Targeting the CXCR4-CXCL12 axis mobilizes autologous hematopoietic stem cells and prolongs islet allograft survival via programmed death ligand 1.
Antagonism of CXCR4 disrupts the interaction between the CXCR4 receptor on hematopoietic stem cells (HSCs) and the CXCL12 expressed by stromal cells in the bone marrow, which subsequently results in the shedding of HSCs to the periphery. Because of 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 costimulatory molecule programmed death ligand 1 (PD-L1), and HSCs extracted from wild-type mice, but not from PD-L1 knockout mice, suppressed the in vitro alloimmune response. Moreover, HSC mobilization in PD-L1 knockout 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.
Transplantation Research Center, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. paolo.fiorina@childrens.harvard.edu
Paolo
P
Fiorina
Mollie
M
Jurewicz
Andrea
A
Vergani
Alessandra
A
Petrelli
Michele
M
Carvello
Francesca
F
D'Addio
Jonathan G
JG
Godwin
Kenneth
K
Law
Erxi
E
Wu
Ze
Z
Tian
Gebhard
G
Thoma
Jiri
J
Kovarik
Stefano
S
La Rosa
Carlo
C
Capella
Scott
S
Rodig
Hans-Guenter
HG
Zerwes
Mohamed H
MH
Sayegh
Reza
R
Abdi
D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000502:physiology*; D060890:B7-H1 Antigen; D001596:Benzylamines; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D000080027:Cyclams; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000473:pathology / Q000601:surgery; D018390:Gene Targeting / Q000379:methods; D006085:Graft Survival / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D006571:Heterocyclic Compounds / Q000494:pharmacology; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D010455:Peptides / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014184:Transplantation, Homologous
D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D001596:Benzylamines; C514936:CXCR4 protein, mouse; C498919:Cd274 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D008562:Membrane Glycoproteins; D010455:Peptides; D019718:Receptors, CXCR4; C088327:plerixafor