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 65
  • ???jsp.display-item.citation.isi??? 60
social impact