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Targeting the CXCR4-CXCL12 axis mobilizes autologous hematopoietic stem cells and prolongs islet allograft survival via PD-L1

Fiorina, Paolo and Jurewicz, Mollie and Vergani, Andrea and Vergelli, Alessandra and Carvello, Michele and D'Addio, Francesca and Godwin, Jonathan and Law, Kenneth and Wu, Erxi and Tian, Ze and Thoma, Gebhard and Kovarik, Jiri and La Rosa, Stefano and Capella, Carlo and Rodig, Scott and Zerwes, Hans-Guenter and Sayegh, Mohammed and Abdi, Reza (2010) Targeting the CXCR4-CXCL12 axis mobilizes autologous hematopoietic stem cells and prolongs islet allograft survival via PD-L1. The Journal of Immunology, 186 (3). pp. 121-131. ISSN 0022-1767

Abstract

Antagonism of CXCR4 disrupts the interaction between the CXCR4 receptor on HSCs and the CXCL12 expressed by stromal cells in the bone marrow, which subsequently results in the shedding of hematopoietic stem cells (HSCs) to the periphery. Due to their profound immunomodulatory effects, HSCs have emerged as a promising therapeutic strategy for autoimmune disorders. We sought to investigate the immunomodulatory role of mobilized autologous HSCs, via target of the CXCR4-CXL12 axis, to promote engraftment of islet cell transplantation. Islets from BALB/c mice were transplanted beneath the kidney capsule of hyperglycemic C57BL/6 mice, and treatment of recipients with CXCR4 antagonist resulted in mobilization of HSCs and in prolongation of islet graft survival. Addition of Rapamycin to anti-CXCR4 therapy further promoted HSC mobilization and islet allograft survival, inducing a robust and transferable host hyporesponsiveness, while administration of an ACK2 (anti-CD117) mAb halted CXCR4 antagonist-mediated HSC release and restored allograft rejection. Mobilized HSCs were shown to express high levels of the negative co-stimulatory molecule PD-L1, and HSCs extracted from WT mice, but not from PD-L1 KO, suppressed the in vitro alloimmune response. Moreover, HSC mobilization in PD-L1 KO mice failed to prolong islet allograft survival. Targeting the CXCR4-CXCL12 axis thus mobilizes autologous HSCs and promotes long-term survival of islet allografts via a PD-L1-mediated mechanism.

Item Type: Article
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Additional Information: The compound was supplied under MTA 22021, executed 11.01.2005. An abstract of this manuscript was released through the old procedure in Dec 2006 for presentation at ATC 2007 The compound used in these studies (NVP-AWJ167) has been published (including the structure) - see: Thoma, G., M. B. Streiff, J. Kovarik, F. Glickman, T. Wagner, C. Beerli, and H. G. Zerwes. 2008. Orally bioavailable isothioureas block function of the chemokine receptor CXCR4 in vitro and in vivo. J Med Chem 51:7915-7920. (ref. 20 in the manuscript) in this publication the compound is coded (NIBR1816 stands for NVP-AWJ167) and the structure is not shown
Keywords: Diabetes, CXCR4-CXCL12 axis, islet transplantation, hematopoietic stem cells
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/3984

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