Immune modulation and Immunomonitoring
Group leader: Anja ten Brinke PhD
Immune activation by dendritic cells
Dendritic cells (DCs) are the most important antigen presenting cells in our body and are able to direct the development of immune responses. Therefore the application of ex vivo generated DCs has potential to treat diseases which need activation of the immune system, e.g. cancer or chronic infections, or to inhibit immune reactions which are unwanted, e.g. in autoimmunity or transplantation.
Clinical applicable DCs
We developed a new clinical grade DC maturation cocktail consisting of monophosphoryl lipid A (MPLA) and IFNγ to generate monocyte-derived DCs as a cellular vaccine against cancer. MPLA/IFNγ DCs produce IL-12p70, induce Th1 cells and induce antigen specific cytotoxic T cells with high cytolytic potential (Ten Brinke, Vaccine 2007, Ten Brinke, Cancer Immunol Immunother 2010, Kolanowski Innate Immune 2014, Kolanowski Cytotherapy 2014, Kolanowski submitted). Besides we compared several approaches to generate clinical-grade tolDCs (e.g. vitamin D3, IL-10, dexamethasone, TGFβ or rapamycin) [Boks Scan J Immunol 2010, Boks Clin Immunol 2012]. All tDCs were shown to be highly stable in pro-inflammatory environments, however IL-10 tolDCs show the best tolerogenic potential with high IL-10 production, low memory T cell activation and strong Treg induction from naïve T cells. Thus, clinical-grade IL-10 tolDCs show functional characteristics that make them very suitable for tolerance-inducing therapies in transplantation or autoimmunity. Furthermore we observed that Treg induction by tolDCs is more efficient when combined with anti-TNFα treatment [Boks Clin Immunol 2014].
Currently we study the Tregs induced by the IL-10 tolDCs in more detail, both phenotypically and functionally.
Regulation of DC function by C5a
The complement anaphylatoxin C5a has been implicated in regulation of adaptive immune responses through modulation of APC function as shown mainly in studies in mice. C5a was shown to enhance cytokine production in immature DCs, but the effect of C5a on DC function during DC activation has not been elucidated in human. We investigated the effect of C5a on human monocyte-derived DCs when simultaneously stimulated with TLR ligands. Whereas C5a indeed enhanced cytokine production of immature DCs, the addition of C5a inhibited production of IL-12, IL-23 and TNFα induced by various TLR ligands such as LPS, R848 and Pam3CSK4 (Zaal, Immunobiology 2012). These data emphasize the complexity of DC regulation by anaphylatoxins. While complement activation may provide proinflammatory signals to immature DCs in the absence of pathogens, the same products may serve to down modulate or deviate immune responses upon combat against infections. Currently we perform unbiased RNA-seq analysis to elucidate in more detail which and how APC functions are affected by C5a.
Regulation of DC function by platelets
Platelets are typically known for their role in primary hemostasis but are increasingly acknowledged for their role in modulating immune responses by chemokine and cytokine release upon activation. Furthermore platelets can express adhesion molecules involved in interactions with immune cells. Platelets have been shown to affect the maturation phenotype of DC, but it is unknown if this also changes the further DC mediated adaptive immune response. We therefore investigate the effect of platelets on monocyte-derived DC maturation, the phagocytic capacity of the latter and most important their ability to stimulate antigen-specific T cells.
Immunomonitoring assays are becoming increasingly important now there is a rapid increase in development of therapies that target or affect the immune system. It can provide proof of mechanism for your drug in development, exploratory additional data during your trials and help select relevant patients. Important steps have been made in the field of immunotherapy, where therapy directly depends on the action of the immune system to achieve efficacy. The current trend is development of ‘tailor-made’ therapies, where patients will receive treatments that are best suited to fit their specific disease. The overall aim is to increase treatment efficiency, lowering the burden of therapy and enhance cost-effectiveness. Tailor-made therapies require tailor-made studies. Sanquin offers expertise in immunomonitoring, from study design and execution to tailored-made assays for patient selection and monitoring for therapy efficacy.
The characterization of CD4+ T cells is crucial for understanding their role in immunotherapeutic approaches such as vaccinations or tolerizing therapies. Currently we are developing assays to monitor antigen-specific CD4 T cell responses in a detailed manner.
- Kolanowski ST, Dieker MC, Lissenberg-Thunnissen SN, van Schijndel GM, van Ham SM, Ten Brinke A. TLR4-mediated pro-inflammatory dendritic cell differentiation in humans requires the combined action of MyD88 and TRIF. Innate Immun 2014; 20(4):423-30.
- Boks MA, Kager-Groenland JR, Mousset CM, van Ham SM, ten Brinke A. Inhibition of TNF receptor signalling by anti-TNFα biologicals primes naïve CD4+ T cells towards IL-10+ T cells with a regulatory phenotype and function. Clin Immunol 2014; 151(2):136-45.
- Paul P, van den Hoorn T, Jongsma M, Bakker M, Hengeveld R, Cresswell P, Egan D, van Ham M, Brinke A, Ovaa H, Beijersbergen R, Kuijl C, Neefjes J. Genome-wide siRNA screen identifies novel pathways controlling MHC class II antigen presentation. Cell 2011; 145:268-83.
- Boks MA, Kager-Groenland JR, Haasjes MSP, Zwaginga JJ, van Ham SM, ten Brinke A. IL-10-generated tolerogenic dendritic cells are optimal for functional regulatory T cell induction – A comparative study of human clinical-applicable DC. Clin Immunol 2012; 142(3):332-42.
- Zaal, Lissenberg-Thunnissen, van Schijndel, Wouters, van Ham, en Brinke. Crosstalk between Toll like receptors and C5a receptor in human monocyte derived DCs suppress inflammatory cytokine production. Immunobiology 201;218(2):175-80.