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Tolerogenic immunotherapy with peptide-pulsed dendritic cells in rheumatoid arthritis

Periodic Reporting for period 1 - TIPPDECRA (Tolerogenic immunotherapy with peptide-pulsed dendritic cells in rheumatoid arthritis)

Reporting period: 2016-05-05 to 2018-05-04

Rheumatoid arthritis (RA) is a disabling and painful disease of the joints. It affects roughly 1 in 400 people world-wide; but in certain regions (Western Europe, North America) it can affect as many as 1 in 160 females. Globally, RA has been ranked as the 42nd highest contributor to disability (out of 291 conditions) – just below malaria. RA is caused by the patient’s own immune system attacking the joints. Although current treatments can be effective at alleviating symptoms they do not provide a cure and the associated general immunosuppression can cause unwanted side effects. We previously developed a new treatment aiming to restrain the immune attack on the joints long-term. The idea behind this new treatment is that the patient’s immune system can be re-educated so that the immune attacks come to a halt, i.e. the immune system becomes tolerant. This can be achieved by treatment with so-called tolerogenic dendritic cells (tolDC). We have developed a robust method to generate these tolDC from the blood of RA patients and subsequently inject them back into a rheumatic knee joint. We recently completed a phase I clinical trial with these tolDC showing that this new cellular therapy is safe. However, in order to take the next step and conduct further trials to demonstrate that tolDC effectively reduce arthritis, we need to improve the treatment to maximise the likelihood of success. This can be achieved by specifically targeting the tolDC to relevant joint components that we know are being attacked by the immune system in RA patients. For this study we used heat shock proteins (HSP) as the relevant joint specific component. Previous studies have shown that certain heat shock proteins are present in the rheumatic joint and become an easy target for destructive immune attacks. Our goal is to stop these attacks by targeting tolDC to these HSP; this can be achieved by ‘loading’ tolDC with the relevant HSP.

The objectives of this research were:
1) to select small, relevant heat shock protein components (called HSP-peptides) that can be loaded onto tolDC
2) to show that these HSP-peptide-loaded tolDC can tolerise immune cells from RA patients
3) to study weather HSP-loaded tolDC are capable of ameliorating disease severity in a mouse model of rheumatoid arthritis
To achieve these objectives, we have produced research results of high quality and we are currently in the process of publishing them in international journals.
• We found 4 different HSP-peptides that could be recognised by immune cells – T cells – from blood in 80% of RA patients and healthy donors. These immune cell responses were of a pro-inflammatory nature, meaning that they can potentially cause harm after binding the HSP-peptide.
• We added tolDC to these cultures to determine whether tolDC could make these same T cells harmless – and make them instead produce immune mediators that can ‘turn off’ other pro-inflammatory – i.e. harmful – immune cells. Indeed, in this research we showed that tolDC can activate these HSP-recognising T cells in such a way that they now produce anti-inflammatory mediators that can potentially suppress harmful immune cells in the arthritic joints.
• Interestingly, when studying the other immune cells also present in the culture, we found that the tolDC also directly suppressed other harmful immune cells by secreting specific anti-inflammatory mediators named TGFβ. The tolDC could severely inhibit these cells from proliferating/multiplying and thereby potentially reduce destruction in the joint.
• We then investigated whether the HSP-peptide-loaded tolDC could suppress disease in a mouse model of arthritis. Indeed, we found that tolDC injected prior to disease induction could significantly suppress disease as compared to mice that did not receive tolDC. However, more work is needed to understand how tolDC affect the immune response in vivo.
The work performed during this fellowship will strongly underpin further clinical trials with tolDC in RA patients. In fact, the results were part of two successful funding applications; a new clinical trial with tolDC, led by Dr. Hilkens and Professor Isaacs (at the University of Newcastle, UK; funded by Arthritis Research UK), and another clinical phase I/II trial, led by Professors van Eden, Broere and van Laar (Utrecht University, The Netherlands, funded by the Reumafonds, ZonMW and Health Holland). One of the peptides tested in this fellowship will be used for tolDC loading, and the experimental methods we developed will be used to study tolDC efficiency in RA patients.
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