GIANT-CELL VASCULITIS IS A T-CELL-DEPENDENT DISEASE

Background: Giant cell arteritis (GCA) is a systemic vasculitis that p referentially targets medium-sized and large arteries. The etiopathoge nesis of the syndrome is not known, and because of the paucity of info rmation concerning the mechanisms of blood vessel wall damage, treatme nt options are limited. Clues to pathogenic events in this arteritis m ay derive from understanding the function of tissue-infiltrating cells . Arterial injury in GCA is associated with the formation of granuloma s that are composed of T cells, activated macrophages, and multinuclea ted giant cells. To examine the role of T cells, we implanted inflamed temporal arteries from patients with GCA into severe combined immunod eficiency (SCID) mice and studied whether the vascular lesions were T cell-dependent. Materials and Methods: Temporal artery specimens from patients with GCA were engrafted into SCID mice. The histomorphologic appearance of fresh arteries and grafts retrieved from the mice was co mpared by two-color immunohistochemistry, and the functional profile o f tissue-infiltrating cells was analyzed by semiquantifying cytokine t ranscription with a polymerase chain reaction (PCR)-based assay system . The repertoire of tissue-infiltrating T cells was assessed for the p resence of dominant T cell populations by using T cell receptor beta-c hain-specific PCR followed by sequencing. To investigate the role of T cells in the activation of tissue-infiltrating macrophages, T cells w ere depleted from the arterial grafts by treating the mice with T cell -specific antibodies and the production of monokines was monitored. To demonstrate the disease relevance of T cells expanding in the implant s, T cells were isolated from tissue segments and adoptively transferr ed into mice implanted with syngeneic arteries. The in situ production of lymphokines was then determined. Results: The inflammatory infiltr ate penetrating all layers of the arterial wall persisted in the xenot ransplants, indicating that the inflammatory foci represent independen t functional units. Similar quantities of T cell-and macrophage-derive d cytokines were detected in fresh and engrafted tissue. However, the diversity of tissue-infiltrating T cells deceased following implantati on. T cells with identical T cell receptors were expanded in different mice that had been engrafted with tissue fragments from the same pati ent, indicating that T cell survival in the arterial wall was a nonran dom process. To confirm the disease relevance of these T cells, T cell depletion and reconstitution experiments were performed. Antibody-med iated elimination of T cells from the xenotransplants resulted in the attenuation of the production of the monokines, IL-1 beta and IL-6. Ad optive transfer of syngeneic tissue-derived T cells, but not of periph eral blood T cells, into engrafted SCID mice enhanced the transcriptio n of IL-2 and IFN-gamma in the implanted arteries. Conclusions: The va scular lesions of GCA are maintained in human artery-mouse chimeras, i ndicating that all cellular and noncellular components necessary for t he disease are present in the temporal artery. Activation of tissue-in filtrating T cells and macrophages depends upon an infrequent subpopul ation of lesional T cells that have a survival advantage in the xenotr ansplants. The selective proliferation of these T cells in the arterie s suggests that there is recognition of a locally expressed antigen. T herefore, these T cells should be candidate targets for the developmen t of novel therapeutic strategies in GCA.