Therapeutical application of B-cell activating factor receptor monoclonal antibody for murine atherosclerosis

Atherosclerosis is a chronic inflammatory disease of the artery wall that is characterised by the accumulation of lipids and immune cells in the intima. Studies from our laboratory have established opposing roles of B cell subsets in atherosclerosis development in ApoE-/- mouse model. B-2 cells were identified as atherogenic whereas B-1 cells were atheroprotective. Atherogenicity of B-2 cells was confirmed by further studies from our laboratory on BAFF-R deficient ApoE-/- mice that are selectively deficient in B-2 but not 8-1 cells. BAFF-R knockouts were selected for study because BAFF is a growth and maturation factor for B-2 cells but not B-1 cells. To further extend these studies with an eye toward potential clinical translation, I used monoclonal antibody to BAFF-R to selectively deplete B-2 cells and spare B-1 cell. I carried out two studies namely, Prevention and Intervention study to test whether depletion B-2 cells with BAFF-R monoclonal antibody can not only reduce development of atherosclerosis and but also ameliorate established atherosclerotic lesions in ApoE-/- mice. Among three receptors of BAFF, BAFF-R restricts to BAFF, a B cell-activating factor regulating B cell generation, maturation and differentiation. Both my Prevention and Intervention studies showed a significant reduction of atherosclerotic lesions assessed by Oil-Red 0 lipid stain and by CD68+ stained macrophage accumulation. Mature B cells were significantly reduced in the spleen, but sparing B-1a and other lymphocyte populations. B cell accumulation was dramatically reduced in both studies, whereas reduction of CD4+ cell accumulation was only found in the prevention study but not in the intervention study of established atherosclerosis. Plasma levels of non-specific antibodies were significantly decreased by the depletion of B-2 cells. However, plasma oxLDL-specific IgG and IgM levels were significantly affected only in the Intervention study. Plasma BAFF level was increased, likely as a compensation for the blockage of BAFF-R. Expression of proinflammatory cytokine IL-1β was significantly reduced in atherosclerotic lesions as well as in aorta arches and in spleens. IFN-y was also reduced in both studies, but reduction of TNF-α in the prevention study was not significant. My results showed that selective depletion B-2 cells with BAFF-R monoclonal antibody reduces the development of atherosclerosis and also attenuates established atherosclerosis. Reduction of CD4+ cell accumulation played important role in reducing the development of atherosclerosis by BAFF-R monoclonal antibody. In closing, my studies suggest BAFF-R monoclonal antibody as a potential therapeutic strategy for the future management of atherosclerotic-based diseases in humans.