Inhibition and genetic ablation of the B7/CD28 T-cell costimulation axis prevents experimental hypertension.

Vinh A, Chen W, Blinder Y, Weiss D, Taylor WR, Goronzy JJ, Weyand CM, Harrison DG, Guzik TJ
Circulation. 2010 122 (24): 2529-37

PMID: 21126972 · PMCID: PMC3064430 · DOI:10.1161/CIRCULATIONAHA.109.930446

BACKGROUND - The pathogenesis of hypertension remains poorly understood, and treatment is often unsuccessful. Recent evidence suggests that the adaptive immune response plays an important role in this disease. Various hypertensive stimuli cause T-cell activation and infiltration into target organs such as the vessel and the kidney, which promotes vascular dysfunction and blood pressure elevation. Classically, T-cell activation requires T-cell receptor ligation and costimulation. The latter often involves interaction between B7 ligands (CD80 and CD86) on antigen-presenting cells with the T-cell coreceptor CD28. This study was therefore performed to examine the role of this pathway in hypertension.

METHODS AND RESULTS - Angiotensin II-induced hypertension increased the presence of activated (CD86(+)) dendritic cells in secondary lymphatic tissues. Blockade of B7-dependent costimulation with CTLA4-Ig reduced both angiotensin II- and deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Activation of circulating T cells, T-cell cytokine production, and vascular T-cell accumulation caused by these hypertensive stimuli were abrogated by CTLA4-Ig. Furthermore, in mice lacking B7 ligands, angiotensin II caused minimal blood pressure elevation and vascular inflammation, and these effects were restored by transplantation with wild-type bone marrow.

CONCLUSIONS - T-cell costimulation via B7 ligands is essential for development of experimental hypertension, and inhibition of this process could have therapeutic benefit in the treatment of this disease.

MeSH Terms (19)

Abatacept Angiotensin II Animals Antihypertensive Agents B7-1 Antigen B7-2 Antigen CD28 Antigens Cells, Cultured Gene Deletion Hypertension Immunoconjugates Immunosuppressive Agents Ligands Lymphocyte Activation Mice Mice, Inbred C57BL Mice, Knockout Random Allocation T-Lymphocytes

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