Dendritic cells : tools to induce efficient T cell mediated immunity

Immune responsiveness is carefully regulated. Cells of the immune system have to respond adequately to invading micro-organisms and possibly to transformed cells, but tolerance for the own body constituents needs to be preserved. Dendritic cells (DC) comprise a family of professional antigen presenting cells (APC) that play a central role in the regulation of the immune response. Immature DC, located in the periphery, can efficiently take up Ag, but lack the co-stimulatory signals for effective T-cell activation. Upon maturation, DC migrate to secondary lymphoid organs and increase the expression of co-stimulatory molecules and MHC molecules. Mature DC are very efficient in priming na____ve T-cells. In contrast to their T-cell priming capacity, DC in peripheral tissues constitutively process and present Ag in the absence of pathogen-related or endogenous inflammatory stimuli, and make a major contribution to peripheral tolerance by inducing unresponsiveness or deletion of specific T-cells. The central role of DC in controlling immunity makes these cells attractive tools for many clinical situations that involve T-cells: induction of tolerance in case of transplantation, allergy and autoimmune disease and induction of efficient T-cell responsiveness in case of infection and tumors. Many tumor components do not elicit Ag-specific T-cell responses in patients, which may be due to the absence of functional DC in tumors or the secretion of factors by tumor cells that reduce DC development and function. Application of tumor Ag to DC ex vivo and reinfusion of these DC leads to induction of specific immunity. In animals this strategy can lead to protection against tumors and even a reduction in size of established tumors. At present similar studies are carried out in patients. The research described in this thesis focuses on the requirements for induction of efficient cytotoxic T lymphocyte (CTL)- responses and tumor immunity by DC. Different modes of Ag presentation were studied for the induction of CTL-responses and tumor protection.LUMCSource Flex Care BV; BD BiosciencesDe rol van de T cel immuun respons, gericht tegen tumorantigenen van virale of cellulaire origine, bij bestrijding van tumore

Dendritic cells : tools to induce efficient T cell mediated immunity

Immune responsiveness is carefully regulated. Cells of the immune system have to respond adequately to invading micro-organisms and possibly to transformed cells, but tolerance for the own body constituents needs to be preserved. Dendritic cells (DC) comprise a family of professional antigen presenting cells (APC) that play a central role in the regulation of the immune response. Immature DC, located in the periphery, can efficiently take up Ag, but lack the co-stimulatory signals for effective T-cell activation. Upon maturation, DC migrate to secondary lymphoid organs and increase the expression of co-stimulatory molecules and MHC molecules. Mature DC are very efficient in priming na____ve T-cells. In contrast to their T-cell priming capacity, DC in peripheral tissues constitutively process and present Ag in the absence of pathogen-related or endogenous inflammatory stimuli, and make a major contribution to peripheral tolerance by inducing unresponsiveness or deletion of specific T-cells. The central role of DC in controlling immunity makes these cells attractive tools for many clinical situations that involve T-cells: induction of tolerance in case of transplantation, allergy and autoimmune disease and induction of efficient T-cell responsiveness in case of infection and tumors. Many tumor components do not elicit Ag-specific T-cell responses in patients, which may be due to the absence of functional DC in tumors or the secretion of factors by tumor cells that reduce DC development and function. Application of tumor Ag to DC ex vivo and reinfusion of these DC leads to induction of specific immunity. In animals this strategy can lead to protection against tumors and even a reduction in size of established tumors. At present similar studies are carried out in patients. The research described in this thesis focuses on the requirements for induction of efficient cytotoxic T lymphocyte (CTL)- responses and tumor immunity by DC. Different modes of Ag presentation were studied for the induction of CTL-responses and tumor protection.</p

Ins and outs of dendritic cells.

