Time table and abstracts


Prof. Carl Figdor (Radboudumc, Netherlands)

http://www.rimls.nl/people/f/figdor/

Towards synthetic immune cells to target the antitumor response

Most cellular therapies targeting cancer require culture of autologous cells. The dedicated facilities and personnel needed, the variability in quality of the product depending on the condition of the patient and state of disease, hamper widespread use. In an attempt to generate an of the shelf product to target cancer we exploit the ever expanding possibilities to build supramolecular structures offered by chemistry to mimic nature including the construction of artificial immune cells or functions thereof. Effective immunotherapy critically depends on efficient production of antigen-specific cytotoxic T-cells. Herein lies an opportunity for both chemists and immunologists to design and synthesize so-called artificial antigen presenting cells that can generate in vivo T-cell expansion. We have designed a novel ‘synthetic dendritic cell (sDC)’ that possesses essential features of natural dendritic cells which are the most efficient antigen presenting cells in our immune system.  Our sDC is based on a semi-flexible poly(isocyano peptide) polymer and, as proof of principle, carries both anti-CD3 antibodies for triggering the T cell receptor/CD3 complex as well as anti-CD28 antibodies as a co-stimulatory signal. Multiple copies of both antibodies facilitate multivalent binding similar to natural DCs. The high mobility of these polymer-bound antibodies, reminiscent of protein motility in a natural plasma membrane, enables receptor rearrangements to occur during T cell activation. I will discuss the rationale in designing such and other synthetic immune cells. These first results demonstrate the enormous potential of multifunctional polymers for mimicking functions of natural DCs or other immune cells, paving the way for their exploitation in immunotherapeutic strategies.


Prof. Quentin Sattentau (Oxford University, UK)

quentin sattentau

http://users.path.ox.ac.uk/~qsattentau/index.htm

Modification of HIV-1 envelope glycoproteins to overcome antibody evasion strategies

The human immunodeficiency virus type 1 (HIV-1) is a pandemic pathogen that currently infects 35 million people and is responsible for the death of more than double that number. Although neutralising antibodies can protect against HIV-1 infection, we do not yet have a vaccine able to elicit such antibodies by active immunisation. This is in large part because the target of neutralising antibodies, the viral envelope glycoproteins (Env) exhibit multiple antibody evasion mechanisms including hypervariability, unwanted immunodominance and conformational instability. We have designed post-translational modifications to overcome these obstacles including: i) targeted adduction of synthetic glycans to Env to reduce exposure of hypervariable regions and block unwanted immunodominance; ii) chemical cross-linking to prevent conformational instability. In vitro characterisation of the modified Env forms for antigenicity, morphology and biophysical parameters revealed increased stability and improved antigenicity. In vivo immunization revealed no global loss of immunogenicity and selectively modified antibody responses. These results confirm that post-translational chemical modification of vaccine antigens may be a broadly applicable approach to enhancing anti-pathogen antibody responses.


Prof.Francesco Berti (GSK)

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https://www.linkedin.com/profile/view?id=57935047&authType=NAME_SEARCH&authToken=wPta&locale=en_US&trk=tyah&trkInfo=clickedVertical%3Amynetwork%2Cidx%3A1-1-1%2CtarId%3A1430842009673%2Ctas%3Aberti

RECENT TRENDS IN THE DESIGN OF CARBOHYDRATE-BASED CONJUGATE VACCINES 

Carbohydrate-based conjugate (glycoconjugate) vaccines represent one of the keys for success of vaccination in children. They are a potent tool for prevention of life-threatening bacterial infectious diseases like meningitis and pneumonia. 

The immunogenicity of these glycoconjugates is influenced by a series of interconnected parameters, some of which are related to the sugar carbohydrate antigen (length, non-end terminal residues,  exposition of charged functional groups, number of sugar copies linked to the protein) and other to the conjugation chemistry to protein carrier (type of linker, length, etc.).

