Notch signaling in hematopoietic cell transplantation and T cell alloimmunity

Christen L. Ebens, Ivan Maillard

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Notch signaling can regulate both hematopoietic progenitors and alloimmune T cells in the setting of allogeneic bone marrow or hematopoietic cell transplantation (allo-HCT). Ex vivo culture of multipotent blood progenitors with immobilized Delta-like ligands induces supraphysiological Notch signals and can markedly enhance progenitor expansion. Infusion of Notch-expanded progenitors shortened myelosuppression in preclinical and early clinical studies, while accelerating T cell reconstitution in preclinical models. Notch also plays an essential role in vivo to regulate pathogenic alloimmune T cells that mediate graft-versus-host disease (GVHD), the most severe complication of allo-HCT. In mouse allo-HCT models, Notch inhibition in donor-derived T cells or transient blockade of Delta-like ligands after transplantation profoundly decreased GVHD incidence and severity, without causing global immunosuppression. These findings identify Notch in T cells as an attractive therapeutic target to control GVHD. In this review, we discuss these contrasting functions of Notch signaling with high translational significance in allo-HCT patients.

Original languageEnglish (US)
Pages (from-to)269-277
Number of pages9
JournalBlood Reviews
Volume27
Issue number6
DOIs
StatePublished - Nov 2013

Bibliographical note

Funding Information:
Work on Notch signaling in the Maillard laboratory has been or is supported by a Damon Runyon-Rachleff Innovation award ( DRR-05A-09 ), a Scholar Award of the American Society of Hematology , a Scholar Award from the Leukemia and Lymphoma Society and the National Institutes of Health ( RO1-AI091627 ). C.L.E. is supported by a T32 training grant from NHLBI ( HL00762-26 ).

Keywords

  • Bone marrow transplantation
  • Graft-versus-host disease
  • Hematopoietic stem cells
  • Notch
  • Notch ligands
  • T cells

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