Document Detail


Expression of tolerance associated gene-1, a mitochondrial protein inhibiting T cell activation, can be used to predict response to immune modulating therapies.
MedLine Citation:
PMID:  19684086     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Immune modulating therapies gain increasing importance in treatment of patients with autoimmune diseases such as psoriasis. None of the currently applied biologics achieves significant clinical improvement in all treated patients. Because the therapy with biologics is cost intensive and sometimes associated with side effects, noninvasive diagnostic tools for early prediction of responders are of major interest. We studied the effects of Alefacept (LFA3Ig), an approved drug for treatment of psoriasis, on leukocytes in vitro and in vivo to identify gene markers predictive for treatment response and to further investigate its molecular mechanisms of action. In an open-label study, 20 psoriasis patients were treated weekly with 15 mg Alefacept over 12 wk. We demonstrate that transcription of the tolerance-associated gene (TOAG-1) is significantly up-regulated whereas receptor for hyaluronic acid mediated migration (RHAMM) transcription is down-regulated in PBMCs of responding patients before clinical improvement. TOAG-1 is exclusively localized within mitochondria. Overexpression of TOAG-1 in murine T cells leads to increased susceptibility to apoptosis. Addition of Alefacept to stimulated human T cells in vitro resulted in reduced frequencies of activated CD137(+) cells, increased TOAG-1 but reduced RHAMM expression. This was accompanied by reduced proliferation and enhanced apoptosis. Inhibition of proliferation was dependent on enhanced PDL1 expression of APCs. Thus, peripheral changes of TOAG-1 and RHAMM expression can be used to predict clinical response to Alefacept treatment in psoriasis patients. In the presence of APCs Alefacept can inhibit T cell activation and survival by increasing expression of TOAG-1 on T cells and PDL1 on APCs.
Authors:
Kathrin Keeren; Markus Friedrich; Inga Gebuhr; Sandra Philipp; Robert Sabat; Wolfram Sterry; Christine Brandt; Christian Meisel; Gerald Grütz; Hans-Dieter Volk; Birgit Sawitzki
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-08-14
Journal Detail:
Title:  Journal of immunology (Baltimore, Md. : 1950)     Volume:  183     ISSN:  1550-6606     ISO Abbreviation:  J. Immunol.     Publication Date:  2009 Sep 
Date Detail:
Created Date:  2009-09-03     Completed Date:  2009-09-23     Revised Date:  2013-05-27    
Medline Journal Info:
Nlm Unique ID:  2985117R     Medline TA:  J Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4077-87     Citation Subset:  AIM; IM    
Affiliation:
Institute of Medical Immunology, Charité University Medicine Berlin Campus Mitte, Germany.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigen-Presenting Cells / metabolism*
Antigens, CD / genetics*
Antigens, CD274
Antigens, CD44
Apoptosis
Autoimmune Diseases / diagnosis*,  therapy
Cell Proliferation
Dermatologic Agents
Extracellular Matrix Proteins
Gene Expression Regulation / drug effects*
Humans
Immunotherapy
Leukocytes / drug effects
Lymphocyte Activation / drug effects*
Mice
Mitochondrial Proteins / genetics*
Predictive Value of Tests*
Psoriasis / diagnosis,  drug therapy
Recombinant Fusion Proteins / pharmacology,  therapeutic use
Chemical
Reg. No./Substance:
0/Antigens, CD; 0/Antigens, CD274; 0/Antigens, CD44; 0/CD274 protein, human; 0/Dermatologic Agents; 0/Extracellular Matrix Proteins; 0/Mitochondrial Proteins; 0/Recombinant Fusion Proteins; 0/TOAG-1 protein, mouse; 0/hyaluronan-mediated motility receptor; ELK3V90G6C/alefacept

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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