Immune modulation by dendritic cells

Project leaders: Anja ten Brinke PhD and Prof S Marieke van Ham PhD

Immune activation by dendritic cells

In this research line we are developing clinically approved, validated, and cost-efficient monocyte-derived DC products. For the development of immuno-activatory DCs we extended our research on our DC maturation-cocktail, MPLA plus IFNγ. Previously, we demonstrated that these DCs can migrate, produce IL-12 and induce high percentage of specific and highly cytotoxic CTLs against tumor antigens. In addition, the DCs are also able to reactivate these tumor-specific CTLs in blood derived from melanoma patients. Furthermore we have shown that the MPLA plus IFNγ matured DCs produce a high level of the effector cell attracting chemokine CXCL10 and low levels of the Treg attracting chemokine CCL22. These data indicate that the MPLA/IFNγ DCs in vivo will preferentially activate inflammatory T cells and will likely not induce unwanted activation of Tregs during immunotherapy. Together with dr Carlijn Voermans and dr Daphne Thijssen (Stem Cell Laboratory), dr Hans Vrielink (Sanquin Blood Bank), dr Sheila Krishnadath, dr Francesca Milano (Dept of Gastroenterology, AMC) and, prof dr Martien Kapsenberg (Dept of Histology and Cell Biology, AMC) we have continued to set up a phase I/II trial to study the toxicity and use of MPLA plus IFNγ matured DCs in the treatment of patients suffering from esophageal or pancreatic cancer.

In addition, in a more basic research approach we are studying if and how the subcellular trafficking pathways of antigen and TLR regulate the DC effector function upon DC maturation. Furthermore, we are studying the role of complement activation products, such as C3a and C5a, on human DCs and the subsequent adaptive T cell response which is elicited. Studies in mice showed an important role for these factors in regulation of the adaptive immune response.

Immune tolerance and dendritic cells

Tolerogenic dendritic cells (tDC) are a promising tool as specific cellular therapy to maintain or restore immunological tolerance in transplantation and autoimmunity. In transplantation, tDCs need to confer donor-specific suppression, without affecting immune responsiveness to viruses that may be co-transferred with the transplant. Many described tDC types are not clinically applicable and lack systematic comparison of required functional characteristics, i.e. migratory capacity, stable immunosuppressive phenotype and regulatory T cell (Treg) induction. Previously, we generated an optimized assay to assess the suppressive capacity of induced Tregs. We now have generated human clinical-grade tDCs using different tolerance-inducing agents. For an optimal migratory and stable phenotype, co-maturation of tDCs with immunoactivatory compounds was required. All tDCs were shown to be highly stable in pro-inflammatory environments, but IL-10 DCs show the most optimal tolerogenic properties with high IL-10 production, low T cell activation and strong Treg induction. Importantly, IL10 DCs induce alloantigen primed Tregs that suppress allo-responsive T cells, but do not suppress CMV–specific T cell reactivity. Thus, clinically applicable IL-10-generated tolerogenic dendritic cells induce allo-specific tolerance without affecting anti-viral responsiveness, which makes them suitable for tolerance inducing therapies in transplantation.

Key publications