The Experts below are selected from a list of 1152 Experts worldwide ranked by ideXlab platform
Anita Levin - One of the best experts on this subject based on the ideXlab platform.
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rn486 a selective bruton s tyrosine kinase inhibitor abrogates immune Hypersensitivity responses and arthritis in rodents
Journal of Pharmacology and Experimental Therapeutics, 2012Co-Authors: Yong Kim, Jennifer Postelnek, Cheng Liao, Jonathan Hsu, Jun Zhang, Michael Bradshaw, Achal Pashine, Dinesh Srinivasan, John Woods, Anita LevinAbstract:Genetic mutation and pharmacological inhibition of Bruton9s tyrosine kinase (Btk) both have been shown to prevent the development of collagen-induced arthritis (CIA) in mice, providing a rationale for the development of Btk inhibitors for treating rheumatoid arthritis (RA). In the present study, we characterized a novel Btk inhibitor, 6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2 H -isoquinolin-1-one (RN486), in vitro and in rodent models of immune Hypersensitivity and arthritis. We demonstrated that RN486 not only potently and selectively inhibited the Btk enzyme, but also displayed functional activities in human cell-based assays in multiple cell Types, blocking Fce receptor cross-linking-induced degranulation in mast cells (IC 50 = 2.9 nM), Fcγ receptor engagement-mediated tumor necrosis factor α production in monocytes (IC 50 = 7.0 nM), and B cell antigen receptor-induced expression of an activation marker, CD69, in B cells in whole blood (IC 50 = 21.0 nM). RN486 displayed similar functional activities in rodent models, effectively preventing Type I and Type III Hypersensitivity responses. More importantly, RN486 produced robust anti-inflammatory and bone-protective effects in mouse CIA and rat adjuvant-induced arthritis (AIA) models. In the AIA model, RN486 inhibited both joint and systemic inflammation either alone or in combination with methotrexate, reducing both paw swelling and inflammatory markers in the blood. Together, our findings not only demonstrate that Btk plays an essential and conserved role in regulating immunoreceptor-mediated immune responses in both humans and rodents, but also provide evidence and mechanistic insights to support the development of selective Btk inhibitors as small-molecule disease-modifying drugs for RA and potentially other autoimmune diseases.
Pedro Dorleansjuste - One of the best experts on this subject based on the ideXlab platform.
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contribution of b2 receptors for bradykinin in arthus reaction induced plasma extravasation in wild Type or b2 transgenic knockout mice
British Journal of Pharmacology, 2000Co-Authors: R Samadfam, Pierre Sirois, Catarina Teixeira, Ghassan Bkaily, A J De Brumfernandes, Pedro DorleansjusteAbstract:The aim of the present study was to investigate the contribution of bradykinin (BK) B1 and B2 receptors in a model of Type III Hypersensitivity, the reverse passive Arthus reaction (RPA), in wild-Type mice and transgenic B2 knockout littermates. BK (10 μg mouse−1) or bovine serum albumin (0.5 mg mouse−1) induced a sustained Evans blue extravasation for more than 80 min in naive or rabbit anti-bovine serum albumin-treated mice (RPA model), respectively. The response to the two stimuli was prevented by the B2 receptor antagonist, HOE-140, but not by [Leu8]desArg9-BK (B1 receptor antagonist). In contrast to the wild-Type littermates, RPA and bradykinin were unable to trigger an increase in plasma extravasation in B2 knockout mice. Furthermore, endothelin-1 (5 μg mouse−1) and a selective NK-1 receptor agonist [Sar9,Met (O2)11]-SP (20 μg mouse−1), triggered a significant increase in peritoneal plasma extravasation in both wild-Type and B2 knockout animals. A pretreatment with indomethacin (200 μg mouse−1) significantly reduced the RPA-induced but not the BK-induced increase in Evans blue extravasation. Furthermore, RPA, but not BK, triggered a significant indomethacin-sensitive increase in peritoneal prostaglandin E2 content. Our results suggest a pivotal role for B2 receptors in the mechanism of plasma extravasation which occurs during the reverse passive Arthus reaction in the mouse. Moreover, our results suggest an important contribution of prostanoids in the plasma leakage mechanisms triggered by RPA but not by bradykinin. British Journal of Pharmacology (2000) 129, 1732–1738; doi:10.1038/sj.bjp.0703225
Yong Kim - One of the best experts on this subject based on the ideXlab platform.