Item does not contain fulltextDendritic cells (DC) are professional antigen-presenting cells which are strategically positioned at the boundaries between the inner and the outside world, in this way bridging innate and adaptive immunity. DC can initiate T cell responses against microbial pathogens and tumors due to their capacity to stimulate naive T cells. The development of DC occurs in distinct stages. DC precursors develop in the bone marrow and home to a large variety of tissues. Immature DC capture antigen (Ag) and, following proinflammatory signals, migrate to the lymphoid organs where, after maturation, they present captured Ag to naive T cells, thereby inducing differentiation of naive T cells into effector T cells. An important cognate event in the development of cell-mediated immunity is the interaction between CD40 and CD40 ligand. Ligation of CD40 on DC by its ligand results in maturation of the DC. In addition to CD40 ligand (expressed by activated Th cells), inflammatory cytokines, bacterial components or Ag-Ab immune complexes can induce maturation of DC. Maturation of DC is crucial for the priming of efficient T cell responses and is characterized by a decreased Ag processing capacity, an increased cell surface expression of MHC and costimulatory molecules, and rearrangement of cytoskeleton, adhesion molecules, and cytokine receptors. Mature DC migrate from peripheral tissues to secondary lymphoid organs, where T cell priming occurs. DC are not only critical in initiating T cell immunity, they also play a role in the induction of T cell tolerance and the regulation of the type of T cell response that is induced. Here we give an overview of the dendritic cell system

Dendritic cell vaccines in melanoma: from promise to proof?

Contains fulltext : 69716.pdf (publisher's version ) (Closed access)Dendritic cells (DC) are the directors of the immune system, capable of inducing tumour antigen-specific T- and B-cell responses. As such, they are currently applied in clinical studies in cancer patients. Early small clinical trials showed promising results, with frequent induction of anti-cancer immune reactivity and clinical responses. In recent years, additional trials have been carried out in melanoma patients, and although immunological responses are often reported, objective clinical responses remain anecdotal with objective response rates not exceeding 5-10%. Thus, DC vaccination research has now entered a stage in between 'proof of principle' and 'proof of efficacy' trials. Crucial questions to answer at this moment are why the clinical responses remain scarce and what can be done to improve the efficacy of vaccination. The answers to these questions probably lie in the preparation and administration of the DC vaccines. Predominantly, cytokine-matured DC are used in clinical studies, while from preclinical studies it is evident that DC that are activated by pathogen-associated molecules are much more potent T cell activators. For sake of easy accessibility monocyte-derived DC are often used, but are these cells also the most potent type of DC? Other yet unsettled issues include the optimal antigen-loading strategy and route of administration. In addition, trials are needed to investigate the value of manipulating tolerizing mechanisms, such as depletion of regulatory T cells or blockade of the inhibitory T cell molecule CTLA-4. These issues need to be addressed in well-designed comparative clinical studies with biological endpoints in order to determine the optimal vaccine characteristics. DC vaccination can then be put to the ultimate test of randomized clinical trials. Here, we review the immunobiology of DC with emphasis on the different aspects that are most relevant for the induction of anti-tumour responses in vivo. The different variables in preparing and administering DC vaccines are discussed in this context and the immunological and clinical results of studies with DC vaccines in melanoma patients are summarized

Murine Fc receptors for IgG are redundant in facilitating presentation of immune complex derived antigen to CD8+ T cells in vivo.

Item does not contain fulltextAntigen(Ag)-immunoglobulin (Ig)G complexes (IC) are more efficiently processed and presented than soluble Ag. IC can bind to various cell types via different types of Fc-Receptors or, upon binding to complement factors, by complement receptors. Murine professional antigen-presenting cells (APC) express four types of FcgammaReceptors (FcgammaR) via which they are able to capture IC; three activating receptors (FcgammaRI, III and IV) and one inhibitory receptor (FcgammaRII). It has been demonstrated that FcgammaR play a pivotal role in facilitating the presentation of Ag derived from IC. Nonetheless, relative little information is available on the relative contribution of the activating or inhibitory FcgammaR or complement to the presentation of immune-complexed Ag to CD8+ T cells. To study the contribution of the different FcgammaR and complement receptors in IC-facilitated Ag-presentation, we analyzed the ovalbumin(OVA)-specific CD8+ T cell proliferation in FcgammaR- and complement component 3 (C3)-deficient mice after subcutaneous injection of OVA-IC. Here we show that the efficient Ag-presentation was FcgammaR-, but not C3-mediated, as it was inhibited in FcgammaRI/II/III-deficient mice but unaffected in the C3-depleted mice. Moreover, FcgammaRIV does not play a role under these conditions. However, no difference was found between wild-type and FcgammaRI/III-deficient or wild-type and FcgammaRII-deficient mice. These results indicate that Ag-presentation via the activating FcgammaR is not enhanced in the absence of FcgammaRII, and point to redundancy of the FcgammaR, including FcgammaRII, in the uptake and presentation of s.c. injected soluble IC to CD8+ T cells

