DC-Based Immunotherapy Combined with Low-Dose Methotrexate Effective in the Treatment of Advanced CIA in Mice

Abstract

We have previously demonstrated that semimature dendritic cell- (smDC-) based immunotherapy is effective for the treatment of collagen-induced arthritis (CIA) prior to disease onset. In the present study, we examined the efficacy of combination therapy with smDCs and methotrexate (MTX) in advanced CIA with a score of 2-3. Combination therapy with low-dose MTX and type II collagen- (CII-) pulsed smDCs (CII-smDCs) was more effective in inhibiting disease progression than high or low-dose MTX alone or a combination of high dose MTX and CII-smDCs. The effect of CII-smDCs alone was also comparable to the combination therapy. CD4+Foxp3+ Treg populations and IL-10 secretion markedly increased, and CII-specific autoreactive T cells decreased in mice treated with CII-smDCs alone or in combination with MTX. Combination therapy reduced the secretion of interferon-γ (IFN-γ) and IL-17 with little influence on the IL-4 secretion in the mixed leukocyte reaction. These results imply that the combination therapy with low-dose MTX and smDCs is effective in controlling advanced CIA by enhancing Treg population and suppresses antigen-specific Th1/Th17 immunity, rather than initiating Th1 to Th2 immune deviation. Our findings provide a better understanding of the DC therapy in combination with MTX for the treatment of patients with rheumatoid arthritis (RA).

Dendritic Cell-based Immunotherapy for Rheumatoid Arthritis: from Bench to Bedside

“…TolDCs generated from naive DCs can induce T cell tolerance, thus, they represent a promising strategy for specific cellular therapy for autoimmune diseases. Even though high doses (2×10 6 ) of TNF-α-treated smDCs uniformly accelerated arthritic symptoms, low doses (2×10 5 ) of smDCs showed excellent anti-arthritic activity in CIA animals, with markedly increased production of FoxP3 + Treg, Th2 cytokines (IL-4/IL-10) and TGF-β ( 20 57 ). Mouse bone marrow-derived CD11b + F4/80 + DCs generated under the stimulation of GM-CSF and IL-4 significantly reduced the pathologic scores in the joints and spleen, which correlated significantly with reduced T cell proliferation and number of Th17 cells, and with increased number of Tregs ( 58 ).…”

Systemic Administration of Proteoglycan Protects BALB/c Retired Breeder Mice from Experimental Arthritis

“…Other reports reinforce the feasibility of tolerogenic approaches in RA therapy [ 45 ]. Combined therapies would also allow decreasing immunosuppressive drugs dosage and, therefore, avoiding a generalized immunosuppression [ 46 ]. In addition, these antigen-specific strategies could be efficacious during the preclinical disease phase when immunological abnormalities are already happening without clinical manifestation.…”

Pharmacotherapy for Rheumatoid Arthritis: New Strategy, New Targets

“…У пациентов с РА под влиянием «провоспалительных» цитокинов наблюдается активация синовиальных ДК, которые начинают синтезировать ИЛ12 и ИЛ23, тем самым способствуя поляризации иммунного ответа по Th1-и Th17типам. При коллагеновом артрите введение толерогенных ДК в низких дозах подавляет прогрессирование артрита, что ассоциируется с активацией Т рег и подавлением антиген-специфической активации Th1-и Th17-клеток [76].…”