title: Acute and chronic rejection: compartmentalization and kinetics of counterbalancing signals in cardiac transplants.
abstract: Acute and chronic rejection impact distinct compartments of cardiac allografts. Intramyocardial mononuclear cell infiltrates define acute rejection, whereas chronic rejection affects large arteries. Hearts transplanted from male to female C57BL/6 mice undergo acute rejection with interstitial infiltrates at 2 weeks that resolve by 6 weeks when large arteries develop arteriopathy. These processes are dependent on T cells because no infiltrates developed in T cell-deficient mice and transfer of CD4 T cells restored T cell as well as macrophage infiltrates and ultimately neointima formation. Markers of inflammatory macrophages were up-regulated in the interstitium acutely and decreased as markers of wound healing macrophages increased chronically. Programmed cell death protein, a negative costimulator, and its ligand PDL1 were up-regulated in the interstitium during resolution of acute rejection. Blocking PDL1:PD1 interactions in the acute phase increased interstitial T cell infiltrates. Toll-like receptor (TLR) 4 and its endogenous ligand hyaluronan were increased in arteries with neointimal expansion. Injection of hyaluronan fragments increased intragraft production of chemokines. Our data indicate that negative costimulatory pathways are critical for the resolution of acute interstitial infiltrates. In the arterial compartment recognition of endogenous ligands including hyaluronan by the innate TLRs may support the progression of arteriopathy.
authors.affiliation: Department of Immunology, Cleveland Clinic, Cleveland, OH; Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, OH.
authors.forename: A M K
authors.initials: AM
authors.lastname: Kaul
authors.forename: S
authors.initials: S
authors.lastname: Goparaju
authors.forename: N
authors.initials: N
authors.lastname: Dvorina
authors.forename: S
authors.initials: S
authors.lastname: Iida
authors.forename: K S
authors.initials: KS
authors.lastname: Keslar
authors.forename: C A
authors.initials: CA
authors.lastname: de la Motte
authors.forename: A
authors.initials: A
authors.lastname: Valujskikh
authors.forename: R L
authors.initials: RL
authors.lastname: Fairchild
authors.forename: W M
authors.initials: WM
authors.lastname: Baldwin
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D018932:Chemokine CCL2 / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000378:metabolism; D005260:Female; D006084:Graft Rejection / Q000503:physiopathology*; D016027:Heart Transplantation; D006820:Hyaluronic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D060890:B7-H1 Antigen; C491768:Ccl2 protein, mouse; C498919:Cd274 protein, mouse; D018932:Chemokine CCL2; D054370:Chemokine CXCL9; C485969:Cxcl9 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D006820:Hyaluronic Acid
keywords: Basic (laboratory) research; chemokine receptors; chemokines; immunobiolog; rejection: acute; rejection: chronic; science