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Towards the clinical use of tolerogenic dendritic cells in multiple sclerosis by applying the immunomodulatory effects of 1,25-dihydroxyvitamin D3

Nathalie Cools1*, Wai Ping Lee1, Maxime De Laere1, Barbara Willekens2, Judith Derdelinckx1, 2, Griet Nijs3, Patrick Cras2, Cristina Ramo Tello4, Eva Martinez-Caceres4 and Zwi Berneman1, 3
  • 1 University of Antwerp, Vaccine and Infectious Disease Institute, Belgium
  • 2 Antwerp University Hospital, Division of Neurology, Belgium
  • 3 Antwerp University Hospital, Center for Cell Therapy and Regenerative Medicine, Belgium
  • 4 Universitat Autonoma Barcelona, German Trias i Pujol University Hospital, Spain

We first investigated the effect of 1,25-dihydroxyvitamin D3 (vitD3) on monocyte-derived DC (mo-DC) from healthy controls and MS patients. VitD3 treatment of mo-DC resulted in a maturation-resistant phenotype and anti-inflammatory cytokine profile as compared to conventional immunogenic DC, in both healthy controls and MS patients. Importantly, vitD3-treated DC induced T cell hyporesponsiveness, as demonstrated by a reduced ability to induce interferon-γ secretion by allogeneic peripheral blood lymphocytes stimulated with vitD3-treated DC as compared with conventional DC. We also investigated the influence of cryopreservation on the phenotype and allogeneic T cell stimulatory capacity of vitD3-treated DC. Following a freeze-thaw cycle, vitD3-treated immature DC could be recovered with a 78% yield and 75% viability. Cryopreservation did not affect the expression of DC membrane markers by vitD3-treated DC nor their capacity to induce T cell hyporesponsiveness in an allogeneic mixed leukocyte reaction. The T cell hyporesponsiveness induced by vitD3-treated DC is antigen-specific since T cells retained their capacity to respond to an unrelated antigen, i.e. cytomegalovirus pp65-derived peptides, while being unresponsive to myelin-derived peptides following tolerization to a myelin oligodendrocyte glycoprotein (MOG)-derived peptide pool and a myelin basic protein (MBP)-derived peptide pool. Furthermore, these T cells did not reactivate upon rechallenge with fully mature conventional DC, demonstrating that this induced T cell hyporesponsiveness was robust. Based on our observations, it can be concluded that vitD3 treatment of DC results in the generation of highly potent toleranceinducing DC (tolerogenic DC (tolDC)). Importantly, we demonstrate the feasibility of cryopreservation of these tolDC. In this perspective, our results contribute to large scale production and preservation of tolDC and further underscore their potential clinical applicability in order to correct the immunological imbalance in auto-immune disease in general and in MS in particular. These data suggest that DC play an important role in MS and that it can be envisaged to develop a new form of immunotherapy for this disease, using tolerogenic DC. Currently, we are initiating a phase I dose escalation clinical study to assess the feasibility and safety of administering myelin-derived peptide-pulsed tolDC in patients with MS. Short summary Cell therapy is rapidly gaining momentum as a clinical option for several diseases. In particular, the clinical benefit and safety of dendritic cell-based immunotherapy has been well-documented in numerous clinical trials in patients with cancer and infectious diseases. More recently, tolerance-inducing or tolerogenic dendritic cells (tolDC) have also become a promising immunotherapeutic tool for restoring immune tolerance in autoimmune diseases, including multiple sclerosis (MS). While Our recent observations indicate that dendritic cells (DC) play a central role in the pathogenesis of multiple sclerosis (MS), their modulation with immunoregulatory agents provides a prospect as disease-modifying therapy Samenvatting in het Nederlands Het gebruik van lichaamseigen cellen als medicijn zou heel wat mogelijkheden kunnen bieden voor de behandeling van ernstige en slopende aandoeningen. In het bijzonder, zou vaccinatie met dendritische cellen die de afweerreactie kunnen onderdrukken - tolerogene dendritische cellen - in de nabije toekomst een belangrijke piste kunnen worden in de aanpak van multiple sclerose. Dendritische cellen (DC) zijn een gespecialiseerde populatie van witte bloedcellen en functioneren als de aan- en uitzetknop van het afweersysteem. Gebaseerd op onze eerdere bevindingen zullen we voorlopercellen van de dendritische cellen isoleren uit het bloed van de patiënt. Deze cellen worden daarna gekweekt met vitamine D in een steriele en ultramoderne laboratoriumomgeving. Vervolgens kunnen ze terug aan de patiënt worden toegediend. Deze behandelingsstrategie zal bij een eerste groep van patiënten met multiple sclerose getest worden. Résumé en Français: La thérapie cellulaire (remplacement/modification de cellules malades par des cellules souches) est une voie thérapeutique nouvelle prometteuse. Dans le cas de la sclérose en plaques (SP), une maladie auto-immune (maladie où les cellules de défense attaque les cellules du SOI), il a été récemment découvert que de telles cellules, appelées dendritiques, étaient une cible thérapeutique car responsables de cette auto-immunité. Dans ce travail, notre équipe a montré que les cellules dendritiques de patients atteints par la SP pouvaient modifiées (rendues tolérantes) grâce à un traitement à la vitamine D.

Keywords: tolerance, Dendritic Cells, Multiple Sclerosis, cell therapy, Vitamin D

Conference: 6th Belgian Brain Congress, MONS, Belgium, 8 Oct - 8 Oct, 2016.

Presentation Type: Oral Presentation

Topic: Brain and brain diseases: between heredity and environment

Citation: Cools N, Lee W, De Laere M, Willekens B, Derdelinckx J, Nijs G, Cras P, Ramo Tello C, Martinez-Caceres E and Berneman Z (2016). Towards the clinical use of tolerogenic dendritic cells in multiple sclerosis by applying the immunomodulatory effects of 1,25-dihydroxyvitamin D3. Conference Abstract: 6th Belgian Brain Congress. doi: 10.3389/conf.fnagi.2016.03.00045

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Received: 29 Jun 2016; Published Online: 05 Jul 2016.

* Correspondence: Prof. Nathalie Cools, University of Antwerp, Vaccine and Infectious Disease Institute, Edegem, 2650, Belgium, Nathalie.Cools@uza.be