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.
Highlights
Tolerogenic dendritic cells have been postulated as a potent immunoregulatory therapy for autoimmune diseases such as multiple sclerosis (MS)
No alterations of phenotypical and functional characteristics of f-Tolerogenic dendritic cells (tolDC)-myelin oligodendrocyte glycoprotein (MOG) To investigate the applicability of cryopreserved tolDCMOG, cells were generated as previously described [9] and frozen in medium containing 10 % DMSO
In contrast to fresh or frozen immature DCs (iDC) re-stimulated with LPS—which exhibited an increased expression of costimulatory molecules due to their maturation—both, fresh and f-tolDC-MOG showed a stable phenotype (Fig. 2)
Summary
Tolerogenic dendritic cells (tolDC) have been postulated as a potent immunoregulatory therapy for autoimmune diseases such as multiple sclerosis (MS). A new strategy has emerged in order to restore self-tolerance in patients with autoimmune disorders and transplantation This approach consists of personalized therapies using the patient’s own cells manipulated or expanded to perform tolerogenic (tolerogenic antigen-presenting cells (APC)) or Mansilla et al Journal of Neuroinflammation (2016) 13:113 regulatory functions (regulatory macrophages and T cells, Mreg and Treg). Different methodologies have been described to generate tolerogenic DCs (tolDC) ex vivo from human peripheral blood monocytes and murine bone marrow cells (pharmacological treatment, cytokines and genetic engineering) [5] All these types of tolDC share different characteristics such as semimature phenotype—low level of costimulatory molecules and maturation-resistance— and poor stimulation of alloproliferation and induce various tolerogenic mechanisms: induction of T cell anergy, generation of Treg and/or T cells deletion [6, 7]
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