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


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.
Cardiology Division, Emory University School of Medicine, 1639 Pierce Dr, Atlanta, GA 30322, USA.
Antony
A
Vinh
Wei
W
Chen
Yelena
Y
Blinder
Daiana
D
Weiss
W Robert
WR
Taylor
Jörg J
JJ
Goronzy
Cornelia M
CM
Weyand
David G
DG
Harrison
Tomasz J
TJ
Guzik
D000069594:Abatacept; D000804:Angiotensin II / Q000008:administration & dosage / Q000502:physiology; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000627:therapeutic use; D018122:B7-1 Antigen / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D051940:B7-2 Antigen / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D018106:CD28 Antigens / Q000235:genetics* / Q000502:physiology; D002478:Cells, Cultured; D017353:Gene Deletion; D006973:Hypertension / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D018796:Immunoconjugates / Q000008:administration & dosage / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011897:Random Allocation; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
D000959:Antihypertensive Agents; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D008024:Ligands; D000804:Angiotensin II; D000069594:Abatacept