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A novel dendritic cell therapy in autoimmunity: preparing for a clinical trial using B29/tolDC for rheumatoid arthritis

Friday 24 July 2015

A novel dendritic cell therapy in autoimmunity: preparing for a clinical trial using B29/tolDC for rheumatoid arthritis
A collaborative project between the UMCU (rheumatology) and UU Veterinary Faculty.

A novel therapy for rheumatoid arthritis (RA) consists of autologous dendritic cells in vitro loaded with antigens and made tolerogenic (tolDC) prior to re-administering into the patient. The Hilkens group (Newcastle) has completed a phase 1 trial with tolDC in RA patients, and demonstrated that the therapy is safe. However, in order to take the next step and conduct a phase 2 efficacy trial, it is needed to establish a more tractable method of loading tolDC with specific (auto)antigens that both tolerises arthritogenic effector T-cells, and induces disease suppressive regulatory T-cells (Treg). Current use of autologous synovial fluid as a source of autoantigen restricts patient selection for such tolDC trials, particularly excluding patients with early RA who would be the ideal target group for tolerogenic therapies.
Heat-shock proteins (Hsp) may provide a unique alternative source of antigens. They are up-regulated by cells in inflamed tissues. HSP peptides effectively down-regulate a variety of autoimmune inflammatory diseases and in humans, where the actual disease trigger is frequently unknown and variable, they may offer chances for antigen-specific therapy. In several arthritis models (adjuvant, avridine, collagen or proteoglycan-induced arthritis) Hsp administration suppressed arthritis via the induction of Hsp specific regulatory T-cells. Recently we showed that the Hsp70 peptide B29 induced powerful CD4+CD25+Foxp3+ Treg (van Herwijnen et al. PNAS 2012). Upon transfer, B29-induced CD4+CD25+Foxp3+ T-cells suppressed established PGIA in mice. Transferred cells exhibited a stable phenotype and were found in joints and draining lymph nodes up to two months after transfer. Altogether, B29 can serve as a therapeutic vaccine, based on a unique quality to mobilize anti-inflammatory T-cell activities. In humans B29 is a promiscuous binder for all major HLA-II molecules, HLA- DRB1*04:01 in particular. Also in humans B29 specific Treg are detected.

For this project the student will: Optimize the protocol for generating tolerizing DCs
Monitor the induction of B29 specific Tregs with MHCII tetramers
Develop the assays to measure the quality of induced tolerant T cells

The following techniques will be used:

Isolation and propagation of dendritic cells
Cell culture (incl. co-cultures of DC and T cells)
Tetramer tracking of CD4+ T cells
Functional T cell suppression assays
Fluorescence activated flow cytometry (FACS)

Duration: 6 or 9 months

Contact: Dr. Femke Broere (f.broere@uu.nl); Prof. Willem van Eden (w.vaneden@uu.nl)