The complexity of randomly prepared glycoconjugates has not made possible to decipher the contribution of all the single parameters that underlay the overall immunological activity of the biomolecules. Recently, different methods for chemical or enzymatic assembly of defined oligosaccharides have rendered feasible the synthesis of complex carbohydrates. The modern methods for site selective conjugation could contribute to the production of a new generation of glycoconjugate vaccines with defined sugar and attachment site and to establish robust structure-immunogenicity relationship.


Dr. Sander Van Kasteren (Universitry of Leiden, Netherlands)

http://biosyn.lic.leidenuniv.nl/people/vankastere

Imaging Degradation

Degradation of antigen into short MHC-loadable polypeptides by antigen presenting cells presents a Heisenbergian conundrum: reporter strategies for imaging these processes affect the processes themselves; often to such an extent that the information obtained from reporter antigen strategies may not be representative of the process itself.

For example genetic fusion constructs of antigens are only imageable until the point they are degraded or separated from the antigen. As processing into MHC-loadable antigens is an essential part of antigen presentation, it means these reporters are of limited use for imaging later aspects of processing. These approaches can also result in "imaging bias": only those sections of the pathway during which reporters remain intact are seen. Complications can also arise from the fact that reporter-constructs can alter the rate of proteolysis and routing by virtue of changing overall physiochemical properties of the antigens.

I will present our perceived methods to address some of these issues, namely ´bioorthgonal antigens´: these are antigens that carry chemical groups of 2 or 3 atoms in size in some amino acid sidechains (e.g. only in a non-MHC-binding position in the epitope) that can be visualised using 'click'-chemistry. This approach has two key advantages, namely the diminutive size and exceptional stability of the groups. The fact that they are not degraded by proteolysis, are uncharged and small means that their altering effect on antigen processing can be minimal.

We are using these bioorthogonal antigens, for example, to determine the spread of degrading antigen inside an APC or the determination of the rate of epitope appearance on the cell surface without the need for peptide-MHC-specific antibodies, as the handles are so small, that the peptides are presented with their detectable groups intact.

We believe this approach offers the first opportunity to get a glimpse into the late events of presentation and cross-presentation, an area that has been notoriously difficult to study to date.


Dr. Celia. R. Berkers (University of Utrecht, Netherlands)

http://www.uu.nl/staff/CRBerkers/0

Finding the metabolic Achilles′ heel of T cells

Regulatory CD4 T cells (Treg) inhibit the response of conventional CD4 and CD8 T cells (Tconv) to self- and foreign antigens. Treg are critical to inhibit autoimmunity. Thus, patients with autoimmune diseases such as rheumatoid arthritis will likely benefit from Treg stimulation. On the other hand, Treg impede anti-tumor immunity and therefore, cancer patients will likely benefit from Treg inhibition. But because Treg and Tconv share many features - including costimulatory and cytokine receptors - compounds that selectively modulate different T cell types are scarce. One aspect in which Treg may differ significantly from Tconv is in their metabolic features. Upon activation in lymphoid organs, T cells proliferate extremely fast and this places unique demands on their metabolism. But whereas proliferation of Tconv is depending on the mTORC1 pathway, Treg proliferation is not. Therefore, we aim to map the metabolic differences between Treg and Tconv using a metabolomics approach. To this end, we use state-of-the-art LC/MS and combine steady-state metabolomics screens with metabolic flux studies using stable isotope-labelled nutrients. By studying not only in vitro expanded T cells but also freshly isolated primary human T cell populations, we now start to see different metabolic signatures in Treg and Tconv, especially during activation. Further exploration of these differences may aid in the identification of novel targets that can be exploited to selectively modulate T cell activity. 


Dr. Aaron Esser-Kahn (University of California, USA)

http://www.chem.uci.edu/~esserkahngroup/

My lab seeks to design effective, long-lived vaccines by design better adjuvants.  Specifically, we want to understand how pattern recognition receptors (PRRs) work together to elicit specific immune responses. My group is focused on (1) manipulating PRRs in new, controlled manners and (2) exploring new means to stimulate immune responses. Many molecules are responsible for activating receptors on innate immune cells, yet an individual molecular interaction is not responsible for the effect of a good vaccine. 

