Document Detail

In vivo apoptosis of diabetogenic T cells in NOD mice by IFN-gamma/TNF-alpha.
MedLine Citation:
PMID:  15492021     Owner:  NLM     Status:  MEDLINE    
Immunization with mycobacterial preparation such as Bacille Calmette-Guerin (BCG) or complete Freund's adjuvant (CFA) prevents the onset and recurrence of type 1 diabetes in non-obese diabetic (NOD) mice. In this study, we explored the mechanism underlying the down-regulation of diabetogenic T cells by BCG treatment. We found that the potential of splenocytes from BCG-immunized diabetic NOD mice to adoptively transfer diabetes was significantly impaired. BCG immunization sequentially induced the production of TNF-alpha, IFN-gamma and IL-4 by splenocytes, increased the expression of Fas(high) (Apo-1/CD95), Fas ligand (FasL, CD95L) and TNF receptor (TNFR) on T cells leading to T cell apoptosis. The primary role of IFN-gamma and TNF-alpha in BCG-immunotherapy was demonstrated by (i) reversing the immune regulatory effect of BCG by in vivo treatment with neutralizing anti-cytokine antibodies, (ii) inducing effect similar to BCG by treatment with these cytokines. We show that Fas and TNF are two pathways in BCG-induced apoptosis of diabetogenic T cells, since in vitro blocking FasL or TNFR1 with antibody reduced T cell apoptosis and increased T cell proliferative response. In addition, TNF-alpha and agonistic anti-Fas antibody had a synergistic effect on the in vitro apoptosis of diabetogenic T cells. Our results suggest that BCG down-regulates destructive autoimmunity by TNF-alpha/IFN-gamma-induced apoptosis of diabetogenic T cells through both Fas and TNF pathways. These studies provide a novel mechanism for blocking disease recurrence and immune modulating effect of BCG immunization in type 1 diabetes.
Hui-Yu Qin; Pratibha Chaturvedi; Bhagirath Singh
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2004-10-18
Journal Detail:
Title:  International immunology     Volume:  16     ISSN:  0953-8178     ISO Abbreviation:  Int. Immunol.     Publication Date:  2004 Dec 
Date Detail:
Created Date:  2004-11-16     Completed Date:  2005-04-18     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  8916182     Medline TA:  Int Immunol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1723-32     Citation Subset:  IM    
Department of Microbiology and Immunology, University of Western Ontario, Canada.
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MeSH Terms
Antigens, CD95 / metabolism
Diabetes Mellitus, Type 1 / immunology*,  therapy
Fas Ligand Protein
Immunotherapy, Active
Interferon-gamma / pharmacology,  physiology*
Interleukin-4 / pharmacology,  physiology
Membrane Glycoproteins / metabolism
Mice, Inbred NOD
Mycobacterium bovis / immunology*
Receptors, Tumor Necrosis Factor, Type I / metabolism
Recurrence / prevention & control
Spleen / cytology,  immunology
T-Lymphocytes / drug effects,  immunology*
Tumor Necrosis Factor-alpha / pharmacology,  physiology*
Reg. No./Substance:
0/Antigens, CD95; 0/Fas Ligand Protein; 0/Fasl protein, mouse; 0/Membrane Glycoproteins; 0/Receptors, Tumor Necrosis Factor, Type I; 0/Tumor Necrosis Factor-alpha; 207137-56-2/Interleukin-4; 82115-62-6/Interferon-gamma

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