Researchers have found that combining tolerogenic dendritic cells with Dimethyl Fumarate improves treatment efficacy for multiple sclerosis, offering a promising new approach for managing the disease.
Multiple sclerosis (MS) is a chronic condition in which the immune system erroneously assaults the myelin sheath, the protective coating around nerve cells, leading to nerve damage and increased disability. Existing treatments such as immunosuppressants mitigate these attacks but compromise the immune system, making patients more susceptible to infections and cancer. Researchers are investigating a new, more targeted approach that involves using a type of immune cell called tolerogenic dendritic cells (tolDCs), derived from the patients themselves, to target the disease more precisely.
TolDCs can restore immune balance without affecting the body’s natural defenses. However, since a hallmark of MS is precisely the dysfunction of the immune system, the effectiveness of these cells for autotransplantation might be compromised. Therefore, it is essential to better understand how the disease affects the starting material for this cellular therapy before it can be applied.
In this study, published at the prestigious Journal of Clinical Investigation, researchers examined CD14+ monocytes, mature dendritic cells (mDCs), and Vitamin D3-treated tolerogenic dendritic cells (VitD3-tolDCs) from MS patients who had not yet received treatment, as well as from healthy individuals.
Personalized Treatment Using Immune Cells
The clinical trials (NCT02618902 and NCT02903537), led in Spain by Dr. Cristina Ramo-Tello and Dr. Eva Martínez Cáceres (Germans Trias i Pujol Research Institute), are designed to assess the effectiveness of VitD3-tolDCs, which are loaded with myelin antigens to help “teach” the immune system to stop attacking the nervous system. This approach is groundbreaking as it uses a patient’s own immune cells, modified to induce immune tolerance, in an effort to treat the autoimmune nature of MS.
The study, led by Dr. Eva Martinez-Cáceres and Dr. Esteban Ballestar (Josep Carreras Institute), with Federico Fondelli as first author, found that the immune cells from MS patients (monocytes, precursors of tolDCs) have a persistent “pro-inflammatory” signature, even after being transformed into VitD3-tolDCs, the actual therapeutic cell type. This signature makes these cells less effective compared to those derived from healthy individuals, missing part of its potential benefits.
A Potential Solution: Aryl Hydrocarbon Receptor Modulation
Using state-of-the-art research methodologies, the researchers identified a pathway, known as the Aryl Hydrocarbon Receptor (AhR), that is linked to this altered immune response. By using an AhR-modulating drug, the team was able to restore the normal function of VitD3-tolDCs from MS patients, in vitro. Interestingly, Dimethyl Fumarate, an already approved MS drug, was found to mimic the effect of AhR modulation and restore the cells’ full efficacy, with a safer toxic profile.
Finally, studies in MS animal models showed that a combination of VitD3-tolDCs and Dimethyl Fumarate led to better results than using either treatment on its own. This combination therapy significantly reduced symptoms in mice, suggesting enhanced potential for treating human patients.
These results could lead to a new, more potent treatment option for multiple sclerosis, offering hope to the millions of patients worldwide who suffer from this debilitating disease. This study represents a significant step forward in the use of personalized cell therapies for autoimmune diseases, potentially revolutionizing how multiple sclerosis is treated.
Reference: “Targeting aryl hydrocarbon receptor functionally restores tolerogenic dendritic cells derived from patients with multiple sclerosis” by Federico Fondelli, Jana Willemyns, Roger Domenech-Garcia, Maria José Mansilla, Gerard Godoy-Tena, Anna G. Ferreté-Bonastre, Alex Agúndez-Moreno, Silvia Presas-Rodriguez, Cristina Ramo-Tello, Esteban Ballestar and Eva Martínez-Cáceres, 17 September 2024, The Journal of Clinical Investigation.
DOI: 10.1172/JCI178949
This research has been partly funded by public funds from the Spanish Government (ISCIII, FEDER, and MICINN) and the EU Horizon program (INsTRuCT and RESTORE projects).