Under natural circumstances, regulatory T-cell induction occurs to protect the body from overreacting to e.g. infection. In case of autoimmune diseases, these mechanisms are malfunctioning. Our approach is to mimic this natural self-controlling system by actively immunizing with the peptide B29 derived from heat shock protein (HSP), which has been shown to induce regulatory T-cells in vivo. Such T-cells are both prophylactically and therapeutically active. As physiological (natural) mechanisms of immunity are involved, the treatment concept can be considered as a (therapeutic) vaccine, and leads to the cure of the disease as opposed to transient suppression of symptoms.
Thus, the basic principle that underpins the therapy is to educate tolerance-invoking regulatory T-cells. An orchestrated series of events needs to happen to achieve this, and hence to allow it to be an effective approach to treatment of RA.
The approach to be used in the clinic will be as follows:
- The presence of tolerogenic B29-specific Treg-cells in the patient is verified with specific assays
- The patient is treated with anti-TNF (or other biologicals) to induce a state of disease remission
- Dendritic cells (DCs) are obtained from the patient by expanding peripheral blood obtained monocytes with growth factors ①, using standardized protocols.
- The dendritic cells are ex-vivo made into tolerizing DCs with Vitamin D/dexamethasone and loaded with B-29 ②, so that they can present this epitope to regulatory T-cells
- The cells are re-introduced into the patient ③ (remission allows for better tolerance induction)
- The epitope is presented to Treg-cells by the tolerizing DCs ④, to activate the tolerogenic cells
- The patient now has a Treg repertoire that naturally suppresses inflammation ⑤ (in the joint)