title: Genetic or pharmaceutical blockade of phosphoinositide 3-kinase p110δ prevents chronic rejection of heart allografts.
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.
authors.affiliation: Department of Immunology, Division of Medicine, Imperial College London, Hammersmith Campus, London, United Kingdom.
authors.forename: Huijun
authors.initials: H
authors.lastname: Ying
authors.forename: Hongmei
authors.initials: H
authors.lastname: Fu
authors.forename: Marlene L
authors.initials: ML
authors.lastname: Rose
authors.forename: Ann M
authors.initials: AM
authors.lastname: McCormack
authors.forename: Padmini
authors.initials: P
authors.lastname: Sarathchandra
authors.forename: Klaus
authors.initials: K
authors.lastname: Okkenhaug
authors.forename: Federica M
authors.initials: FM
authors.lastname: Marelli-Berg
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002908:Chronic Disease; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006084:Graft Rejection / Q000209:etiology / Q000235:genetics* / Q000517:prevention & control*; D006182:H-Y Antigen / Q000378:metabolism; D016027:Heart Transplantation / Q000009:adverse effects* / Q000379:methods; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines / Q000494:pharmacology; D016038:Skin Transplantation / Q000009:adverse effects / Q000379:methods; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014184:Transplantation, Homologous
chemical_list: D006182:H-Y Antigen; C477872:IC 87114; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines; D058543:Class Ia Phosphatidylinositol 3-Kinase; D000225:Adenine