The central questions my lab seeks to address are the “who, what, where, and when” of innate immune activation. We will accomplish this goal by applying the tools and knowledge of chemical and synthetic biology to challenges in innate immunity. Toll-Like Receptors (TLRs) control, in part, the innate immune response. In particular, the process of TLR synergies – multiple receptors working in concert – is a key aspect of many effective vaccinations. I have taken the intellectual approach that the activation of the innate immune system is a new type of molecular code, analogous to the genetic code. This immune code has no physical location (e.g., DNA or chromosome); it exists transiently upon interaction with the innate immune system. We define an immune stimulating code as the activated receptors, their location within the body, and the sequence in which each receptor was activated. These elements combine to elicit a specific innate immune response (a code). Operating under this hypothesis, we use chemical tools to study activation of multiple receptors (learn codes) and elicit specific, desired adaptive immune responses. We report on molecules that let us translate activation of a set of receptors to a rapid and/or sustained immune response. We use this information to create polymeric molecules that activate and direct the immune response. To develop these molecules, we must understand how these receptors work, where they traffic and interact, and how their synergistic activity works to elicit strong responses for which we have developed a new tool for probing innate immune activity - photo-active TLR agonists. We report on the development of photo-active TLR agonists and their use in quantifying measurements of the innate immune system.


Prof. Simon J. Davis (Oxford University, UK)

http://www.rdm.ox.ac.uk/principal-investigators/researcher/simon-davis-2

The kinetic-segregation model: an unconventional mode of signalling in T cells

It has been proposed that the local segregation of kinases and the tyrosine phosphatase CD45 underpins T-cell receptor (TCR) triggering, but how segregation would occur is uncertain, and whether it can initiate signalling is unclear. In my talk I will show that the extracellular region of CD45 is rigid and extends beyond the distance spanned by TCR/ligand complexes, implying that sites of TCR/ligand engagement would sterically exclude CD45. I will also show that the formation of new structures characterized by spontaneous sub-micron scale CD45/kinase segregation, called “close-contacts”, initiates signalling even when TCR ligands are absent. Our work reveals the structural basis for, and the unexpectedly potent signalling effects of, local CD45/kinase segregation. Finally, I will consider the translation implications of our work.


Dr. Amin Moghaddam (Oxford University, UK)

https://www.researchgate.net/profile/Amin_E_Moghaddam

The impact of protein carbonylation on antigen presentation and immune induction

Protein oxidative modification is widely implicated in altered immunogenicity and disease propagation. Such non-enzymatic modification can occur as a result of a diverse array of chemical reactions under oxidative stress, exemplified by sugar and lipid oxidation-derived aldehyde attacks on free amino groups of proteins. The resultant chemical adducts are known to change the physiochemical and biological properties of modified proteins. Our work investigates how these changes modulate the immunogenicity of proteins and thereby contribute to pathological processes. Protein oxidative modification can generate adducts that are recognised by receptors of the innate immune system that can mediate endocytic uptake and/or intracellular signaling. Additionally, physiochemical changes in oxidised proteins can subject them to altered antigen processing and presentation, thereby influencing subsequent adaptive immune responses. We have previously shown that reactive carbonyl (RC) moieties generated upon protein carbonylation, a common consequence of protein oxidation, are a major driver of adaptive immune induction that can contribute to immune disregulation and pathology. Our more recent research focuses on the mechanistic pathways by which RC adducts impact immune responses, and identifies altered antigen processing and enhanced presentation via MHC class II as a key event in the boosting of CD4 T effector cell elicitation by RC-adducted proteins. The identification of this potential novel pathway has significant implications for understanding the role of oxidative stress in the priming of pathological immune responses. 


