Abstract
Chronic rejection is the major cause of long-term heart allograft failure, characterized by tissue infiltration by recipient T cells with indirect allospecificity. Phosphoinositol-3-kinase p110δ is a key mediator of T cell receptor signaling, regulating both T cell activation and migration of primed T cells to non-lymphoid antigen-rich tissue. We investigated the effect of genetic or pharmacologic inactivation of PI3K p110δ on the development of chronic allograft rejection in a murine model in which HY-mismatched male hearts were transplanted into female recipients. We show that suppression of p110δ activity significantly attenuates the development of chronic rejection of heart grafts in the absence of any additional immunosuppressive treatment by impairing the localization of antigen-specific T cells to the grafts, while not inducing specific T cell tolerance. p110δ pharmacologic inactivation is effective when initiated after transplantation. Targeting p110δ activity might be a viable strategy for the treatment of heart chronic rejection in humans.
Highlights
Chronic rejection is the main cause of late heart allograft failure and the leading cause of death in patients surviving more than 1 year after transplantation [1,2]
In this study we have investigated the effect of genetic or pharmacologic inactivation of phosphoinositide 3-kinases (PI3Ks) p110d on the development of chronic allograft rejection in a murine model of minor histocompatibility antigens (mHC) (HY)mismatched heart allograft
We show that inhibition of PI3K p110d activity significantly reduces the development of chronic rejection by inhibiting memory T cell access to the allograft
Summary
Chronic rejection is the main cause of late heart allograft failure and the leading cause of death in patients surviving more than 1 year after transplantation [1,2]. We and others have shown that T cell receptor (TCR) engagement by antigenpresenting endothelium leads to the migration of antigen-specific memory T cells to non-lymphoid antigen-rich target tissue following priming [16,17,18,19,20]. This effect is required for the development of a number of T cell-mediated diseases in mice [20,21,22]. We have recently shown that, while chemotaxis and constitutive trafficking of memory T lymphocytes with impaired p110d activity are unaffected, these T cells are not susceptible to TCR-mediated T cell recruitment to antigenic sites, which they fail to infiltrate [21]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
