OBJECTIVE: To determine the effects of anti-tumor necrosis factor (anti-TNF) therapy in the inflammatory and autoimmune disease in motheaten (me/me) mice, which exhibit a Fas apoptosis signaling defect. METHODS: Arthritis, pneumonitis, and mortality were analyzed in me/me mice treated with a novel, soluble, dimeric TNF receptor I (sTNFRI) molecule capable of high-affinity binding and neutralization of TNFalpha. RESULTS: Soluble TNFRI reduced serum levels of TNFalpha and led to a 2-fold increase in the lifespan of me/me mice, compared with the control treatment group. The treatment also reduced the development of the "motheaten" skin patches and alleviated pneumonitis and inflammatory lesions in the extremities of me/me mice compared with controls. However, the serum levels of IgM and IgM anti-double-stranded DNA autoantibody were comparable to those of untreated control mice. CONCLUSION: TNFalpha is an important cytokine involved in the pathogenesis of inflammatory disease in me/me mice, resulting in tissue damage and early mortality. Therapies directed at blocking TNF/TNFR interactions, such as the sTNFRI used in these experiments, may be effective in diseases associated with apoptosis defects leading to overutilization of the TNF/TNFR pathway.
OBJECTIVE: To determine the effects of anti-tumor necrosis factor (anti-TNF) therapy in the inflammatory and autoimmune disease in motheaten (me/me) mice, which exhibit a Fas apoptosis signaling defect. METHODS:Arthritis, pneumonitis, and mortality were analyzed in me/me mice treated with a novel, soluble, dimeric TNF receptor I (sTNFRI) molecule capable of high-affinity binding and neutralization of TNFalpha. RESULTS: Soluble TNFRI reduced serum levels of TNFalpha and led to a 2-fold increase in the lifespan of me/me mice, compared with the control treatment group. The treatment also reduced the development of the "motheaten" skin patches and alleviated pneumonitis and inflammatory lesions in the extremities of me/me mice compared with controls. However, the serum levels of IgM and IgM anti-double-stranded DNA autoantibody were comparable to those of untreated control mice. CONCLUSION:TNFalpha is an important cytokine involved in the pathogenesis of inflammatory disease in me/me mice, resulting in tissue damage and early mortality. Therapies directed at blocking TNF/TNFR interactions, such as the sTNFRI used in these experiments, may be effective in diseases associated with apoptosis defects leading to overutilization of the TNF/TNFR pathway.
Authors: Ben A Croker; Brian R Lawson; Sophie Rutschmann; Michael Berger; Celine Eidenschenk; Amanda L Blasius; Eva Marie Y Moresco; Sosathya Sovath; Louise Cengia; Leonard D Shultz; Argyrios N Theofilopoulos; Sven Pettersson; Bruce Alan Beutler Journal: Proc Natl Acad Sci U S A Date: 2008-09-19 Impact factor: 11.205
Authors: F Nicoletti; R Di Marco; P Sacerdote; P Meroni; K Mangano; C Edwards; A Bartorelli; K Bendtzen; A Panerai Journal: Antimicrob Agents Chemother Date: 2001-05 Impact factor: 5.191
Authors: Wenpu Zhao; Seth G Thacker; Jeffrey B Hodgin; Hongyu Zhang; Jeffrey H Wang; James L Park; Ann Randolph; Emily C Somers; Subramaniam Pennathur; Matthias Kretzler; Frank C Brosius; Mariana J Kaplan Journal: J Immunol Date: 2009-07-20 Impact factor: 5.422