Cell cycle regulation therapy combined with cytokine blockade enhances antiarthritic effects without increasing immune suppression

Autor: Hitoshi Kohsaka, Nobuyuki Miyasaka, Hideyuki Iwai, Kimito Kawahata, Yu Yamaguchi, Tadashi Hosoya
Rok vydání: 2014
Předmět:
Male
musculoskeletal diseases
0301 basic medicine
Pyridines
medicine.medical_treatment
Immunology
Drug Evaluation
Preclinical
Arthritis
Pharmacology
Palbociclib
Lymphocyte Activation
Piperazines
General Biochemistry
Genetics and Molecular Biology
Etanercept
Arthritis
Rheumatoid
03 medical and health sciences
0302 clinical medicine
Immune system
Rheumatology
medicine
Animals
Immunology and Allergy
Molecular Targeted Therapy
030203 arthritis & rheumatology
Biological Products
Dose-Response Relationship
Drug
biology
business.industry
Antibodies
Monoclonal
Acquired immune system
medicine.disease
Arthritis
Experimental
Receptors
Interleukin-6
030104 developmental biology
Cytokine
Mice
Inbred DBA
Antirheumatic Agents
Rheumatoid arthritis
Antibody Formation
biology.protein
Drug Therapy
Combination
Antibody
business
medicine.drug
Zdroj: Annals of the Rheumatic Diseases. 75:253-259
ISSN: 1468-2060
0003-4967
DOI: 10.1136/annrheumdis-2014-205566
Popis: 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. 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. 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. 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.
Databáze: OpenAIRE
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