Autologous tolerogenic dendritic cells for rheumatoid and inflammatory arthritis

Abstract

ObjectivesTo assess the safety of intra-articular (IA) autologous tolerogenic dendritic cells (tolDC) in patients with inflammatory arthritis and an inflamed knee; to assess the feasibility and acceptability of the approach and to assess potential effects on local and systemic disease activities.MethodsAn unblinded, randomised, controlled, dose escalation Phase I trial. TolDC were differentiated from CD14+ monocytes and loaded with autologous synovial fluid as a source of autoantigens. Cohorts of three participants received 1×106, 3×106 or 10×106 tolDC arthroscopically following saline irrigation of an inflamed (target) knee. Control participants received saline irrigation only. Primary outcome was flare of disease in the target knee within 5 days of treatment. Feasibility was assessed by successful tolDC manufacture and acceptability via patient questionnaire. Potential effects on disease activity were assessed by arthroscopic synovitis score, disease activity score (DAS)28 and Health Assessment Questionnaire (HAQ). Immunomodulatory effects were sought in peripheral blood.ResultsThere were no target knee flares within 5 days of treatment. At day 14, arthroscopic synovitis was present in all participants except for one who received 10×106 tolDC; a further participant in this cohort declined day 14 arthroscopy because symptoms had remitted; both remained stable throughout 91 days of observation. There were no trends in DAS28 or HAQ score or consistent immunomodulatory effects in peripheral blood. 9 of 10 manufactured products met quality control release criteria; acceptability of the protocol by participants was high.ConclusionIA tolDC therapy appears safe, feasible and acceptable. Knee symptoms stabilised in two patients who received 10×106 tolDC but no systemic clinical or immunomodulatory effects were detectable.Trial registration numberNCT01352858.

MicroRNA-34a dependent regulation of AXL controls the activation of dendritic cells in inflammatory arthritis

“…In support of this concept, a phase I clinical trial demonstrated improvement in DAS28 in RA patients transfused with autologous tolerogenic DCs modified in vitro with an NF-kB inhibitor51, and this was associated with a decrease in antigen-specific effector T cells and serum pro-inflammatory cytokines, and an increase in regulatory T cells. A similar study with intra-articular delivery of autologous tolerogenic DCs showed stabilization of knee symptoms52. Thus, a better understanding of the regulatory mechanisms operating in DCs of RA could help development next generation DC-based therapies.…”

Dendritic cell recruitment and activation in autoimmunity

“…Another attempt has been performed in RA patients by using autologous DC generated in the presence of Dex and VitD3 and pulsed with synovial fluid (named AutoDECRA, ClinicalTrials.gov identifier NCT01352858) and then injected into the inflamed joints. Two out of nine patients treated with this approach showed stabilization of the local symptoms but not systemic clinic improvements [250]. The potential therapeutic administration of autologous DC pulsed with self-antigen involved in SLE pathogenesis, such as nucleosomes, Ro, La, and Sm is under investigations [251e253].…”

Treatment with Dexamethasone and Monophosphoryl Lipid A Removes Disease-Associated Transcriptional Signatures in Monocyte-Derived Dendritic Cells from Rheumatoid Arthritis Patients and Confers Tolerogenic Features

“…Application of TolDCs for RA treatment has been successfully tested in animal models (23, 24). Phase I clinical trials using in vitro modified autologous TolDCs demonstrated feasibility and safety in patients with type 1 diabetes (25) and RA (15, 26). …”