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RN486, a Selective Bruton's Tyrosine Kinase Inhibitor, Abrogates Immune Hypersensitivity Responses and Arthritis in Rodents
2020Co-Authors: □ S, Yong Kim, Jennifer Postelnek, Cheng Liao, Mike Bradshaw, Jonathan Hsu, Jun ZhangAbstract:ABSTRACT Genetic mutation and pharmacological inhibition of Bruton's tyrosine kinase (Btk) both have been shown to prevent the development of collagen-induced arthritis (CIA) in mice, providing a rationale for the development of Btk inhibitors for treating rheumatoid arthritis (RA). In the present study, we characterized a novel Btk inhibitor, 6-cyclopro- , in vitro and in rodent models of immune Hypersensitivity and arthritis. We demonstrated that RN486 not only potently and selectively inhibited the Btk enzyme, but also displayed functional activities in human cell-based assays in multiple cell Types, blocking Fc receptor cross-linking-induced degranulation in mast cells (IC 50 ϭ 2.9 nM), Fc␥ receptor engagement-mediated tumor necrosis factor ␣ production in monocytes (IC 50 ϭ 7.0 nM), and B cell antigen receptor-induced expression of an activation marker, CD69, in B cells in whole blood (IC 50 ϭ 21.0 nM). RN486 displayed similar functional activities in rodent models, effectively preventing Type I and Type III Hypersensitivity responses. More importantly, RN486 produced robust anti-inflammatory and boneprotective effects in mouse CIA and rat adjuvant-induced arthritis (AIA) models. In the AIA model, RN486 inhibited both joint and systemic inflammation either alone or in combination with methotrexate, reducing both paw swelling and inflammatory markers in the blood. Together, our findings not only demonstrate that Btk plays an essential and conserved role in regulating immunoreceptor-mediated immune responses in both humans and rodents, but also provide evidence and mechanistic insights to support the development of selective Btk inhibitors as small-molecule disease-modifying drugs for RA and potentially other autoimmune diseases
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rn486 a selective bruton s tyrosine kinase inhibitor abrogates immune Hypersensitivity responses and arthritis in rodents
Journal of Pharmacology and Experimental Therapeutics, 2012Co-Authors: Yong Kim, Jennifer Postelnek, Cheng Liao, Jonathan Hsu, Jun Zhang, Michael Bradshaw, Achal Pashine, Dinesh Srinivasan, John Woods, Anita LevinAbstract:Genetic mutation and pharmacological inhibition of Bruton9s tyrosine kinase (Btk) both have been shown to prevent the development of collagen-induced arthritis (CIA) in mice, providing a rationale for the development of Btk inhibitors for treating rheumatoid arthritis (RA). In the present study, we characterized a novel Btk inhibitor, 6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2 H -isoquinolin-1-one (RN486), in vitro and in rodent models of immune Hypersensitivity and arthritis. We demonstrated that RN486 not only potently and selectively inhibited the Btk enzyme, but also displayed functional activities in human cell-based assays in multiple cell Types, blocking Fce receptor cross-linking-induced degranulation in mast cells (IC 50 = 2.9 nM), Fcγ receptor engagement-mediated tumor necrosis factor α production in monocytes (IC 50 = 7.0 nM), and B cell antigen receptor-induced expression of an activation marker, CD69, in B cells in whole blood (IC 50 = 21.0 nM). RN486 displayed similar functional activities in rodent models, effectively preventing Type I and Type III Hypersensitivity responses. More importantly, RN486 produced robust anti-inflammatory and bone-protective effects in mouse CIA and rat adjuvant-induced arthritis (AIA) models. In the AIA model, RN486 inhibited both joint and systemic inflammation either alone or in combination with methotrexate, reducing both paw swelling and inflammatory markers in the blood. Together, our findings not only demonstrate that Btk plays an essential and conserved role in regulating immunoreceptor-mediated immune responses in both humans and rodents, but also provide evidence and mechanistic insights to support the development of selective Btk inhibitors as small-molecule disease-modifying drugs for RA and potentially other autoimmune diseases.
Jun Zhang - One of the best experts on this subject based on the ideXlab platform.
