Abstract
A lymphotoxin-beta (LTbeta) receptor-Ig fusion protein (LTbetaR-Ig) was used to evaluate the importance of the lymphotoxin/LIGHT axis in the development and perpetuation of arthritis. Prophylactic treatment with the inhibitor protein LTbetaR-Ig blocked the induction of collagen-induced arthritis in mice and adjuvant arthritis in Lewis rats. Treatment of mice with established collagen-induced arthritis reduced the severity of arthritic symptoms and joint tissue damage. However, in a passive model of anti-collagen Ab-triggered arthritis, joint inflammation was not affected by LTbetaR-Ig treatment precluding LT/LIGHT involvement in the very terminal immune complex/complement/FcR-mediated effector phase. Collagen-II and Mycobacterium-specific T cell responses were not impaired, yet there was evidence that the overall response to the mycobacterium was blunted. Serum titers of anti-collagen-II Abs were reduced especially during the late phase of disease. Treatment with LTbetaR-Ig ablated follicular dendritic cell networks in the draining lymph nodes, suggesting that impaired class switching and affinity maturation may have led to a decreased level of pathological autoantibodies. These data are consistent with a model in which the LT/LIGHT axis controls microenvironments in the draining lymph nodes. These environments are critical in shaping the adjuvant-driven initiating events that impact the subsequent quality of the anti-collagen response in the later phases. Consequently, blockade of the LT/LIGHT axis may represent a novel approach to the treatment of autoimmune diseases such as rheumatoid arthritis that involve both T cell and Ab components.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antigen-Antibody Complex / administration & dosage
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Arthritis, Experimental / etiology
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Arthritis, Experimental / immunology*
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Arthritis, Experimental / prevention & control
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Autoantibodies / biosynthesis
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Cells, Cultured
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Collagen / administration & dosage
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Collagen / immunology*
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Disease Progression
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Epitopes, T-Lymphocyte / administration & dosage
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Epitopes, T-Lymphocyte / immunology
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Female
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Freund's Adjuvant / administration & dosage
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Freund's Adjuvant / immunology
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Humans
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Immunization, Passive
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Lymph Nodes / immunology
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Lymph Nodes / pathology
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Lymphotoxin beta Receptor
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Lymphotoxin-alpha / antagonists & inhibitors
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Lymphotoxin-alpha / physiology*
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Lymphotoxin-beta
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Male
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Membrane Proteins / antagonists & inhibitors
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Membrane Proteins / physiology*
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Mice
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Mice, Inbred BALB C
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Mice, Inbred DBA
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Rats
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Rats, Inbred Lew
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Receptors, IgG / genetics
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Receptors, Tumor Necrosis Factor / administration & dosage
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Receptors, Tumor Necrosis Factor / genetics
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Receptors, Tumor Necrosis Factor / physiology*
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Recombinant Fusion Proteins / administration & dosage
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Recombinant Fusion Proteins / pharmacology
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Spleen / immunology
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Spleen / pathology
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T-Lymphocyte Subsets / immunology
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Tumor Necrosis Factor Ligand Superfamily Member 14
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / physiology*
Substances
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Antigen-Antibody Complex
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Autoantibodies
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Epitopes, T-Lymphocyte
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LTB protein, human
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LTBR protein, human
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Ltb protein, mouse
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Ltb protein, rat
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Ltbr protein, mouse
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Lymphotoxin beta Receptor
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Lymphotoxin-alpha
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Lymphotoxin-beta
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Membrane Proteins
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Receptors, IgG
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Receptors, Tumor Necrosis Factor
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Recombinant Fusion Proteins
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TNFSF14 protein, human
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Tnfsf14 protein, mouse
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Tumor Necrosis Factor Ligand Superfamily Member 14
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Tumor Necrosis Factor-alpha
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Collagen
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Freund's Adjuvant