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, ex vivo 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 in vitro 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.

Prostaglandin E2 stimulates the expansion of regulatory hematopoietic stem and progenitor cells in type 1 diabetes / M. Ben Nasr, F. D'Addio, A.M. Malvandi, S. Faravelli, E. Castillo-Leon, V. Usuelli, F. Rocchio, T. Letizia, A.B. El Essawy, E. Assi, C. Mameli, E. Giani, M. Macedoni, A. Maestroni, A. Dassano, C. Loretelli, M. Paroni, G. Cannalire, G. Biasucci, M. Sala, A. Biffi, G.V. Zuccotti, P. Fiorina. - In: FRONTIERS IN IMMUNOLOGY. - ISSN 1664-3224. - 9:(2018 Jun), pp. 1387.1-1387.12. [10.3389/fimmu.2018.01387]

Prostaglandin E2 stimulates the expansion of regulatory hematopoietic stem and progenitor cells in type 1 diabetes

M. Ben Nasr;F. D'Addio;A.M. Malvandi;S. Faravelli;V. Usuelli;F. Rocchio;T. Letizia;E. Assi;C. Mameli;E. Giani;M. Macedoni;A. Maestroni;A. Dassano;C. Loretelli;M. Paroni;M. Sala;G.V. Zuccotti;P. Fiorina
Ultimo
2018

Abstract

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, ex vivo 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 in vitro 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.
Autoimmune diseases; CXCR4; Hematopoietic stem and progenitor cells; PD-L1; Prostaglandins; Immunology and Allergy; Immunology
Settore MED/13 - Endocrinologia
giu-2018
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/582841
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