B-Cell Depletion Reduces the Maturation of Cerebral Cavernous Malformations in Murine Models
- 377 Downloads
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.
KeywordsCerebral cavernous malformation B cells B-cell depletion Inflammation Immune response Stroke
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.
Compliance with Ethical Standards
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.
Conflict of Interest
The authors declare that they have no conflict of interest.
- Al-Shahi Salman R, Hall JM, Horne MA, Moultrie F, Josephson CB, Bhattacharya JJ, Counsell CE, Murray GD, Papanastassiou V, Ritchie V, Roberts RC, Sellar RJ, Warlow CP, Scottish Audit of Intracranial Vascular Malformations c (2012) Untreated clinical course of cerebral cavernous malformations: a prospective, population-based cohort study. Lancet Neurol 11:217–224. doi: 10.1016/S1474-4422(12)70004-2 CrossRefPubMedGoogle Scholar
- Choquet H, Pawlikowska L, Nelson J, McCulloch CE, Akers A, Baca B, Khan Y, Hart B, Morrison L, Kim H, Brain Vascular Malformation Consortium S (2014) Polymorphisms in inflammatory and immune response genes associated with cerebral cavernous malformation type 1 severity. Cerebrovasc Dis 38:433–440. doi: 10.1159/000369200 CrossRefPubMedPubMedCentralGoogle Scholar
- Coles AJ, Fox E, Vladic A, Gazda SK, Brinar V, Selmaj KW, Skoromets A, Stolyarov I, Bass A, Sullivan H, Margolin DH, Lake SL, Moran S, Palmer J, Smith MS, Compston DA (2012) Alemtuzumab more effective than interferon beta-1a at 5-year follow-up of CAMMS223 clinical trial. Neurology 78:1069–1078. doi: 10.1212/WNL.0b013e31824e8ee7 CrossRefPubMedGoogle Scholar
- Landis SC, Amara SG, Asadullah K, Austin CP, Blumenstein R, Bradley EW, Crystal RG, Darnell RB, Ferrante RJ, Fillit H, Finkelstein R, Fisher M, Gendelman HE, Golub RM, Goudreau JL, Gross RA, Gubitz AK, Hesterlee SE, Howells DW, Huguenard J, Kelner K, Koroshetz W, Krainc D, Lazic SE, Levine MS, Macleod MR, McCall JM, Moxley RT 3rd, Narasimhan K, Noble LJ, Perrin S, Porter JD, Steward O, Unger E, Utz U, Silberberg SD (2012) A call for transparent reporting to optimize the predictive value of preclinical research. Nature 490:187–191. doi: 10.1038/nature11556 CrossRefPubMedPubMedCentralGoogle Scholar
- Lin WY, Gong Q, Seshasayee D, Lin Z, Ou Q, Ye S, Suto E, Shu J, Lee WP, Lee CW, Fuh G, Leabman M, Iyer S, Howell K, Gelzleichter T, Beyer J, Danilenko D, Yeh S, DeForge LE, Ebens A, Thompson JS, Ambrose C, Balazs M, Starovasnik MA, Martin F (2007) Anti-BR3 antibodies: a new class of B-cell immunotherapy combining cellular depletion and survival blockade. Blood 110:3959–3967. doi: 10.1182/blood-2007-04-088088 CrossRefPubMedGoogle Scholar
- Lu D, Nakagawa R, Lazzaro S, Staudacher P, Abreu-Goodger C, Henley T, Boiani S, Leyland R, Galloway A, Andrews S, Butcher G, Nutt SL, Turner M, Vigorito E (2014) The miR-155-PU.1 axis acts on Pax5 to enable efficient terminal B cell differentiation. J Exp Med 211:2183–2198. doi: 10.1084/jem.20140338 CrossRefPubMedPubMedCentralGoogle Scholar
- McDonald DA, Shenkar R, Shi C, Stockton RA, Akers AL, Kucherlapati MH, Kucherlapati R, Brainer J, Ginsberg MH, Awad IA, Marchuk DA (2011) A novel mouse model of cerebral cavernous malformations based on the two-hit mutation hypothesis recapitulates the human disease. Hum Mol Genet 20:211–222. doi: 10.1093/hmg/ddq433 CrossRefPubMedPubMedCentralGoogle Scholar
- Sehn LH, Donaldson J, Chhanabhai M, Fitzgerald C, Gill K, Klasa R, MacPherson N, O’Reilly S, Spinelli JJ, Sutherland J, Wilson KS, Gascoyne RD, Connors JM (2005) Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol 23:5027–5033. doi: 10.1200/JCO.2005.09.137 CrossRefPubMedGoogle Scholar
- Shenkar R, Shi C, Rebeiz T, Stockton RA, McDonald DA, Mikati AG, Zhang L, Austin C, Akers AL, Gallione CJ, Rorrer A, Gunel M, Min W, Marcondes de Souza J, Lee C, Marchuk DA, Awad IA (2015) Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations. Genet Med 17:188–196. doi: 10.1038/gim.2014.97 CrossRefPubMedPubMedCentralGoogle Scholar
- Tan H, Liu T, Wu Y, Thacker J, Shenkar R, Mikati AG, Shi C, Dykstra C, Wang Y, Prasad PV, Edelman RR, Awad IA (2014) Evaluation of iron content in human cerebral cavernous malformation using quantitative susceptibility mapping. Invest Radiol 49:498–504. doi: 10.1097/RLI.0000000000000043 CrossRefPubMedPubMedCentralGoogle Scholar
- Tulamo R, Frosen J, Junnikkala S, Paetau A, Pitkaniemi J, Kangasniemi M, Niemela M, Jaaskelainen J, Jokitalo E, Karatas A, Hernesniemi J, Meri S (2006) Complement activation associates with saccular cerebral artery aneurysm wall degeneration and rupture. Neurosurgery 59:1069–1076. doi: 10.1227/01.NEU.0000245598.84698.26, discussion 1076-1067PubMedGoogle Scholar
- Vugmeyster Y, Seshasayee D, Chang W, Storn A, Howell K, Sa S, Nelson T, Martin F, Grewal I, Gilkerson E, Wu B, Thompson J, Ehrenfels BN, Ren S, Song A, Gelzleichter TR, Danilenko DM (2006) A soluble BAFF antagonist, BR3-Fc, decreases peripheral blood B cells and lymphoid tissue marginal zone and follicular B cells in cynomolgus monkeys. Am J Pathol 168:476–489. doi: 10.2353/ajpath.2006.050600 CrossRefPubMedPubMedCentralGoogle Scholar
- Whitehead KJ, Chan AC, Navankasattusas S, Koh W, London NR, Ling J, Mayo AH, Drakos SG, Jones CA, Zhu W, Marchuk DA, Davis GE, Li DY (2009) The cerebral cavernous malformation signaling pathway promotes vascular integrity via Rho GTPases. Nat Med 15:177–184. doi: 10.1038/nm.1911 CrossRefPubMedPubMedCentralGoogle Scholar