Abstract

Project 4: """"""""Preventing anti-NMDAR Ab neurotoxicity: Rational therapies for NPSLE"""""""" (Diamond PI) Compelling data demonstrate that antibodies cross-reactive with DMA and NMDA receptors (NMDARs) can mediate manifestations of neuropsychiatric lupus (NPSLE) in mice. These antibodies can be found in serum, cerebrospinal fluid and brain of lupus patients. We will test the efficacy of the D pentapeptide or candidate modified peptides in models of NPSLE simulating antibody penetration of the blood-brain barrier and antibody production locally within the brain and will determine whether the same peptide(s) can protect fetal brain against potentially neurotoxic antibody when it is present in the maternal circulation. Second, we will inhibit inflammatory mediators of the innate immune response that increase permeability of the blood-brain barrier to see if these agents can prevent LPS or epinephrine-mediated neuroexposure. These studies, in conjunction with other projects in this Program, will hopefully lead to a clinical trial in NPSLE, and provide a paradigm for the development of other therapeutics in immune-mediated brain disease.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI073693-05
Application #
8380684
Study Section
Special Emphasis Panel (ZAI1-KS-I)
Project Start
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$318,645
Indirect Cost
$110,421

  Institution

Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
110565913
City
Manhasset
State
NY
Country
United States
Zip Code
11030

  Publications

Mader, Simone; Brimberg, Lior; Soltys, John N et al. (2018) Mutations of Recombinant Aquaporin-4 Antibody in the Fc Domain Can Impair Complement-Dependent Cellular Cytotoxicity and Transplacental Transport. Front Immunol 9:1599
Suurmond, Jolien; Atisha-Fregoso, Yemil; Marasco, Emiliano et al. (2018) Loss of an IgG plasma cell checkpoint in patients with lupus. J Allergy Clin Immunol :
Nestor, Jacquelyn; Arinuma, Yoshiyuki; Huerta, Tomás S et al. (2018) Lupus antibodies induce behavioral changes mediated by microglia and blocked by ACE inhibitors. J Exp Med 215:2554-2566
Kim, Sook Young; Son, Myoungsun; Lee, Sang Eun et al. (2018) High-Mobility Group Box 1-Induced Complement Activation Causes Sterile Inflammation. Front Immunol 9:705
Malkiel, Susan; Barlev, Ashley N; Atisha-Fregoso, Yemil et al. (2018) Plasma Cell Differentiation Pathways in Systemic Lupus Erythematosus. Front Immunol 9:427
Brimberg, L; Mader, S; Jeganathan, V et al. (2016) Caspr2-reactive antibody cloned from a mother of an ASD child mediates an ASD-like phenotype in mice. Mol Psychiatry 21:1663-1671
Honig, Gerard; Mader, Simone; Chen, Huiyi et al. (2016) Blood-Brain Barrier Deterioration and Hippocampal Gene Expression in Polymicrobial Sepsis: An Evaluation of Endothelial MyD88 and the Vagus Nerve. PLoS One 11:e0144215
Malkiel, Susan; Jeganathan, Venkatesh; Wolfson, Stacey et al. (2016) Checkpoints for Autoreactive B Cells in the Peripheral Blood of Lupus Patients Assessed by Flow Cytometry. Arthritis Rheumatol 68:2210-20
VanPatten, Sonya; Sun, Shan; He, Mingzhu et al. (2016) Amending HIV Drugs: A Novel Small-Molecule Approach To Target Lupus Anti-DNA Antibodies. J Med Chem 59:8859-8867
Vingtdeux, Valérie; Chang, Eric H; Frattini, Stephen A et al. (2016) CALHM1 deficiency impairs cerebral neuron activity and memory flexibility in mice. Sci Rep 6:24250

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