| Inflammatory vascular diseases, including arteritis, atherosclerosis, and transplant stenosis, are critical medical problems in our society. Defining the mechanisms of vascular inflammation is fundamental to the understanding of disease pathogenesis and integral to developing interventions. In this thesis, a novel animal model of viral-induced vasculitis is characterized. It examines the interaction between infection and the resulting immune response within the vascular system.; Arteritis of the large elastic arteries develops 4 to 12 weeks post infection with γHV68. Disease can be established in mice with a variety of specific immunodeficiencies, or in wild type mice after high-dose infection. Intimal and adventitial inflammation develop in the aorta and pulmonary artery in response to infection of the tunica media. Infection persists in the medial smooth muscle cells in chronic disease despite a strong inflammatory response. In contrast, adventitial infection is effectively cleared early in pathogenesis. Consequently, increased resistance against arteritis in wild-type mice depends at least in part upon inhibiting the establishment of persistent medial infection.; Persistent infection of the media is necessary for chronic arteritis, since antiviral treatment of diseased mice results in viral clearance and dramatic amelioration of the inflammatory lesions. Thus, even in chronic disease, the inflammation remains virus-specific and autoimmunity does not develop. It is therefore imperative to determine whether human vascular diseases have infectious etiologies since antimicrobial therapy would be of great benefit.; IFNγ is one critical mediator of arteritis. It regulates pathogenesis during both acute and chronic infection. IFNγ regulates the nature of the inflammatory response during chronic disease, as neutrophilic medial infiltrates are only seen in IFNγR−/− mice or chronically IFNγ-depleted wild-type mice. During acute infection, however, IFNγ regulates susceptibility to medial infection and arteritis via actions on somatic cells. While wild-type mice require 100-fold more virus to develop lesions than IFNγR−/− mice, transient IFNγ depletions in wild-type mice increase susceptibility to chronic disease. Furthermore, IFNγ can directly inhibit infection of aortic cells in vitro. Thus, IFNγ can inhibit the development of arteritis during acute infection by preventing infection of the media and can affect the nature of the inflammatory lesions during chronic disease. |
