Combination of subtherapeutic anti-TNF dose with dasatinib restores clinical and molecular arthritogenic profiles better than standard anti-TNF treatment
| Autor: | Panagiotis Chouvardas, Lydia Ntari, Florian Meier, Niki Karagianni, Christoforos Nikolaou, Maria C Denis, Ksanthi Kranidioti, Dimitra Papadopoulou, Eleni Christodoulou-Vafeiadou, George Kollias, Christina Geka |
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| Přispěvatelé: | Publica |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Combination therapy Dasatinib Arthritis 610 Medicine & health Pharmacology General Biochemistry Genetics and Molecular Biology Arthritis Rheumatoid 03 medical and health sciences Mice 0302 clinical medicine Medicine Animals Humans Anti-hTNF 030203 arthritis & rheumatology Tofacitinib business.industry Research General Medicine Chronic inflammation medicine.disease Infliximab 3. Good health 030104 developmental biology Rheumatoid arthritis Antirheumatic Agents Bosutinib Tumor Necrosis Factor Inhibitors business Tyrosine Kinase inhibitors Tyrosine kinase medicine.drug |
| Zdroj: | Journal of Translational Medicine, Vol 19, Iss 1, Pp 1-13 (2021) Journal of Translational Medicine Ntari, Lydia; Nikolaou, Christoforos; Kranidioti, Ksanthi; Papadopoulou, Dimitra; Christodoulou-Vafeiadou, Eleni; Chouvardas, Panagiotis; Meier, Florian; Geka, Christina; Denis, Maria C; Karagianni, Niki; Kollias, George (2021). Combination of subtherapeutic anti-TNF dose with dasatinib restores clinical and molecular arthritogenic profiles better than standard anti-TNF treatment. Journal of translational medicine, 19(1), p. 165. BioMed Central 10.1186/s12967-021-02764-y |
| DOI: | 10.1186/s12967-021-02764-y |
| Popis: | Background New medications for Rheumatoid Arthritis (RA) have emerged in the last decades, including Disease Modifying Antirheumatic Drugs (DMARDs) and biologics. However, there is no known cure, since a significant proportion of patients remain or become non-responders to current therapies. The development of new mode-of-action treatment schemes involving combination therapies could prove successful for the treatment of a greater number of RA patients. Methods We investigated the effect of the Tyrosine Kinase inhibitors (TKIs) dasatinib and bosutinib, on the human TNF-dependent Tg197 arthritis mouse model. The inhibitors were administered either as a monotherapy or in combination with a subtherapeutic dose of anti-hTNF biologics and their therapeutic effect was assessed clinically, histopathologically as well as via gene expression analysis and was compared to that of an efficient TNF monotherapy. Results Dasatinib and, to a lesser extent, bosutinib inhibited the production of TNF and proinflammatory chemokines from arthritogenic synovial fibroblasts. Dasatinib, but not bosutinib, also ameliorated significantly and in a dose-dependent manner both the clinical and histopathological signs of Tg197 arthritis. Combination of dasatinib with a subtherapeutic dose of anti-hTNF biologic agents, resulted in a synergistic inhibitory effect abolishing all arthritis symptoms. Gene expression analysis of whole joint tissue of Tg197 mice revealed that the combination of dasatinib with a low subtherapeutic dose of Infliximab most efficiently restores the pathogenic gene expression profile to that of the healthy state compared to either treatment administered as a monotherapy. Conclusion Our findings show that dasatinib exhibits a therapeutic effect in TNF-driven arthritis and can act in synergy with a subtherapeutic anti-hTNF dose to effectively treat the clinical and histopathological signs of the pathology. The combination of dasatinib and anti-hTNF exhibits a distinct mode of action in restoring the arthritogenic gene signature to that of a healthy profile. Potential clinical applications of combination therapies with kinase inhibitors and anti-TNF agents may provide an interesting alternative to high-dose anti-hTNF monotherapy and increase the number of patients responding to treatment. |
| Databáze: | OpenAIRE |
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