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RN486, a Selective Bruton's Tyrosine Kinase Inhibitor, Abrogates Immune Hypersensitivity Responses and Arthritis in Rodents
2020Co-Authors: □ S, Yong Kim, Jennifer Postelnek, Cheng Liao, Mike Bradshaw, Jonathan Hsu, Jun ZhangAbstract:ABSTRACT Genetic mutation and pharmacological inhibition of Bruton's tyrosine kinase (Btk) both have been shown to prevent the development of collagen-induced arthritis (CIA) in mice, providing a rationale for the development of Btk inhibitors for treating rheumatoid arthritis (RA). In the present study, we characterized a novel Btk inhibitor, 6-cyclopro- , in vitro and in rodent models of immune Hypersensitivity and arthritis. We demonstrated that RN486 not only potently and selectively inhibited the Btk enzyme, but also displayed functional activities in human cell-based assays in multiple cell Types, blocking Fc receptor cross-linking-induced degranulation in mast cells (IC 50 ϭ 2.9 nM), Fc␥ receptor engagement-mediated tumor necrosis factor ␣ production in monocytes (IC 50 ϭ 7.0 nM), and B cell antigen receptor-induced expression of an activation marker, CD69, in B cells in whole blood (IC 50 ϭ 21.0 nM). RN486 displayed similar functional activities in rodent models, effectively preventing Type I and Type III Hypersensitivity responses. More importantly, RN486 produced robust anti-inflammatory and boneprotective effects in mouse CIA and rat adjuvant-induced arthritis (AIA) models. In the AIA model, RN486 inhibited both joint and systemic inflammation either alone or in combination with methotrexate, reducing both paw swelling and inflammatory markers in the blood. Together, our findings not only demonstrate that Btk plays an essential and conserved role in regulating immunoreceptor-mediated immune responses in both humans and rodents, but also provide evidence and mechanistic insights to support the development of selective Btk inhibitors as small-molecule disease-modifying drugs for RA and potentially other autoimmune diseases
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rn486 a selective bruton s tyrosine kinase inhibitor abrogates immune Hypersensitivity responses and arthritis in rodents
Journal of Pharmacology and Experimental Therapeutics, 2012Co-Authors: Yong Kim, Jennifer Postelnek, Cheng Liao, Jonathan Hsu, Jun Zhang, Michael Bradshaw, Achal Pashine, Dinesh Srinivasan, John Woods, Anita LevinAbstract:Genetic mutation and pharmacological inhibition of Bruton9s tyrosine kinase (Btk) both have been shown to prevent the development of collagen-induced arthritis (CIA) in mice, providing a rationale for the development of Btk inhibitors for treating rheumatoid arthritis (RA). In the present study, we characterized a novel Btk inhibitor, 6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2 H -isoquinolin-1-one (RN486), in vitro and in rodent models of immune Hypersensitivity and arthritis. We demonstrated that RN486 not only potently and selectively inhibited the Btk enzyme, but also displayed functional activities in human cell-based assays in multiple cell Types, blocking Fce receptor cross-linking-induced degranulation in mast cells (IC 50 = 2.9 nM), Fcγ receptor engagement-mediated tumor necrosis factor α production in monocytes (IC 50 = 7.0 nM), and B cell antigen receptor-induced expression of an activation marker, CD69, in B cells in whole blood (IC 50 = 21.0 nM). RN486 displayed similar functional activities in rodent models, effectively preventing Type I and Type III Hypersensitivity responses. More importantly, RN486 produced robust anti-inflammatory and bone-protective effects in mouse CIA and rat adjuvant-induced arthritis (AIA) models. In the AIA model, RN486 inhibited both joint and systemic inflammation either alone or in combination with methotrexate, reducing both paw swelling and inflammatory markers in the blood. Together, our findings not only demonstrate that Btk plays an essential and conserved role in regulating immunoreceptor-mediated immune responses in both humans and rodents, but also provide evidence and mechanistic insights to support the development of selective Btk inhibitors as small-molecule disease-modifying drugs for RA and potentially other autoimmune diseases.
Lício A. Velloso - One of the best experts on this subject based on the ideXlab platform.
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Type III Hypersensitivity to insulin leading to leukocytoclastic vasculitis.
Diabetes research and clinical practice, 2010Co-Authors: B. Rachid, M. Rabelo-santos, Eli Mansour, R. L. De Lima Zollner, Lício A. VellosoAbstract:Here, we report the occurrence of leukocytoclastic vasculitis as an outcome of Type III allergy to insulin in a patient with Type II diabetes mellitus. The diagnosis was made on the basis of anatomo-pathological examination of a skin biopsy.
