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Cell cycle regulation therapy combined with cytokine blockade enhances antiarthritic effects without increasing immune suppression.
- Source :
-
Annals of the rheumatic diseases [Ann Rheum Dis] 2016 Jan; Vol. 75 (1), pp. 253-9. Date of Electronic Publication: 2014 Aug 27. - Publication Year :
- 2016
-
Abstract
- Objective: Biological disease-modifying antirheumatic drugs (DMARDs) that inhibit aberrant immune reactions in rheumatoid arthritis (RA) cannot induce complete remission in all patients. Combination therapies using two biological DMARDs have failed to exert additive effects and increased serious infections. We have found that cell cycle inhibition of synovial fibroblasts with cyclin-dependent kinase (CDK) inhibitors ameliorated the disease in animal models of RA without attenuating acquired immunity. The objective of this study was to determine whether a clinically well-tolerated selective CDK 4/6 inhibitor (CDKI), palbociclib, is effective and whether combination with cytokine blockers acts additively without enhancing immune suppression.<br />Methods: The effects of CDKI on haematopoiesis and physical and behavioural findings in mice were evaluated. Mice with collagen-induced arthritis (CIA) were treated with CDKI, etanercept or anti-interleukin (IL)-6 receptor antibody (MR16-1) alone or with a combination of CDKI with etanercept or MR16-1. Their clinical, histological and radiographic scores, serum anti-(type II collagen (CII)) antibody levels and proliferative responses of lymph node cells to CII were determined.<br />Results: Although CDKI induced marginal myelosuppression, it was well tolerated and ameliorated CIA dose-dependently. The combinations of low-dose CDKI and either tumour necrosis factor-α or IL-6 blocker enhanced the antiarthritic effects additively. The addition of CDKI to either cytokine blocker did not affect the levels of anti-CII antibodies and proliferative responses of lymphocytes to CII.<br />Conclusions: A clinically well-tolerated CDK4/6 inhibitor exerted antiarthritic effects in this mouse model. By combining therapeutic agents targeting immune reaction and synovial proliferation, we have demonstrated for the first time that two molecular targeting treatments act additively and may not increase immune suppression.<br /> (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)
- Subjects :
- Animals
Antibodies, Monoclonal immunology
Antibodies, Monoclonal therapeutic use
Antibodies, Monoclonal toxicity
Antibody Formation drug effects
Antirheumatic Agents administration & dosage
Antirheumatic Agents toxicity
Arthritis, Experimental immunology
Arthritis, Experimental pathology
Arthritis, Rheumatoid immunology
Arthritis, Rheumatoid pathology
Biological Products administration & dosage
Biological Products toxicity
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical methods
Drug Therapy, Combination
Etanercept administration & dosage
Etanercept therapeutic use
Etanercept toxicity
Lymphocyte Activation drug effects
Male
Mice, Inbred DBA
Molecular Targeted Therapy methods
Piperazines administration & dosage
Piperazines toxicity
Pyridines administration & dosage
Pyridines toxicity
Receptors, Interleukin-6 antagonists & inhibitors
Antirheumatic Agents therapeutic use
Arthritis, Experimental drug therapy
Arthritis, Rheumatoid drug therapy
Biological Products therapeutic use
Piperazines therapeutic use
Pyridines therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1468-2060
- Volume :
- 75
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Annals of the rheumatic diseases
- Publication Type :
- Academic Journal
- Accession number :
- 25165034
- Full Text :
- https://doi.org/10.1136/annrheumdis-2014-205566