Ex vivo expansion of regulatory T cells from abdominal aortic aneurysm patients inhibits aneurysm in humanized murine model.

OBJECTIVE

Abdominal aortic aneurysm (AAA) is a chronic inflammatory disease. Studies of human aneurysm tissue demonstrate dense inflammatory cell infiltrates with CD4 T cells predominating. Regulatory T cells (Tregs) play an important role in inhibiting pro-inflammatory T cell proliferation, therefore, limiting collateral tissue destruction. The aim of this study was to investigate whether ex vivo augmentation of human Tregs attenuates aneurysm formation in humanized murine model of AAA.

METHODS

Circulating Treg population in AAA patients and age- and gender-matched controls were determined by real-time polymerase chain reaction and flow cytometry. To create humanized murine model of AAA, irradiated Rag1-deficient (Rag1) mice, without mature T lymphocytes, at 7 weeks of age were given 5 × 10 of human CD4 T cells intraperitoneally. Then the mice underwent CaCl aneurysm induction. Aortic diameters were measured before and at 6 weeks after aneurysm induction. Aortic tissue was collected for histology and protein extraction. Verhoeff-Van Gieson stain was used for staining elastic fiber. CD4 T cells in the aortic tissue were detected by immunohistochemical staining.

RESULTS

In human peripheral blood mononuclear cells, the proportion of Tregs are decreased in AAA patients compared with matched control patients with significant vascular disease. We first validated the role of Tregs in the CaCl model of AAA. To determine the role of human T cells in AAA formation, Rag1 mice, resistant to CaCl-aneurysm induction, were transplanted with human CD4 T cells. Human CD4 T cells were able to drive aneurysm formation in Rag1 mice. We show that ex vivo augmentation of human Tregs by interleukin-2 resulted in decreased aneurysm progression.

CONCLUSIONS

These data suggest that the ex vivo expansion of human Tregs may be a potential therapeutic strategy for inhibiting progression of AAA.