Immunomodulation via targeted inhibition of antigen receptor signal transduction

Cardiovasc Hematol Disord Drug Targets. 2008 Mar;8(1):1-6. doi: 10.2174/187152908783884948.


Coronary artery vasculopathy (CAV), characterized by diffuse concentric coronary artery intimal thickening with fibrosis, remains a significant complication impeding long term engraftment in heart transplantation. The pathophysiologic processes driving CAV are not well understood, however T cell mediated cellular immunity and cytokines have been implicated. The inability to prevent CAV may be related in part to a limited spectrum of inhibition that that current immunosuppressive therapies exhibit against second messenger pathways elicited by T cell receptor (TCR) activation and dose limiting toxicities. Therefore, considering that antigen specific T cell activation is initiated at the TCR, including alloresponses involving direct and indirect antigen presentation, targeting the proximal kinases involved in this process may provide novel therapeutic options for controlling rejection. Src family kinases (SFK), particularly p56(lck) (Lck) and p59(fyn) (Fyn), are intimately associated with the earliest signaling events through the TCR and could provide targets for immunomodulatory agents. Such targeted inhibition of TCR signaling may institute a novel approach for diminishing the T cell mediated response associated with CAV. In this review we discuss therapeutic agents that have been shown to inhibit SFK and the rationale for investigating the potential application of these agents in heart transplantation.

Publication types

  • Review

MeSH terms

  • Animals
  • Coronary Artery Disease / etiology
  • Coronary Artery Disease / physiopathology
  • Coronary Artery Disease / prevention & control
  • Heart Transplantation / adverse effects
  • Heart Transplantation / methods
  • Humans
  • Immunosuppressive Agents / therapeutic use*
  • Receptors, Antigen, T-Cell / physiology*
  • Signal Transduction / drug effects*
  • Transplantation Conditioning / adverse effects
  • Transplantation Conditioning / methods
  • src-Family Kinases / antagonists & inhibitors


  • Immunosuppressive Agents
  • Receptors, Antigen, T-Cell
  • src-Family Kinases