title: Blockade of Notch ligand δ1 promotes allograft survival by inhibiting alloreactive Th1 cells and cytotoxic T cell generation.
abstract: The Notch signaling pathway has been recently shown to contribute to T cell differentiation in vitro. However, the in vivo function of Notch signaling in transplantation remains unknown. In this study, we investigated the importance of Delta1 in regulating the alloimmune response in vivo. Delta1 expression was upregulated on dendritic cells and monocytes/macrophages upon transplantation in a BALB/c into B6 vascularized cardiac transplant model. Whereas administration of anti-Delta1 mAb only slightly delayed survival of cardiac allografts in this fully MHC-mismatched model, it significantly prolonged graft survival in combination with single-dose CTLA4-Ig or in CD28 knockout recipients. The prolongation of allograft survival was associated with Th2 polarization and a decrease in Th1 and granzyme B-producing cytotoxic T cells. The survival benefit of Delta1 blockade was abrogated after IL-4 neutralization and in STAT6KO recipients, but was maintained in STAT4KO recipients, reinforcing the key role of Th2 cell development in its graft-prolonging effects. To our knowledge, these data demonstrate for the first time an important role of Delta1 in alloimmunity, identifying Delta1 ligand as a potential novel target for immunomodulation in transplantation.
authors.affiliation: Renal Division, Transplantation Research Center, Brigham and Women's Hospital, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Leonardo V
authors.initials: LV
authors.lastname: Riella
authors.forename: Takuya
authors.initials: T
authors.lastname: Ueno
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Batal
authors.forename: Sacha A
authors.initials: SA
authors.lastname: De Serres
authors.forename: Ribal
authors.initials: R
authors.lastname: Bassil
authors.forename: Wassim
authors.initials: W
authors.lastname: Elyaman
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: José O
authors.initials: JO
authors.lastname: Medina-Pestana
authors.forename: Anil
authors.initials: A
authors.lastname: Chandraker
authors.forename: Nader
authors.initials: N
authors.lastname: Najafian
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D016764:Cell Polarity / Q000235:genetics / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D006085:Graft Survival / Q000235:genetics / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000627:therapeutic use; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018448:Models, Immunological; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C064045:delta protein