التفاصيل البيبلوغرافية
| العنوان: |
Selective Inhibition of BTK Prevents Murine Lupus and Antibody-Mediated Glomerulonephritis. |
| المؤلفون: |
Rankin, Andrew L.1, Seth, Nilufer1, Keegan, Sean1, Andreyeva, Tatyana1, Cook, Tim A.1, Edmonds, Jason1, Mathialagan, Nagappan2, Benson, Micah J.1, Syed, Jameel3, Yutian Zhan3, Benoit, Stephen E.4, Miyashiro, Joy S.1, Wood, Nancy1, Mohan, Shashi1, Peeva, Elena4, Ramaiah, Shashi K.5, Messing, Dean6, Homer, Bruce L.5, Dunussi-Joannopoulos, Kyri1, Nickerson-Nutter, Cheryl L.1 |
| المصدر: |
Journal of Immunology. 11/1/2013, Vol. 191 Issue 9, p4540-4550. 11p. |
| مصطلحات موضوعية: |
*AUTOANTIBODIES, *LUPUS nephritis, *IMMUNE complexes, *GLOMERULONEPHRITIS, *KIDNEY disease risk factors, *TREATMENT effectiveness, *THERAPEUTICS, *IMMUNOLOGY, ANIMAL models of immunologic diseases |
| مستخلص: |
Autoantibody production and immune complex deposition within the kidney promote renal disease in patients with lupus nephritis. Thus, therapeutics that inhibit these pathways may be efficacious in the treatment of systemic lupus erythematosus. Bruton's tyrosine kinase (BTK) is a critical signaling component of both BCR and FcR signaling. We sought to assess the efficacy of inhibiting BTK in the development of lupus-like disease, and in this article describe (R)-5-amino-1-(1-cyanopiperidin-3-yl)-3- (4-[2,4-difluorophenoxy]phenyl)-1H-pyrazole-4-carboxamide (PF-06250112), a novel highly selective and potent BTK inhibitor. We demonstrate in vitro that PF-06250112 inhibits both BCR-mediated signaling and proliferation, as well as FcR-mediated activation. To assess the therapeutic impact of BTK inhibition, we treated aged NZBxW_F1 mice with PF-06250112 and demonstrate that PF-06250112 significantly limits the spontaneous accumulation of splenic germinal center B cells and plasma cells. Correspondingly, anti-dsDNA and autoantibody levels were reduced in a dose-dependent manner. Moreover, administration of PF- 06250112 prevented the development of proteinuria and improved glomerular pathology scores in all treatment groups. Strikingly, this therapeutic effect could occur with only a modest reduction observed in anti-dsDNA titers, implying a critical role for BTK signaling in disease pathogenesis beyond inhibition of autoantibody production. We subsequently demonstrate that PF- 06250112 prevents proteinuria in an FcR-dependent, Ab-mediated model of glomerulonephritis. Importantly, these results highlight that BTK inhibition potently limits the development of glomerulonephritis by impacting both cell- and effector moleculemediated pathways. These data provide support for evaluating the efficacy of BTK inhibition in systemic lupus erythematosus patients. [ABSTRACT FROM AUTHOR] |
| قاعدة البيانات: |
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