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Notch Signaling Inhibition via Blockade of Delta-Like Ligand 4 Prevents Co-Stimulation Blockade Resistant Allograft Rejection

A. J. Matar, B. P. Lovasik, Y. Dong, D. A. Faber, J. Habib, C. A. Breeden, J. Regenold, A. Ghosh, A. Stephenson, W. H. Kitchens, A. B. Adams

Surgery and Transplantation, Emory University, Atlanta, GA

Meeting: 2020 American Transplant Congress

Abstract number: 313

Keywords: Alloantibodies, Co-stimulation, Rejection, T cell activation

Session Information

Session Name: Immunosuppression Preclinical Studies

Session Type: Oral Abstract Session

Date: Saturday, May 30, 2020

Session Time: 3:15pm-4:45pm

 Presentation Time: 3:15pm-3:27pm

Location: Virtual

*Purpose: Co-stimulation blockade (CoB) has emerged as a promising immunosuppression strategy with the advent of Belatacept, a novel CTLA4-Ig fusion protein that blocks CD28-mediated T cell co-stimulation. Belatacept confers long-term advantages in graft survival and function in renal transplant recipients compared to traditional calcineurin inhibitor-based immunosuppression but is associated with increased rates of early acute rejection. The aim of this study was to investigate the role of Notch signaling inhibition via blockade of Delta-like ligand 4 (DLL4) on CoB-resistant rejection (CoBRR).

*Methods: We utilized a murine model of MHC mismatched skin transplantation (Balb/C -> C57BL/6) to assess graft survival, T cell activation and anti-donor antibody responses. Donor-specific T cell responses were assessed using mOVA skin grafts in recipients which received an adoptive transfer of Thy1.1+ ovalbumin-specific OT-I T cells. DLL4 blockade was also tested in a large animal non-human primate (NHP) model of MHC mismatched renal transplantation.

*Results: Combined CoB (CTLA4-Ig + anti-CD154) and DLL4 blockade significantly prolonged skin graft survival compared to CoB alone (MST 32 days vs. 85 days, p = 0.001**). DLL4 blockade inhibited T cell activation as measured by CD44 expression and suppressed the formation of anti-donor antibody. In an mOVA model, combined CTLA4-Ig and DLL4 blockade suppressed donor-specific CD8+ T cell effector function via IFN-gamma and TNF-a production. Finally, in non-human primates, preliminary studies suggest combination Belatacept and DLL4 blockade may prolong graft survival compared to Belatacept alone (MST 35 days (n=2 – currently ongoing) vs. 29 days (n=5).

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*Conclusions: These murine data and ongoing NHP studies demonstrate that DLL4 blockade suppresses both T and B cell responses in the setting of CoB and prevents CoB-resistant rejection. We have identified the Notch signaling pathway as a promising target for future large animal and clinical studies of CoB-resistant rejection.

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To cite this abstract in AMA style:

Matar AJ, Lovasik BP, Dong Y, Faber DA, Habib J, Breeden CA, Regenold J, Ghosh A, Stephenson A, Kitchens WH, Adams AB. Notch Signaling Inhibition via Blockade of Delta-Like Ligand 4 Prevents Co-Stimulation Blockade Resistant Allograft Rejection [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/notch-signaling-inhibition-via-blockade-of-delta-like-ligand-4-prevents-co-stimulation-blockade-resistant-allograft-rejection/. Accessed May 11, 2025.

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