Cryopreserved vitamin D3-tolerogenic dendritic cells pulsed with autoantigens as a potential therapy for multiple sclerosis patients

Abstract

BackgroundTolerogenic dendritic cells (tolDC) have been postulated as a potent immunoregulatory therapy for autoimmune diseases such as multiple sclerosis (MS). In a previous study, we demonstrated that the administration of antigen-specific vitamin D3 (vitD3) tolDC in mice showing clinical signs of experimental autoimmune encephalomyelitis (EAE; the animal model of MS) resulted in abrogation of disease progression. With the purpose to translate this beneficial therapy to the clinics, we have investigated the effectivity of vitD3-frozen antigen-specific tolDC pulsed with myelin oligodendrocyte glycoprotein 40-55 peptide (f-tolDC-MOG) since it would reduce the cost, functional variability and number of leukapheresis to perform to the patients.MethodsMice showing EAE clinical signs were treated with repetitive doses of f-tolDC-MOG. Tolerogenic mechanisms induced by the therapy were analysed by flow cytometry and T cell proliferation assays.ResultsTreatment with f-tolDC-MOG was effective in ameliorating clinical signs of mice with EAE, inhibiting antigen-specific reactivity and inducing Treg. In addition, the long-term treatment was well tolerated and leading to a prolonged maintenance of tolerogenicity mediated by induction of Breg, reduction of NK cells and activation of immunoregulatory NKT cells.ConclusionsThe outcomes of this study show that the use of antigen-specific f-tolDC promotes multiple and potent tolerogenic mechanisms. Moreover, these cells can be kept frozen maintaining their tolerogenic properties, which is a relevant step for their translation to the clinic. Altogether, vitD3 f-tolDC-MOG is a potential strategy to arrest the autoimmune destruction in MS patients.

Tolerogenic Dendritic Cells Generated with Tofacitinib Ameliorate Experimental Autoimmune Encephalomyelitis through Modulation of Th17/Treg Balance

“…Because of these contradictory results, we suggested that the adoptive transfer of tofacitinib modified DCs for the treatment of MS may be a better choice than the administration of tofacitinib directly. Moreover, Mansilla et al reported that cryopreservation did not affect typical characters of tolerogenic dendritic cells, which made this field particularly exciting [35]. Furthermore, the major barrier of tolDC-mediated immunotherapy in autoimmune diseases was the identification of autoantigen loaded onto the tolDCs [36].…”

Targeting of tolerogenic dendritic cells towards heat‐shock proteins: a novel therapeutic strategy for autoimmune diseases?

“…Efforts have been made to translate these findings from animal studies to the clinical setting. Good Manufacturing Protocols to generate tolDCs from human donor cells have been developed, and methods to preserve the tolDCs and reduce the production costs are being explored . As there are diverse methods of generating tolDCs and other types of tolerogenic APC (tolAPCs), a minimum information model for tolAPC (MITAP) was generated.…”

“…These different types of tolDCs have been shown to reduce or prevent autoimmune diseases or transplant rejection in animal models, providing important proof of principle evidence that these cells can be applied therapeutically. 27,[29][30][31][32][33] Their therapeutic benefit is associated with a reduction of proinflammatory effector T cells and natural killer cells, and the induction of Treg cells or IL-10-producing T cells. 27,29,[34][35][36] Efforts have been made to translate these findings from animal studies to the clinical setting.…”

“…27,[29][30][31][32][33] Their therapeutic benefit is associated with a reduction of proinflammatory effector T cells and natural killer cells, and the induction of Treg cells or IL-10-producing T cells. 27,29,[34][35][36] Efforts have been made to translate these findings from animal studies to the clinical setting. Good Manufacturing Protocols to generate tolDCs from human donor cells have been developed, 26,37 and methods to preserve the tolDCs and reduce the production costs are being explored.…”

Checkpoints to the Brain: Directing Myeloid Cell Migration to the Central Nervous System

“…Although dendritic cells have long been recognized as potent antigen-presenting cells, it has only recently been discovered that they can also regulate autoreactive T cells via the induction of apoptosis, or by modulating their phenotype towards a T-regulatory (Treg) cell profile [172]. Despite challenges with inducing a stable tolerogenic phenotype in vitro, one laboratory has developed a method of inducing human and mouse tolDCs [173,174], and has successfully applied MOG-loaded tolDCs to a mouse model of EAE with promising results [174,175]. Further research, in particular the upcoming phase I clinical trial (NCT02618902), is anticipated with interest.…”