Prof. Tim Elliott (Southampton University, UK)

http://www.southampton.ac.uk/medicine/about/staff/tje.page#background

A combined computational modelling, cellular biochemistry and structural biology approach to investigate peptide selector function of MHC I molecules 

The selection of peptides for presentation at the surface of most nucleated cells in vertebrates by major histocompatibility complex class I molecules (MHC I) is crucial to the immune response. However, the precise mechanisms of the rapid selection of high affinity peptides from amongst many thousands of mostly low affinity peptides by MHC I are not well understood. To gain a better understanding of the mechanisms of peptide selection by MHC I, we developed computational systems models encoding distinct mechanistic hypotheses for two MHC I molecules HLA-B*44:02 (B*4402) and HLA-B*44:05 (B*4405). These MHC I differ by a single residue, yet they lie at opposite ends of the spectrum in their intrinsic ability to select high affinity peptides. We fitted these models to in vivo biochemical data to infer that a conformational intermediate of MHC I is significant for peptide selection. We also show that peptide selector function correlates with protein plasticity using molecular dynamics simulations, using site-directed mutagenesis to test predictions arising from the model directly. This approach also provided evidence that the chaperone molecule tapasin increases MHC I plasticity by a mechanism of allosteric coupling, resulting in enhanced peptide selector function. 


Prof. Mark J. Mamula (Yale, USA)

http://medicine.yale.edu/intmed/rheumat/people/mark_mamula-1.profile

It is clear that autoimmune diseases are marked by a variety of abnormalities, including those found at a macroscopic scale, both cells and soluble cytokines, as well as intracellular influences, ranging from the immune cell signaling and the biochemical processing of self antigens.  The convergence of genetic, epigenetic, and biochemical influences all lead to the overt clinical expression of disease, reflected by the presence of autoantibodies and tissue pathology.  Overall, I will address several biochemical influences that contribute to autoimmunity in lupus, type 1 diabetes and related syndromes.  In particular, we will discuss the importance of understanding various protein posttranslational modifications (PTMs) that are amplified in inflammation and mechanisms that mediate the ability of ‘modified self’ to trigger autoimmunity. I will discuss how PTMs alter both the processing of self proteins to the immune system as well as metabolic pathways of cells.


Prof. Paul Lehner (University of Cambridge, UK)


http://www.cimr.cam.ac.uk/research/principal-investigators/principal-investigators-i-p/lehner

Complementary genetic and proteomic approaches to viral evasion 

Viruses manipulate host cell signaling pathways to enable viral replication and evade immune recognition. In turn, infected cells need to sense and respond appropriately to intracellular viral infections. We have adopted a gene discovery platform that involves functional proteomic approaches to identify receptors manipulated by viruses and genome-wide genetic screens to identify key components of intracellular signalling pathways. We use ‘Plasma Membrane Profiling’ to gain an overview of cellular receptors manipulated by viruses. TMT-based quantitation allows us to create a temporal cell surface map of receptors manipulated by both integrating (HIV) and non-integrating viruses (HCMV) and established a novel paradigm of viral interference with immunometabolism, through downregulation of amino acid carriers and transporters.

To complement this proteomic approach we use fluorescence-based phenotypic selection for forward genetic screens in human haploid cells. This identified novel genes including (i) ERAD E3 ubiquitin ligases and (ii) the transcriptional repressor complex we termed ‘HUSH’ (Human Silencing Hub) a widely active epigenetic repressor complex that plays a major role in somatic transgene silencing, including the silencing of newly inserted retroviruses.


Prof. Yvette Van Kooyk (VUmc, Amsterdam, Netherlands)

foto-vanKooyk

http://www.vumc.nl/afdelingen/moleculairecelbiologie/Research-MCBI/Yvette-van-Kooyk-Group/ 

Glycan-nanotechnology for the design of cancer vaccines overcoming tumor induced suppression

Dendritic cells (DC) are specialized in the recognition of antigen and play a pivotal role in the control of immunity and tolerance.  Innate receptors on DC such as C-type lectins facilitate antigen uptake and cross-presentation. Many of these receptors also modify responses through signalling interference with TLR. By modifying nanoparticles including tumour antigens with Lewis glycans we can favour directional targeting of tumor antigens to human DC and Langerhans Cells (LC) in situ, in the skin, facilitating the induction of melanoma specific CD4+ and CD8+ T cell responses and Th1 differentiation. Therapeutic vaccination of mice with glycan modified antigen show long term anti-melanoma immunity when tumor induced T regulatory cells are temporarily reduced.