Immune complex-loaded dendritic cells are superior to soluble immune complexes as antitumor vaccine.

Item does not contain fulltextDendritic cells (DCs) play an important role in the induction of T cell responses. Fc gammaRs, expressed on DCs, facilitate the uptake of complexed Ag, resulting in efficient MHC class I and MHC class II Ag presentation and DC maturation. In the present study, we show that prophylactic immunization with DCs loaded with Ag-IgG immune complexes (ICs) leads to efficient induction of tumor protection in mice. Therapeutic vaccinations strongly delay tumor growth or even prevent tumors from growing out. By depleting CD4+ and CD8+ cell populations before tumor challenge, we identify CD8+ cells as the main effector cells involved in tumor eradication. Importantly, we show that DCs that are preloaded in vitro with ICs are at least 1000-fold more potent than ICs injected directly into mice or DCs loaded with the same amount of noncomplexed protein. The contribution of individual Fc gammaRs to Ag presentation, T cell response induction, and induction of tumor protection was assessed. We show that Fc gammaRI and Fc gammaRIII are capable of enhancing MHC class I-restricted Ag presentation to CD8+ T cells in vitro and that these activating Fc gammaRs on DCs are required for efficient priming of Ag-specific CD8+ cells in vivo and induction of tumor protection. These findings show that targeting ICs via the activating Fc gammaRs to DCs in vitro is superior to direct IC vaccination to induce protective tumor immunity in vivo

CD3-Bispecific Antibody Therapy Turns Solid Tumors into Inflammatory Sites but Does Not Install Protective Memory

Functional Genomics of Systemic Disorder

Vaccination of colorectal cancer patients with carcincembryonic antigen peptide-loaded dendritic cells

Item does not contain fulltex

Vaccination of colorectal cancer patients with CEA-loaded dendritic cells: antigen-specific T cell responses in DTH skin tests

Contains fulltext : 27296.pdf (publisher's version ) (Closed access

Differential expression regulation of the alpha and beta subunits of the PA28 proteasome activator in mature dendritic cells.

Contains fulltext : 49076.pdf (publisher's version ) (Closed access)Activation of dendritic cells (DC) by Th-dependent (CD40) or -independent (LPS, CpG, or immune complexes) agonistic stimuli strongly enhances the expression of the proteasome activator PA28alphabeta complex. Upon activation of DC, increased MHC class I presentation occurred of the melanocyte-associated epitope tyrosinase-related protein 2(180-188) in a PA28alphabeta-dependent manner. In contrast to other cell types, regulation of PA28alphabeta expression in DC after maturation was found to be IFN-gamma independent. In the present study, we show that expression of PA28alpha and beta subunits was differentially regulated. Firstly, PA28alpha expression is high in both immature and mature DC. In contrast, PA28beta expression is low in immature DC and strongly increased in mature DC. Secondly, we show the presence of a functional NF-kappaB site in the PA28beta promoter, which is absent in the PA28alpha promoter, indicating regulation of PA28beta expression by transcription factors of the NF-kappaB family. In addition, glycerol gradient analysis of DC lysates revealed elevated PA28alphabeta complex formation upon maturation. Thus, induction of PA28beta expression allows proper PA28alphabeta complex formation, thereby enhancing proteasome activity in activated DC. Therefore, maturation of DC not only improves costimulation but also MHC class I processing. This mechanism enhances the CD8(+) CTL (cross)-priming capacity of mature DC