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Giant cell vasculitis is a T cell-dependent disease
A Brack1, A Geisler, V M Martinez-Taboada
1Division of Rheumatology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Insights
Giant cell arteritis (GCA) vascular lesions persist in human artery-mouse models, revealing T-cell dependence. Specific T-cell populations drive GCA pathogenesis, suggesting targeted therapies.
Area of Science:
- Immunology
- Pathology
- Vascular Biology
Background:
- Giant cell arteritis (GCA) is a systemic vasculitis affecting large arteries with unknown causes.
- Limited understanding of blood vessel wall damage mechanisms hinders effective treatment options.
- GCA pathogenesis involves T cells, macrophages, and giant cells forming granulomas in arterial walls.
Purpose of the Study:
- To investigate the role of T cells in maintaining vascular lesions in GCA.
- To determine if GCA vascular lesions are T cell-dependent using a xenotransplantation model.
Main Methods:
- Temporal artery specimens from GCA patients were engrafted into severe combined immunodeficiency (SCID) mice.
- Immunohistochemistry and PCR-based cytokine analysis assessed cellular infiltrates and function.
- T cell depletion and adoptive transfer experiments were used to evaluate T cell roles in GCA pathogenesis.
Main Results:
- Inflammatory infiltrates persisted in xenotransplanted GCA arteries, functioning as independent units.
- T cell depletion reduced monokine production (IL-1β, IL-6), while adoptive transfer of tissue-derived T cells enhanced lymphokine transcription (IL-2, IFN-γ).
- A specific subpopulation of T cells with shared T cell receptors expanded in grafts, indicating antigen recognition and selective survival.
Conclusions:
- GCA vascular lesions are maintained in human artery-mouse chimeras, containing all necessary disease components.
- Tissue-infiltrating T cells, particularly a select subpopulation, are crucial for activating macrophages and sustaining GCA.
- These specific lesional T cells, potentially recognizing a local antigen, represent promising targets for novel GCA therapeutic strategies.
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.
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 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.