Abstract
Cerebral cavernous malformations (CCMs) are relatively common vascular malformations, characterized by increased Rho kinase (ROCK) activity, vascular hyper-permeability and the presence of blood degradation products including non-heme iron. Previous studies revealed robust inflammatory cell infiltration, selective synthesis of IgG, in situ antigen driven B-cell clonal expansion, and deposition of immune complexes and complement proteins within CCM lesions. We aimed to evaluate the impact of suppressing the immune response on the formation and maturation of CCM lesions, as well as lesional iron deposition and ROCK activity. Two murine models of heterozygous Ccm3 (Pdcd10), which spontaneously develop CCM lesions with severe and milder phenotypes, were either untreated or received anti-mouse BR3 to deplete B cells. Brains from anti-mouse BR3-treated mice exhibited significantly fewer mature CCM lesions and smaller lesions compared to untreated mice. B cell depletion halted the progression of lesions into mature stage 2 lesions but did not prevent their genesis. Non-heme iron deposition and ROCK activity was decreased in lesions of B cell depleted mice. This represents the first report of the therapeutic benefit of B-cell depletion in the development and progression of CCMs, and provides a proof of principle that B cells play a critical role in CCM lesion genesis and maturation. These findings add biologics to the list of potential therapeutic agents for CCM disease. Future studies would characterize the putative antigenic trigger and further define the mechanism of immune response in the lesions.
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Acknowledgments
This work was supported by the Scientist Development Grant of the American Heart Association AHA-11DG48900009 (C.S.), a pilot grant from the Angioma Alliance, and the Bill and Judy Davis Fund in Neurovascular Surgery Research at the University of Chicago. We thank Genentech Inc. for providing the anti-BR3 antibody through Material Transfer Agreement to IAA, and Flavius Martin for advice on the dosing regimen.
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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted.
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Changbin Shi and Robert Shenkar contributed equally as first authors. Douglas A. Marchuk and Issam A. Awad contributed equally as senior authors.
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Shi, C., Shenkar, R., Zeineddine, H.A. et al. B-Cell Depletion Reduces the Maturation of Cerebral Cavernous Malformations in Murine Models. J Neuroimmune Pharmacol 11, 369–377 (2016). https://doi.org/10.1007/s11481-016-9670-0
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DOI: https://doi.org/10.1007/s11481-016-9670-0