| Day 1 - Wednesday, January 29, 2014 |
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12:00 | Check In & Registration |
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1:00 | Welcome & Opening Remarks |
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| 1:05 | Workshop (Speaker TBA) |
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2:35 | Afternoon Networking & Coffee Break |
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| 3:15 | Workshop (Speaker TBA) |
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4:55 | Day 1 of Summit Concludes |
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| Day 2 - Thursday, January 30, 2014 |
7:00 | Check In & Registration |
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8:00 | Welcome & Opening Remarks for Summit |
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| Plenary Keynote Session |
8:05 | 
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Jules Hoffmann
Director
Institut de Biologie Moléculaire et Cellulaire, Université
Louis Pasteur de Strasbourg
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8:50 | Welcome & Opening Remarks |
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Targeting Cytokines & Chemokines for Therapeutic Interventions
Moderator: Linda Burkly, Distinguished Investigator, Biogen Idec |
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| 9:00 | The TWEAK/Fn14 Pathway: At the Bench and Bedside in Lupus Nephritis |
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Linda Burkly
Distinguished Investigator
Biogen Idec
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9:25 | Control of Antibody Responses by Interleukin-2 |
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Andre Ballesteros-Tato
Assistant Professor of Medicine
Division of Clinical Immunology and Rheumatology
University of Alabama, Birmingham
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| | Although the underlying mechanisms that drive Systemic Lupus Erythematosus (SLE) remain unclear, auto-reactive antibodies, particularly those against nuclear and cytoplasmic antigens, are thought to play a major role in disease progression. B cell depletion therapy has been used to treat SLE based on the rationale that depletion of auto-reactive B cells would reduce auto-antibody production and thereby prevent immunopathology. However, the majority of the current B cell-depleting agents do not substantially eliminate effector B cells, including Germinal Center (GC) B cells and long-lived plasma cells (PC) and the clinical efficacy of these treatments is lower than expected. Importantly, GC formation and PC differentiation are dependent on help provided by CD4+ T follicular helper (Tfh) cells. In the absence of Tfh cells, GCs do not develop and antibody responses are impaired, suggesting that targeting Tfh may be a good strategy to prevent effector B cell responses and treating SLE. We found that IL-2 availability is a critical factor that controls Tfh development in vivo and that exogenous IL-2 administration prevents the accumulation of Tfh and GC B cell in various infection models. Additionally, in vivo administration of IL-2 also impairs Tfh cell development in SLE-prone mice. As a result, self-reactive GC B cell response and PC responses are reduced after IL-2 treatment in lupus-prone mice. Our results indicate a new potential therapeutic use of IL-2 to prevent Tfh cell responses in vivo and treat autoimmune diseases. |
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9:50 | Targeting CD25 in Autoimmune Disease: Lessons from Daclizumab in Multiple Sclerosis |
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Jason Fontenot
Principal Scientist
Biogen Idec
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10:15 | Morning Networking & Coffee Break |
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10:45 | IL-7R: A Target in ALL and Autoimmunity |
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Scott K. Durum
Senior Investigator
Center for Cancer Research, National Cancer Institute, NIH
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| T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy resulting from leukemic transformation of T-cell progenitors in the thymus. It accounts for approximately 15% of ALL cases in childhood and 20-25% in adults and is a leading cause of death in children. IL-7 and its receptor (IL-7R) play a critical role in normal T-cell development and homeostasis. Mutations in IL-7R were identified in 9% of pediatric T-ALL patients. These mutations usually involved insertions of three amino acids including cysteine and proline in the extracellular juxtamembrane region. WT or mutant forms of the human IL-7R (hIL-7R) from patients were retrovirally transfected into an IL-7-dependent murine thymic cell line D1. Mutant hIL-7Rs induced ligand-independent