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3 results on '"Gelfand BD"'

1. DICER1/Alu RNA dysmetabolism induces Caspase-8-mediated cell death in age-related macular degeneration

Author

Kim Y, Tarallo V, Kerur N, Yasuma T, Gelfand BD, Bastos-Carvalho A, Hirano Y, Yasuma R, Mizutani T, Fowler BJ, Li S, Kaneko H, Bogdanovich S, Ambati BK, Hinton DR, Hauswirth WW, Hakem R, Wright C, and Ambati J.

Subjects
sense organs, eye diseases
Abstract

Geographic atrophy, an advanced form of age-related macular degeneration (AMD) characterized by death of the retinal pigmented epithelium (RPE), causes untreatable blindness in millions worldwide. The RPE of human eyes with geographic atrophy accumulates toxic Alu RNA in response to a deficit in the enzyme DICER1, which in turn leads to activation of the NLRP3 inflammasome and elaboration of IL-18. Despite these recent insights, it is still unclear how RPE cells die during the course of the disease. In this study, we implicate the involvement of Caspase-8 as a critical mediator of RPE degeneration. Here we show that DICER1 deficiency, Alu RNA accumulation, and IL-18 up-regulation lead to RPE cell death via activation of Caspase-8 through a Fas ligand-dependent mechanism. Coupled with our observation of increased Caspase-8 expression in the RPE of human eyes with geographic atrophy, our findings provide a rationale for targeting this apoptotic pathway in this disease.

Published
2014

2. Intravenous immune globulin suppresses angiogenesis in mice and humans

Author

Ivana Apicella, Sasha Bogdanovich, Bradley D. Gelfand, Arturo Brunetti, J. Sjef Verbeek, Charles B. Wright, Shengjian Li, Younghee Kim, Laura Tudisco, Tetsuhiro Yasuma, Jeanette H. W. Leusen, Yoshio Hirano, Ana Bastos-Carvalho, Jayakrishna Ambati, Takeshi Mizutani, Sandro De Falco, Valeria Cicatiello, Ingrid E. Lundberg, Benjamin J. Fowler, Balamurali K. Ambati, Adelaide Greco, Valeria Tarallo, Nagaraj Kerur, Sevim Barbasso Helmers, Ondrej Viklicky, Reo Yasuma, Yasuma, R, Cicatiello, V, Mizutani, T, Tudisco, L, Kim, Y, Tarallo, V, Bogdanovich, S, Hirano, Y, Kerur, N, Li, S, Yasuma, T, Fowler, Bj, Wright, Cb, Apicella, I, Greco, Adelaide, Brunetti, Arturo, Ambati, Bk, Helmers, Sb, Lundberg, Ie, Viklicky, O, Leusen, Jh, Verbeek, J, Gelfand, Bd, Bastos Carvalho, A, De Falco, S, and Ambati, J.

Subjects
0301 basic medicine, Genetically modified mouse, Cancer Research, Angiogenesis, Article, 03 medical and health sciences, angiogenesis, hemic and lymphatic diseases, Genetics, medicine, Journal Article, Receptor, biology, immuneglobuline, angioinhibition, mice, business.industry, medicine.disease, immune globulin, Fragment crystallizable region, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Polyclonal antibodies, Corneal neovascularization, Immunology, biology.protein, Antibody, business, Blood vessel
Abstract

Human intravenous immune globulin (IVIg), a purified IgG fraction composed of ~60% IgG1 and obtained from the pooled plasma of thousands of donors, is clinically used for a wide range of diseases. The biological actions of IVIg are incompletely understood and have been attributed both to the polyclonal antibodies therein and also to their IgG (IgG) Fc regions. Recently, we demonstrated that multiple therapeutic human IgG1 antibodies suppress angiogenesis in a target-independent manner via FcγRI, a high-affinity receptor for IgG1. Here we show that IVIg possesses similar anti-angiogenic activity and inhibited blood vessel growth in five different mouse models of prevalent human diseases, namely, neovascular age-related macular degeneration, corneal neovascularization, colorectal cancer, fibrosarcoma and peripheral arterial ischemic disease. Angioinhibition was mediated by the Fc region of IVIg, required FcγRI and had similar potency in transgenic mice expressing human FcγRs. Finally, IVIg therapy administered to humans for the treatment of inflammatory or autoimmune diseases reduced kidney and muscle blood vessel densities. These data place IVIg, an agent approved by the US Food and Drug Administration, as a novel angioinhibitory drug in doses that are currently administered in the clinical setting. In addition, they raise the possibility of an unintended effect of IVIg on blood vessels.