We also identified new mechanisms of immune tolerance through the modification of glycosylation of tumors (melanoma and glioblastoma). In particular high sialylation of tumors results in increase of FoxP3 CD4+ T cells (Treg) and lower frequencies of effector T cells and NK cells at the tumor site. In contrast, low sialylation of tumors converts the frequencies Treg/Teff to favourable anti-tumor immunity.

All together our work sheds new light on the contribution of glycans to control tumor surveillance by either contributing to the induction of anti-cancer immunity or tumor induced immune suppression.


Prof. Martin Bachmann (Oxford University, UK)

http://www.jenner.ac.uk/jenner-researchers/researcher/martin-bachmann

Researchers working on the development of vaccines face an inherent dilemma: to maximize immunogenicity without compromising safety and tolerability. Early vaccines often induced long-lived protective immune responses, but tolerability was a major problem. Newer vaccines have very few side effects but can be of limited immunogenicity. One way to tackle this problem is to design vaccines that have all the properties of pathogens with the exception of causing disease. Key features of pathogens can be mimicked by virus-like particle (VLP) based delivery systems. Most important properties for induction of strong immune responses  are the size, shape and surface molecule organization of VLPs. In addition, pathogen-associated molecular patterns can be co-delivered to induce innate immune responses that promote adaptive immunity. Approaches currently being used to optimize the delivery of antigens and enhance vaccine efficacy will be discussed.


Prof. Stella Knight (Imperial College, London)

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http://www.imperial.ac.uk/people/s.knight

Dendritic antigen presenting cells (DC) determine whether there is an immune response, the type of immunity - e.g. pro-inflammatory or tolerogenic- and its location.  DC generated in bone marrow migrate to different peripheral tissues and, under the influence of the local microenvironment, become tissue specific.  In gut, tissue specificity is in part dictated by local retinoic acid which promotes gut specificity and TGF beta which reduces T cell activation.   Gut DC exposed to antigens migrate to draining lymph nodes, activate lymphocytes, generate immune responses and direct stimulated lymphocytes back to the gut thus creating a circuit of responsiveness.  In inflammatory bowel disease (IBD), we have evidence of systemic metabolic changes in DC and alterations in their migration potential with normalisation following successful therapy. Infliximab, an antibody to TNF alpha used for treatment of IBD, as well as some probiotic bacteria can contribute to regulation of gut immunity and change DC from gut specific to skin- specific, directing stimulated lymphocytes to the skin.  Products of probiotic bacteria can also reduce pro-inflammatory activity of DC and direct lymphocytes to the skin. A peptide of the commensal bacterium Lactobacillus plantarum was identified that lacks cleavage sites and therefore resists degradation in the gut.  This peptide, high in serine and threonine, reduces pro-inflammatory activity of DC and stimulates lymphocytes to become skin-homing rather than gut-homing. Preliminary preclinical studies suggest that the peptide can block inflammation in experimentally induced mouse colitis.  On screening effects of supernatants of other commensal bacteria isolated from human gut we find different modifications of DC activity and function.  We may have unearthed a goldmine of new bacterially-derived substances with potential for immunological modification acting via dendritic cells which could be harnessed therapeutically; however, we need to identify which molecular species produce the effects and the metabolic pathways involved


Prof. Antonio Lanzavecchia (USI, Switzerland

220px-Antonio Lanzavecchia


http://www.irb.usi.ch/antonio-lanzavecchia


Prof. Benoit van den Eynde (Ludwig cancer institute) 

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http://www.ludwig.ox.ac.uk/professor-benoit-van-den-eynde-tumour-immunology







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