activation of the Jak-Stat and PI3K pathways, cell survival and proliferation. Notably, mutant hIL-7R-expressing D1 cells formed subcutaneous tumors in Rag1-/- mice, with substantial infiltration into various organs that are normally affected in advanced stages of T-ALL, such as bone marrow, liver, lymph nodes and spleen. Further functional assays revealed that mutant hIL-7Rs constitutive signaling required homodimerization via cysteines in the inserted sequences and downstream Jak1 activation, and was IL-7, gc and Jak3-independent. Jak inhibitors were effective in blocking proliferation and survival of transformed cells. The hotspot for insertions lies in exon 6 in precisely the same region as a coding polymorphism regulating risk for MS and other autoimmune diseases, and we observe that this polymorphism affects strength of signaling. Our findings indicate that IL-7R mutations drive T-ALL, whereas polymorphisms that increase signaling promote autoimmunity, implicating IL-7R and Jak1 as therapeutic targets in these diseases. |
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11:10 | Modulating Cytokines by Targeting Dendritic Cells – a Therapy for Lupus |
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Dania Rabah
Principal Scientist
Biogen Idec
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11:35 | Development of rhIL-22 (F-652) to Treat Inflammatory Diseases |
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Xiaoqiang Yan
Chief Scientific Officer
Generon Bioscience
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| | IL-22 is produced by CD4 T-cell subsets, NK cells and recently identified neutrophils. IL-22 plays an important role in controlling bacteria infection, homeostasis, and tissue repair. IL-22 binds to its cell surface receptor complex and subsequently activating the downstream STAT3 signaling pathways. IL-22 receptor complex consists of IL-22 R2, or IL-10 R2 which is ubiquitously expressed, and IL-22 R1 which restrictedly expressed on keratinocytes, bronchial and intestinal epithelial cells and hepatocytes. The specific IL-22 R1 is absent in immune and hematopoietic cells. A large number of studies have demonstrated that IL-22 plays a critical role in tissue protection and regeneration during inflammation. We have developed a rhIL-22 dimer (F-652) and produced in Chinese Hamster Ovary (CHO) cells in serum-free culture. In pre-clinical studies, F-652 demonstrated expected bioactivity in vitro and in vivo with excellent pharmacokinetics and safety profile. We have conducted the first-in-man study for F-652 in healthy volunteers. The safety, pharmacokinetics and biomarker were evaluated. Our studies demonstrated that F-652 could potentially address several unmet medical needs in inflammatory diseases including acute hepatitis, pancreatitis, inflammatory bowel disease and acute inflammation in the respiratory system. |
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12:00 | Lunch on Your Own |
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Cytokine Regulation
Moderator: Domagoj Vucic, Senior Scientist, Early Discovery Biochemistry, Genentech |
| | KEYNOTE PRESENTATION |
1:30 |
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Michael Croft
Division Head and Professor, Immune Regulation
Allergy & Asthma Research, Cancer Research
La Jolla Institute for Allergy & Immunology
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2:10 | Critical Role of TNF-TNFR2 Pathway in CD4 T Cell Immunity: from Basic to Translational Research |
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Joost Oppenheim
Chief
Laboratory of Molecular Immunoregulation
NIH, Center for Cancer Research, National Cancer Institute
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| We have reported that TNF has the capacity to activate Tregs through TNFR2; TNF receptor preferentially expressed by highly suppressive human and mouse Tregs. In addition, TNF up-regulates the expression of TNFR2 and other co-stimulatory TNFRSF members on Tregs. The number of Tregs is reduced by 50% in the thymus and periphery in mouse strains following genetic ablation of TNFR2 or its ligands, or IKK? , an important component of TNFR2 signaling pathway. More recently, we showed that TNFR2 is critical for in vivo function of Tregs and to stabilize Foxp3 expression. Among Th subsets, Th17 cells express the highest levels of TNF, and consequently most markedly promote Foxp3 expression and expansion of Tregs when co-transferred into Rag1 KO mice. The Treg-stimulatory effect of Th17 cells is abolished when Tregs are deficient in TNFR2. Intriguingly, co-transfer of TNFR2-deficient Tregs also results in a marked reduction of Th17 signature cytokine expressed by Th17 cells. Thus, TNF-TNFR2 interaction actually results in a reciprocal stimulatory effect between Th17 cells and Tregs.
