Researchers from the Germans Trias i Pujol Institute and the Josep Carreras Leukaemia Research Institute in Barcelona have discovered a promising new approach to enhance multiple sclerosis (MS) treatment through an innovative combined therapy. The findings, published in the Journal of Clinical Investigation, draw from two aligned Phase I clinical trials supported by the European Union, focusing on the role of Vitamin D3 tolerogenic dendritic cells (VitD3-tolDCs) in modulating the immune response of MS patients. The researchers are gearing up to initiate Phase II trials to delve deeper into these discoveries.
Multiple Sclerosis (MS) is a chronic condition where the immune system mistakenly attacks the protective myelin sheath surrounding nerve cells. This damage leads to impaired nerve function and increased disability. Current treatments, such as immunosuppressants, can lessen these harmful immune attacks but also weaken the immune system overall, making patients more susceptible to infections and cancers. Researchers are now investigating a more targeted treatment option using specialized immune cells, known as tolerogenic dendritic cells (tolDCs), derived from the same patients.
TolDCs have the potential to restore immune balance while preserving the body’s natural defenses. However, given that MS is characterized by immune dysfunction, the effectiveness of these cells for autologous transplantation may be limited. Thus, a deeper understanding of how the disease influences the preparation of these cells for therapy is crucial before implementing this treatment.
The study presented in the Journal of Clinical Investigation evaluated CD14+ monocytes, mature dendritic cells (mDCs), and Vitamin D3-modified tolerogenic dendritic cells (VitD3-tolDCs) obtained from MS patients who had not received any treatment and from healthy individuals. The clinical trials (NCT02618902 and NCT02903537), conducted in Spain by Dr. Cristina Ramo-Tello and Dr. Eva MartÃnez Cáceres (of the Germans Trias i Pujol Research Institute), aim to evaluate the effectiveness of VitD3-tolDCs, which are infused with myelin antigens to “educate” the immune system to cease its attacks on the nervous system. This innovative approach seeks to employ a patient’s unique immune cells, modified to foster immune tolerance, as a therapeutic means to address MS’s autoimmune characteristics.
The research team, led by Dr. Eva Martinez-Cáceres and Dr. Esteban Ballestar (Josep Carreras Institute), with Federico Fondelli as the lead author, observed that immune cells from MS patients (monocytes, which are precursors to tolDCs) exhibit a lasting “pro-inflammatory” signature, even after they are converted into VitD3-tolDCs, the therapeutic cell type. This persistent signature hampers the effectiveness of these cells compared to those derived from healthy donors, thus limiting their potential advantages.
Utilizing advanced research techniques, the team identified a pathway, named the Aryl Hydrocarbon Receptor (AhR), associated with this altered immune response. When an AhR-modulating medication was applied, the researchers successfully restored the normal functionality of VitD3-tolDCs from MS patients in vitro. Notably, Dimethyl Fumarate, an existing medication for MS, was found to replicate the effects of AhR modulation, restoring the full functionality of these cells while maintaining a safer toxicity profile.
Moreover, experiments conducted with MS animal models indicated that combining VitD3-tolDCs with Dimethyl Fumarate produced superior outcomes compared to using either treatment alone. This combination treatment significantly alleviated symptoms in mice, implying greater potential for effective treatment in humans.
These findings may pave the way for a new, more powerful treatment option for multiple sclerosis, offering renewed hope to the millions struggling with this challenging condition worldwide. This research marks a substantial advancement in the development of personalized cell therapies for autoimmune disorders, potentially transforming the landscape of multiple sclerosis treatments.
This investigation received partial funding from public resources provided by the Spanish Government (ISCIII, FEDER, and MICINN) and the EU Horizon program (INsTRuCT and RESTORE projects). No artificial intelligence tools were utilized in composing this text.
