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Review
. 2013 May;172(2):148-57.
doi: 10.1111/cei.12038.

V体育平台登录 - Tolerogenic dendritic cell therapy for rheumatoid arthritis: where are we now?

C M U Hilkens  1 , J D Isaacs
Affiliations
Review

"V体育平台登录" Tolerogenic dendritic cell therapy for rheumatoid arthritis: where are we now?

C M U Hilkens et al. Clin Exp Immunol. 2013 May.

Abstract

Dendritic cells with tolerogenic function (tolDC) have become a promising immunotherapeutic tool for reinstating immune tolerance in rheumatoid arthritis (RA) and other autoimmune diseases VSports手机版. The concept underpinning tolDC therapy is that it specifically targets the pathogenic autoimmune response while leaving protective immunity intact. Findings from human in-vitro and mouse in-vivo studies have been translated into the development of clinical grade tolDC for the treatment of autoimmune disorders. Recently, two tolDC trials in RA and type I diabetes have been carried out and other trials are in progress or are imminent. In this review, we provide an update on tolDC therapy, in particular in relation to the treatment of RA, and discuss the challenges and the future perspectives of this new experimental immunotherapy. .

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Figures

Fig. 1
Fig. 1
Generation of tolerogenic dendritic cells (tolDC). Peripheral blood CD14+ monocytes are cultured with interleukin (IL)-4 and granulocyte–macrophage colony-stimulating factor (GM-CSF) to generate immature DC. On day 3 of culture, cells receive fresh medium containing IL-4, GM-CSF and dexamethasone (Dex). After 6 days of culture monocytes will have differentiated into immature DC. These immature DC are then treated with Dex, vitamin D3 (VitD3) and a Toll-like receptor (TLR)-4 agonist [e.g. lipopolysaccharide (LPS) or for therapeutic grade tolDC, the current good manufacturing practice (cGMP)-compatible monophosphoryl lipid A] for 24 h to generate tolDC. During the final 24 h synovial fluid (SF) can be added to the cultures as a source of joint-associated autoantigen. The box summarizes typical tolDC features: +++ high expression; ++ intermediate expression; + low expression; +/– very low but detectable expression; – undetectable expression.
Fig. 2
Fig. 2
Autologous dendritic cells (DC) for rheumatoid arthritis (RA) (AUTODECRA) trial. The diagram depicts the autologous nature of tolerogenic dendritic cell (tolDC) treatment: monocytes are isolated from the patient's own peripheral blood product obtained by leucopheresis, cultured ex vivo under current good manufacturing practice (cGMP) conditions to generate tolDC (as depicted in Fig. 1) and injected into the patient's knee joint under arthroscopic guidance. The boxes summarize the procedures at different time-points during the trial (anti-clockwise). The trial starts 14 days before the patient is injected with tolDC (day −14). The patient is screened for mandatory disease markers to ensure a clean blood product in the cGMP facilities. Synovial fluid (SF) is collected as a source of joint-associated antigens and is added to the tolDC culture (see Fig. 1). Patient assessment takes place at this and other time-points during the trial (see boxes) and includes a knee assessment, health questionnaire and establishment of the disease activity score of 28 joints (DAS28). Peripheral blood samples (for collection of immune cell and serum) and synovial biopsies for biomarker analyses are taken before and after tolDC treatment (see boxes). If no serious adverse effects of tolDC are observed (e.g. knee flare) the study closes on day 91.
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