Published
2016

3. Human IgG1 antibodies suppress angiogenesis in a target-independent manner

Author

Tetsuhiro Yasuma, Hiroko Terasaki, Mike Clark, Valeria Cicatiello, Laura Tudisco, Yuichiro Ogura, Wallace Y. Langdon, Judit Z. Baffi, Miho Nozaki, Pierre Bruhns, Younghee Kim, Parthasarathy Arpitha, Sasha Bogdanovich, Nagaraj Kerur, Takeshi Mizutani, Yoshio Hirano, Bradley D. Gelfand, Benjamin J. Fowler, Balamurali K. Ambati, Ivana Apicella, Kathryn L. Armour, Shengjian Li, Sandro De Falco, Ryo Ijima, Hiroki Kaneko, Ana Bastos-Carvalho, Valeria Tarallo, Jeanette H. W. Leusen, Charles B. Wright, Jayakrishna Ambati, J. Sjef Verbeek, Arturo Brunetti, Reo Yasuma, Annamaria Sandomenico, Adelaide Greco, Menotti Ruvo, Bogdanovich, S, Kim, Y, Mizutani, T, Yasuma, R, Tudisco, L, Cicatiello, V, Bastos Carvalho, A, Kerur, N, Hirano, Y, Baffi, Jz, Tarallo, V, Li, S, Yasuma, T, Arpitha, P, Fowler, Bj, Wright, Cb, Apicella, I, Greco, Adelaide, Brunetti, Arturo, Ruvo, M, Sandomenico, A, Nozaki, M, Ijima, R, Kaneko, H, Ogura, Y, Terasaki, H, Ambati, Bk, Leusen, Jh, Langdon, Wy, Clark, Mr, Armour, Kl, Bruhns, P, Verbeek, J, Gelfand, Bd, De Falco, S, Ambati, J., University of Kentucky, Nagoya City University [Nagoya, Japan], Institute of Genetics and Biophysics - 'Adriano Buzzati-Traverso' [Naples, Italy] ( IGB-CNR), BIO-KER (Multimedica Group) [Naples], University of Naples Federico II, CEINGE - Biotecnologie Avanzate, CNR – Istituto di Biostrutture e Bioimmagini, University of Utah School of Medicine [Salt Lake City], Salt Lake City Veterans Affairs Health Care System, University Medical Center [Utrecht], The University of Western Australia (UWA), University of Cambridge [UK] (CAM), Anticorps en thérapie et pathologie - Antibodies in Therapy and Pathology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Leiden University Medical Center (LUMC), IRCCS Multimedica, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), JA was supported by NIH grants DP1GM114862, R01EY018350, R01EY018836, R01EY020672, R01EY022238, R01EY024068, R21EY019778 and RC1EY020442, Doris Duke Distinguished Clinical Scientist Award, Burroughs Wellcome Fund Clinical Scientist Award in Translational Research, Ellison Medical Foundation Senior Scholar in Aging Award, Foundation Fighting Blindness Individual Investigator Research Award, Carl Marshall Reeves Foundation, Harrington Discovery Institute Scholar-Innovator Award, John Templeton Foundation, Dr E. Vernon Smith and Eloise C. Smith Macular Degeneration Endowed Chair, and Research to Prevent Blindness departmental unrestricted grant, SDF by Associazione Italiana Ricerca sul Cancro (AIRC) grant no. IG11420 and Italian Ministry for Scientific Research, projects PON01_02342 and PON01_01434, MR and AS by Italian Ministry for Scientific Research, grants FIRB MERIT N° RBNE08NKH7_003 and PON01_01602, PON01_02342. JZB by NIH K08EY021521 and University of Kentucky Physician Scientist Award, BJF and SB by NIH T32HL091812 and UL1RR033173, YH by Alcon Research Award, AB-C by the Program for Advanced Medical Education (sponsored by Fundação Calouste Gulbenkian, Fundação Champalimaud, Ministério da Saúde and Fundação para a Ciência e Tecnologia, Portugal) and Bayer Global Ophthalmology Research Award, YH by Alcon Japan Research award, NK by Beckman Initiative for Macular Research and NIH K99/R00EY024336, TY by Fight for Sight Postdoctoral Award, CBW by International Retinal Research Foundation, BDG by American Heart Association and International Retinal Research Foundation, BKA by NIH R01EY017182 and R01EY017950, VA Merit Award, and Department of Defense., University of Kentucky (UK), University of Naples Federico II = Università degli studi di Napoli Federico II, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Universiteit Leiden

Subjects
0301 basic medicine, Cancer Research, Bevacizumab, medicine.drug_class, Angiogenesis, Population, Pharmacology, Monoclonal antibody, Ofatumumab, Article, 03 medical and health sciences, chemistry.chemical_compound, Genetics, Journal Article, angiogenesis, mice, antibodies, Medicine, education, Gene knockdown, education.field_of_study, business.industry, 3. Good health, Blockade, Vascular endothelial growth factor A, 030104 developmental biology, chemistry, [SDV.IMM]Life Sciences [q-bio]/Immunology, business, medicine.drug
Abstract

Aberrant angiogenesis is implicated in diseases affecting nearly 10% of the world’s population. The most widely used anti-angiogenic drug is bevacizumab, a humanized IgG1 monoclonal antibody that targets human VEGFA. Although bevacizumab does not recognize mouse Vegfa, it inhibits angiogenesis in mice. Here we show bevacizumab suppressed angiogenesis in three mouse models not via Vegfa blockade but rather Fc-mediated signaling through FcγRI (CD64) and c-Cbl, impairing macrophage migration. Other approved humanized or human IgG1 antibodies without mouse targets (adalimumab, alemtuzumab, ofatumumab, omalizumab, palivizumab and tocilizumab), mouse IgG2a, and overexpression of human IgG1-Fc or mouse IgG2a-Fc, also inhibited angiogenesis in wild-type and FcγR humanized mice. This anti-angiogenic effect was abolished by Fcgr1 ablation or knockdown, Fc cleavage, IgG-Fc inhibition, disruption of Fc-FcγR interaction, or elimination of FcRγ-initated signaling. Furthermore, bevacizumab’s Fc region potentiated its anti-angiogenic activity in humanized VEGFA mice. Finally, mice deficient in FcγRI exhibited increased developmental and pathological angiogenesis. These findings reveal an unexpected anti-angiogenic function for FcγRI and a potentially concerning off-target effect of hIgG1 therapies.

Published
2016

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