Document Detail


Neonatal Fc receptor blockade by Fc engineering ameliorates arthritis in a murine model.
MedLine Citation:
PMID:  21690327     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Multiple autoimmune diseases are characterized by the involvement of autoreactive Abs in pathogenesis. Problems associated with existing therapeutics such as the delivery of intravenous immunoglobulin have led to interest in developing alternative approaches using recombinant or synthetic methods. Toward this aim, in the current study, we demonstrate that the use of Fc-engineered Abs (Abs that enhance IgG degradation [Abdegs]) to block neonatal FcR (FcRn) through high-affinity, Fc region binding is an effective strategy for the treatment of Ab-mediated disease. Specifically, Abdegs can be used at low, single doses to treat disease in the K/B×N serum transfer model of arthritis using BALB/c mice as recipients. Similar therapeutic effects are induced by 25- to 50-fold higher doses of i.v. Ig. Importantly, we show that FcRn blockade is a primary contributing factor toward the observed reduction in disease severity. The levels of albumin, which is also recycled by FcRn, are not affected by Abdeg delivery. Consequently, Abdegs do not alter FcRn expression levels or subcellular trafficking behavior. The engineering of Ab Fc regions to generate potent FcRn blockers therefore holds promise for the therapy of Ab-mediated autoimmunity.
Authors:
Dipesh A Patel; Alberto Puig-Canto; Dilip Kumar Challa; Héctor Perez Montoyo; Raimund J Ober; E Sally Ward
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural     Date:  2011-06-20
Journal Detail:
Title:  Journal of immunology (Baltimore, Md. : 1950)     Volume:  187     ISSN:  1550-6606     ISO Abbreviation:  J. Immunol.     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-07-07     Completed Date:  2011-09-23     Revised Date:  2013-06-28    
Medline Journal Info:
Nlm Unique ID:  2985117R     Medline TA:  J Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1015-22     Citation Subset:  AIM; IM    
Affiliation:
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9093, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Anti-Inflammatory Agents, Non-Steroidal / metabolism,  therapeutic use
Antibodies, Blocking / genetics,  metabolism,  therapeutic use
Antibody Affinity* / genetics
Arthritis, Experimental / immunology*,  pathology,  therapy*
Glucose-6-Phosphate Isomerase / immunology
Histocompatibility Antigens Class I / metabolism
Humans
Immunoglobulin Fc Fragments / genetics,  metabolism,  therapeutic use*
Immunoglobulin G / genetics,  metabolism,  therapeutic use
Mice
Mice, Inbred BALB C
Mice, Inbred NOD
Mice, Transgenic
Protein Engineering / methods*
Receptors, Antigen, T-Cell, alpha-beta / genetics,  immunology,  metabolism
Receptors, Fc / antagonists & inhibitors*,  deficiency,  metabolism
Recombinant Proteins / chemical synthesis,  metabolism,  therapeutic use
Severity of Illness Index
Grant Support
ID/Acronym/Agency:
R01 AI 39167/AI/NIAID NIH HHS; R01 AI039167-12/AI/NIAID NIH HHS; R01 AR 56478/AR/NIAMS NIH HHS; R01 AR056478-03/AR/NIAMS NIH HHS; R01 AR056478-05/AR/NIAMS NIH HHS
Chemical
Reg. No./Substance:
0/Anti-Inflammatory Agents, Non-Steroidal; 0/Antibodies, Blocking; 0/Fc receptor, neonatal; 0/Histocompatibility Antigens Class I; 0/Immunoglobulin Fc Fragments; 0/Immunoglobulin G; 0/Receptors, Antigen, T-Cell, alpha-beta; 0/Receptors, Fc; 0/Recombinant Proteins; 0/T cell receptor Vbeta6, human; EC 5.3.1.9/Glucose-6-Phosphate Isomerase
Comments/Corrections
Comment In:
Nat Rev Rheumatol. 2011 Sep;7(9):496   [PMID:  21769129 ]

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