Inhibition of TNF-TNFR2 interaction is likely to enhance the efficacy of immunotherapy of cancer, by eliminating Treg activity. Our preliminary data indicates that a neutralizing/blocking anti TNFR2 Ab improves anti-tumor effect of CpG ODN in mouse CT26 colon cancer. Furthermore, combination treatment with anti TNFR2 and anti-CD40 antibodies markedly inhibits the growth of established mouse 4T1 breast cancer. Our results suggest that anti-TNFR2 treatment may prove to be an useful adjuvant agent in cancer immunotherapy or in a cancer vaccine, and thus merits further investigation. |
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2:35 | Diverse Ubiquitin Modifications Regulate Signaling Initiated by TNF Family Cytokines |
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Domagoj Vucic
Senior Scientist
Early Discovery Biochemistry
Genentech
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3:00 | Concurrent Targeting of Functionally Redundant Th1 and Th17 Responses in CNS Autoimmunity |
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Rachel Caspi
Chief, Immunoregulation Section, Deputy Chief, Laboratory of Immunology
NEI, NIH
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| | Central nervous system (CNS) autoimmunity such as uveitis and multiple sclerosis is accompanied by Th1 and Th17 responses. In their corresponding animal models, experimental autoimmune uveitis (EAU) and experimental autoimmune encephalomyelitis (EAE), both responses are induced and can drive disease independently. Because immune responses have inherent plasticity, therapeutic targeting of only one pathway could promote the other, without reducing pathology. IL 27p28 antagonizes gp130, required for signaling by IL-27 and IL-6, which respectively promote Th1 and Th17 responses. We therefore examined its ability to protect the CNS by concurrently targeting both effector responses. Overexpression of IL-27p28 in vivo ameliorated EAU as well as EAE pathology and reduced tissue infiltration by Th1 and Th17 cells in a disease prevention, as well as in a disease reversal protocol. Mechanistic studies revealed inhibition of Th1 and Th17 commitment in vitro and decreased lineage stability of pre-formed effectors in vivo, with reduction in expression of gp130-dependent transcription factors and cytokines. Importantly, IL-27p28 inhibited polarization of human T cells to the Th1 and Th17 effector pathways. The ability of IL-27p28 to inhibit generation as well as function of pathogenic Th1 and Th17 effector cells has therapeutic implications for controlling immunologically complex autoimmune diseases. |
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3:25 | Regulation of TLR-induced Cytokine Expression by Environmental Stress |
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Thomas Hamilton
Chair
Department of Immunology, Lerner Research Institute
Cleveland Clinic
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3:50 | Signal 0’s: Damage Associated Molecular Pattern Molecules, Chemokines, and Cytokines |
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Michael Lotze
Professor of Surgery
Immunology, and Bioengineering
University of Pittsburgh School of Medicine
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| | • Understand the basic biology of DAMPs
• Consider how cytokines and chemokines regulate metabolism and autophagy
• Make the connection between chronic inflammation and cancer
• Appreciate the current clinical trials used to inhibit autophagy in cancer
• Understand the emergence of autophagy inhibitors in the clinic
Damage Associated Molecular Pattern Molecules (DAMPs): Signal 0’s Promoting Inflammation, Metabolism, and Cancer. HMGB1 (High-mobility group box 1) is a 25kD protein with distinct compartmental roles . Initially identified as a nuclear protein, chromatin-bound HMGB1 facilitates DNA accessibility in a variety of transcriptional activities including p53/p73 transactivation and V(D)J recombination through stabilization of V(D)J recombinases and recombination-activating gene (RAG) 1 and 2. Under conditions of cellular stress, HMGB1 is translocated from the nucleus to the cytosol where it induces a state of heightened autophagy by displacing Bcl-2 bound to the autophagic protein, Beclin1. Autophagy serves to selectively degrade cytosolic factors and plays a role in enhanced antigen presentation in response to TLR ligation-induced HMGB1 translocation. HMGB1 is the prototypical DAMP, molecules function much like their pathogen-associated counterparts in that they serve to alert immunologically relevant cells to potential problems within the host; in this case, cell or tissue damage. During cytotoxic insult or necrosis, cellular components normally located within the cell become released either passively or actively into the extracellular milieu where they bind to receptors on resident macrophages and DCs such as TLRs and the Receptor for Advanced Glycation End-products (RAGE). This results in the propagation of inflammatory responses to injury or infection and the recruitment of macrophages, neutrophils, and fibroblasts via NF-?B-dependent chemotaxis. Recent findings suggest that posttranslational modifications dictate the cellular localization and secretion of HMGB1 . When oxidized, it chronically suppresses the immune system to promote cancer growth and progression, thereby enhancing resistance to cancer therapeutics. In its reduced form, it can facilitate and elicit innate and adaptive anti-tumor immunity, recruiting and activating immune cells, in conjunction with cytotoxic agents.. |
