Dendritic cells are central players of the immune response and they have the unique ability to activate naïve T-cells. They can either induce immunity or establish tolerance by interacting with multiple cells of the immune system. Like this, dendritic cells are crucial in maintaining the balance between attacking pathogens or foreign molecules and sparing the body’s own tissue.
In autoimmune diseases, this tolerance against self-tissue has broken down. Worldwide, it is estimated that approximately 1 in 15 individuals suffers from autoimmune disease. Existing therapies against autoimmune diseases mostly include treatment with non-specific immunomodulatory drugs. Those systematically suppress the function of many immune effector cells and therefore often cause serious and sometimes life-threating side effects. There is an urgent need of more disease-specific treatments and for treatments that have a curative effect and help to re-establish the tolerance against self-antigens.
Tolerogenic DCs (tolDCs) are essential in the maintenance of central and peripheral tolerance by induction of clonal T-cell deletion and anergy, inhibition of memory and effector T-cell responses and generation and activation of regulatory T-cells. TolDC therefore are promising candidates for the re-establishing of a permanent antigen-specific tolerance.
In the last years, researchers have developed many protocols for the in vitro generation of potent and stable tolerogenic dendritic cells from monocytes. TolDC cells can be induced from immature monocyte derived dendritic cells i. e. by:
- Pharmacological agents: using immunosuppressive drugs like corticosteroids, rapamycin, aspirin or Vitamin D3
- Cytokines: incubation with TGF-beta or IL-10 or a combination of both
- Genetic engineering: recombinant expression of apoptosis inducing elements, such as FasL PD-L1 and TRAIL or suppression of NF-Kappa etc
For a review see i.e. in Domogalla et al Front. Immunol. 2017
In the publication of Zubizarreta et al in PNAS the authors describe a phase 1b clinical trial to investigate the safety and feasibility of tolDC therapy for the CNS-related autoimmune disorders Multiple Sclerosis and Neuromyelitis optica with peptide-loaded tolerogenic dendritic cells.
Autologous tolerogenic dendritic cells have been generated from patients PBMCS under GMP compliant conditions using the Lonza X-VIVOTM Medium. In the protocol, GM-CSF and IL-4 have been used for differentiation and addition of Dexamethasone for the induction of the regulatory phenotype. TolDC from MS patients were loaded with seven myelin peptides and DC from NMOSD patients were stimulated with peptides from AQP4 patients
As primary endpoint, the safety of CNS-peptide loaded tolDC therapy was tested and as a secondary endpoint, signs of efficacy and markers of immune tolerance in treated patients with MS and NMOSD were determined. More information on the clinical trial can be found in the National Clinical Trial No NCT02283671
The researchers showed, that i. v. administration of peptide-loaded tolDC is safe and feasible. Immunological assessment confirmed the induction of Tr1 cells producing high levels of IL-10. This is the basis for future trials to determine if the observed increase of regulatory T-cells and IL-10 production can modify the disease course in MS or NMODS.
Currently, two further phase I clinical trials for tolerogenic dendritic cell-based treatment for multiple sclerosis are running (Trial registration numbers NCT02618902 and NCT02903537) described in Willekens et al, BMJ Open 2019. In the two harmonized trials two different routes of cell administration (intradermal vs intranodal) are compared. In this study, VitD3-treated tolDC loaded with myelin-peptides are prepared from leukapheresis from MS patients.
Results from phase I clinical trials using tolDC also in other autoimmune disease (review for example) also showed promising results with regards to safety of administration. Future phase II trials will need to investigate the efficacy of these patient-tailored treatments. I am excited to see, if tolerogenic dendritic cells with become a new tool for treatment of autoimmune diseases.
Written by SST
