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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.

SUBMITTER: Kaul AM

PROVIDER: S-EPMC4304877 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Acute and chronic rejection: compartmentalization and kinetics of counterbalancing signals in cardiac transplants.

Kaul A M K AM Goparaju S S Dvorina N N Iida S S Keslar K S KS de la Motte C A CA Valujskikh A A Fairchild R L RL Baldwin W M WM

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 20150112 2

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 CD ...[more]

PMID: 25582188

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Project description:During acute rejection of cardiac transplants endothelial cell-leukocyte interaction fueled by co-stimulatory molecules like CD40/CD154 may ultimately lead to graft loss. One key player in up-regulating the expression of such pro-inflammatory gene products is the interferon-gamma-dependent transcription factor STAT-1. Hence down-regulating interferon-gamma-stimulated pro-inflammatory gene expression in the graft endothelial cells by employing a decoy oligodeoxynucleotide (dODN) neutralising STAT-1 may protect the graft. To verify this hypothesis, heterotopic mouse heart transplantation was performed in the allogeneic B10.A(2R) to C57BL/6 and syngeneic C57BL/6 to C57BL/6 strain combination without immunosuppression. Graft vessels were pre-treated with STAT-1 dODN, mutant control ODN (10 muM each) or vehicle (Ringer solution). Cellular rejection (vascular and interstitial component) was graded histologically and CD40, ICAM-1, VCAM-1, MCP-1, E-selectin and RANTES expression in the graft monitored by real time PCR 24 h and 9 days post-transplantation. Nine days after transplantation both rejection scores were significantly diminished by 85 and 70%, respectively, in STAT-1 dODN-treated allografts as compared to mutant control ODN-treated allografts. According to immunohistochemistry analysis, this was accompanied by a reduced infiltration of monocyte/macrophages and T cells into the graft myocardium. In addition, pro-inflammatory gene expression was strongly impaired by more than 80% in STAT-1 dODN-treated allografts 24 h post-transplantation but not in mutant control ODN or vehicle-treated allografts. This inhibitory effect on pro-inflammatory gene expression was no longer detectable 9 days post-transplantation. Single periprocedural treatment with a STAT-1 dODN thus effectively reduces cellular rejection in mouse heart allografts. This effect is associated both with an early decline in pro-inflammatory gene expression and a later drop in mononuclear cell infiltration.

Dataset Information

Acute and chronic rejection: compartmentalization and kinetics of counterbalancing signals in cardiac transplants.

Publications

Acute and chronic rejection: compartmentalization and kinetics of counterbalancing signals in cardiac transplants.

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