Targeting the Notch Pathway to Prevent Rejection

Abstract

Immune rejection is mediated by a complex interplay of cellular and humoral mechanisms. Current therapeutic strategies, which rely on global immunosuppression, can result in serious complications and are not completely effective. Notch signaling is a cell-to-cell communication pathway that plays an important role during T cell development and in the regulation of peripheral immune responses. Initial work, performed mainly through gain-of-function approaches, paradoxically identified Notch as an inducer of tolerance; however, recent studies using loss-of-function approaches in mouse models of transplant rejection and graft-versus-host disease have clarified an important role for Notch as a central mediator of T cell alloreactivity. Short-term inhibition of individual Notch ligands in the peritransplant period had long-lasting protective effects. In a vascularized heart allograft model, blockade of Delta-like Notch ligands dampened both cellular and humoral rejection. In this minireview, we summarize current knowledge about the role of Notch signaling during allograft rejection and provide an overarching mechanism through which Notch acts to promote T cell pathogenicity and allograft damage. We propose that targeting elements of the Notch pathway could provide a new therapeutic approach to prevent allograft rejection.

Notch signalling in T cell homeostasis and differentiation

“…GVHD is the life-threatening consequence of an alloimmune response following bone marrow transplantation, whereby donor T cells attack recipient tissues [82]. We found dramatic protection against GVHD in MHC-mismatched transplants when Notch signalling was blocked in donor T cells via either conditional DNMAML expression or loss of RBP-Jκ [58,59].…”

Notch1 regulates the JNK signaling pathway and increases apoptosis in hepatocellular carcinoma

“…Notch signaling plays an important role in the tumor biology, including cell differentiation, proliferation, apoptosis, migration and invasion [ 7 – 10 ]. Increasing reports demonstrated that deregulation of Notch1 signaling can be observed in diverse tumor types, such as cervical cancer.…”

Solid organ transplantation in the 21st century

“…Future directions of transplant research focus on attempting to minimize the immune response by inhibiting aspects of these various mechanisms. An example of an immunomodulatory target is the Notch signaling pathway (65). The Notch pathway is a cellto-cell communication cascade that plays an important role during T cell development and in the regulation of innate lymphoid cells, B cells, and dendritic cells (66).…”

“…The Notch pathway is a cellto-cell communication cascade that plays an important role during T cell development and in the regulation of innate lymphoid cells, B cells, and dendritic cells (66). The signaling pathway is a central mediator of T cell reactivity to allografts (65). Recent studies have shown that inhibition of the Notch pathway in animal models can reduce both allograft rejection (67) and graft vs. host disease (68).…”