Transient blockade of delta-like Notch ligands prevents allograft rejection mediated by cellular and humoral mechanisms in a mouse model of heart transplantation

S Wood, J Feng, J Chung, V Radojcic… - The Journal of …, 2015 - journals.aai.org
S Wood, J Feng, J Chung, V Radojcic, AR Sandy-Sloat, A Friedman, A Shelton, M Yan
The Journal of Immunology, 2015journals.aai.org
Rejection remains a major clinical challenge limiting allograft survival after solid organ
transplantation. Both cellular and humoral immunity contribute to this complication, with
increased recognition of Ab-mediated damage during acute and chronic rejection. Using a
mouse model of MHC-mismatched heart transplantation, we report markedly protective
effects of Notch inhibition, dampening both T cell and Ab-driven rejection. T cell–specific pan-
Notch blockade prolonged heart allograft survival and decreased IFN-γ and IL-4 production …
Abstract
Rejection remains a major clinical challenge limiting allograft survival after solid organ transplantation. Both cellular and humoral immunity contribute to this complication, with increased recognition of Ab-mediated damage during acute and chronic rejection. Using a mouse model of MHC-mismatched heart transplantation, we report markedly protective effects of Notch inhibition, dampening both T cell and Ab-driven rejection. T cell–specific pan-Notch blockade prolonged heart allograft survival and decreased IFN-γ and IL-4 production by alloreactive T cells, especially when combined with depletion of recipient CD8+ T cells. These effects were associated with decreased infiltration by conventional T cells and an increased proportion of regulatory T cells in the graft. Transient administration of neutralizing Abs specific for delta-like (Dll) 1/4 Notch ligands in the peritransplant period led to prolonged acceptance of allogeneic hearts, with superior outcome over Notch inhibition only in T cells. Systemic Dll1/4 inhibition decreased T cell cytokines and graft infiltration, germinal center B cell and plasmablast numbers, as well as production of donor-specific alloantibodies and complement deposition in the transplanted hearts. Dll1 or Dll4 inhibition alone provided partial protection. Thus, pathogenic signals delivered by Dll1/4 Notch ligands early after transplantation promote organ rejection through several complementary mechanisms. Transient interruption of these signals represents an attractive new therapeutic strategy to enhance long-term allograft survival.
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