Giant cell vasculitis is a T cell-dependent disease.
BACKGROUND
Giant cell arteritis (GCA) is a systemic vasculitis that preferentially targets medium-sized and large arteries. The etiopathogenesis of the syndrome is not known, and because of the paucity of information concerning the mechanisms of blood vessel wall damage, treatment options are limited. Clues to pathogenic events in this arteritis may derive from understanding the function of tissue-infiltrating cells. Arterial injury in GCA is associated with the formation of granulomas that are composed of T cells, activated macrophages, and multinucleated giant cells. To examine the role of T cells, we implanted inflamed temporal arteries from patients with GCA into severe combined immunodeficiency (SCID) mice and studied whether the vascular lesions were T cell-dependent.


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 compared by two-color immunohistochemistry, and the functional profile of tissue-infiltrating cells was analyzed by semiquantifying cytokine transcription with a polymerase chain reaction (PCR)-based assay system. The repertoire of tissue-infiltrating T cells was assessed for the presence of dominant T cell populations by using T cell receptor beta-chain-specific PCR followed by sequencing. To investigate the role of T cells in the activation of tissue-infiltrating macrophages, T cells were 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 implants, T cells were isolated from tissue segments and adoptively transferred into mice implanted with syngeneic arteries. The in situ production of lymphokines was then determined.


RESULTS
The inflammatory infiltrate penetrating all layers of the arterial wall persisted in the xenotransplants, indicating that the inflammatory foci represent independent functional units. Similar quantities of T cell- and macrophage-derived cytokines were detected in fresh and engrafted tissue. However, the diversity of tissue-infiltrating T cells decreased following implantation. T cells with identical T cell receptors were expanded in different mice that had been engrafted with tissue fragments from the same patient, indicating that T cell survival in the arterial wall was a nonrandom process. To confirm the disease relevance of these T cells, T cell depletion and reconstitution experiments were performed. Antibody-mediated elimination of T cells from the xenotransplants resulted in the attenuation of the production of the monokines, IL-1 beta and IL-6. Adoptive transfer of syngeneic tissue-derived T cells, but not of peripheral blood T cells, into engrafted SCID mice enhanced the transcription of IL-2 and IFN-gamma in the implanted arteries.


CONCLUSIONS
The vascular lesions of GCA are maintained in human artery-mouse chimeras, indicating that all cellular and noncellular components necessary for the disease are present in the temporal artery. Activation of tissue-infiltrating T cells and macrophages depends upon an infrequent subpopulation of lesional T cells that have a survival advantage in the xenotransplants. The selective proliferation of these T cells in the arteries suggests that there is recognition of a locally expressed antigen. Therefore, these T cells should be candidate targets for the development of novel therapeutic strategies in GCA.
Brack
A
A
Division of Rheumatology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Geisler
A
A
Martinez-Taboada
V M
VM
Younge
B R
BR
Goronzy
J J
JJ
Weyand
C M
CM
D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D001483:Base Sequence; D002460:Cell Line; D016207:Cytokines / Q000235:genetics; D019674:Genes, T-Cell Receptor beta / Q000235:genetics; D013700:Giant Cell Arteritis / Q000276:immunology*; D006801:Humans; D016131:Lymphocyte Subsets; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000032:analysis; D017422:Sequence Analysis, DNA; D013601:T-Lymphocytes / Q000276:immunology*; D013699:Temporal Arteries / Q000276:immunology* / Q000637:transplantation
D000945:Antigens, Differentiation, T-Lymphocyte; D016207:Cytokines; D012333:RNA, Messenger