Date of Award

2014

Degree Type

Dissertation

Department

Biological, Geological and Environmental Sciences

First Advisor

Baldwin III, William

Subject Headings

Heart -- Transplantation -- Complications, Graft rejection -- Diagnosis, Heart -- Surgery, Heart -- Transplantation -- Immunological aspects, Biochemical markers, Biology, immunology, acute rejection, chronic rejection, CAV, cardiac allograft vasculopathy, cardiac transplant, PDL1, programed cell death 1, hyaluronan

Abstract

Heart disease is the major cause of mortality in the United States and other parts of the world. Heart transplantation is the treatment of choice for patients with end stage heart failure. However, transplanted organs fail due to either acute or chronic rejection. This acute and chronic rejection impacts distinct compartments of cardiac allografts. Acute rejection is characterized by infiltration of mononuclear cells whereas chronic rejection is characterized by progressive narrowing of coronary arteries. In a minor histoincompatibility mismatch mouse model we found hearts transplanted from male to female C57BL/6 mice undergo an acute rejection with diffuse interstitial infiltrates at 2 weeks that resolve by 6 weeks when about half of the large arteries develop CAV. These processes are dependent on T cells because no infiltrate developed in T cell deficient mice. Markers of M1 macrophages were upregulated in the interstitium acutely and then decreased as markers of M2 macrophages increased chronically. Interstitial and arterial infiltrates were microdissected and expression of an array of 86 genes was screened by real time PCR. Programmed cell death protein 1 (PD1), a negative costimulator, and its ligand PDL1 were highly upregulated in the interstitium during the resolution of acute rejection. Flow cytometry analysis of graft infiltrating cells confirmed an enrichment of macrophages expressing PDL1. Treatment with a blocking antibody to PDL1 in the acute phase increased interstitial T cell infiltrates. In the arterial compartment, Toll Like Receptor 4 (TLR4) was upregulated at 6 weeks. Hyaluronan, an endogenous ligand of TLR4, was increased in arteries with neointimal expansion. Injection of hyaluronan fragments increased intragraft production of chemokines. Our data indicate that negative co-stimulatory pathways are critical for the resolution of acute interstitial infiltrates. In the arterial compartment recognition of endogenous ligands including hyaluronan by innate TLR4 may support the progression of cardi

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