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4:15 | Afternoon Networking & Coffee Break |
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Cytokines & Metabolism
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4:45 | 
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Jennifer Towne
Principal Scientist
Amgen
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5:10 | mTOR and Metabolic Control of Regulatory T Cell Function |
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Hongbo Chi
Associate Member, St. Jude Faculty
Immunology
St. Jude Children's Research Hospital
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5:35 |
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Grant Gallagher
Managing Director, Head of Genetic Immunology
Humigen
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6:00 | Oral Presentations from Exemplary Submitted Abstracts |
| To be considered for an oral presentation, please submit an abstract here by December 29, 2013. Selected presentations will be based on quality of abstract and availability. Presentation slots fill up fast so please submit your abstract ASAP. |
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6:30 | Evening Networking Reception |
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| Day 3 - Friday, January 31, 2014 |
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8:00 | Welcoming Remarks |
Cytokines Signaling Pathways
Moderator: Howard A. Young, Principal Investigator, Center for Cancer Research, NIH |
8:05 | Chronic Interferon-gamma Expression Alters mRNA and miRNA Expression and the Host Metabolome |
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Howard A. Young
Principal Investigator
Center for Cancer Research, NIH
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| Interferon-gamma (IFN-g) is a key player in immunoregulation, inflammation and autoimmune disease. Our laboratory has targeted a 162 nt substitution of the AU-rich element (ARE) in the 3’UTR of the IFN-g gene, resulting in chronic low levels of circulating IFN-g. In a C57BL/6 genetic background, the ARE-deleted (ARE-Del) mice develop a lupus-like disease characterized by the presence of DNA and nuclear antigen-specific autoantibodies and glomerulonephritis. In the Balb/c genetic background, these mice exhibited signs of immunodeficiency resembling aplastic anemia (AA) as IFN-y directly inhibits the generation of ST-HSCs from LT-HSCs. Analysis of both mRNA and miRNA expression in the spleen thymus and lymph node revealed significant changes in mRNA and miRNA expression patterns in the ARE-del mice. Bioinformatics analysis reveals that these changes could alter the expression of genes involved in specific target pathways whose dysregulation is correlated with disease. Futhermore, metabolome analysis of the serum indicates that changes in mRNA gene expression, induced by chronic exposure to IFN-g results in detectable changes in serum metabolites. Thus our data demonstrates that low, chronic IFN-g levels are sufficient to alter the phenotype and metabolome in the host and result in significant pathophysiology.
Talk will demonstrate that low circulating levels of a cytokine are sufficient to trigger disease
Talk will discuss how IFN-g; triggers changes in mRNA and miRNA expression in specific tissues
Talk will show that the changes in mRNAs trigger alterations in the serum metabolome, consistent with the changes in gene expression patterns |
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8:30 |
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Jane Grogan
Scientist
Genentech
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8:55 |
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Jon Wigginton
Vice President
Clinical Development
Macrogenics
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9:20 | Epigenetic Regulation of Inflammatory Cytokine Responses |
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Lionel Ivashkiv
Director of Basic Research; David H. Koch Chair in Arthritis and Tissue Degeneration
Hospital for Special Surgery
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9:45 |
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Simon Fricker
Distinguished Scientific Fellow
Genzyme
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10:10 | Morning Networking & Coffee Break |
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| Cytokines & Innate Lymphoid Cells |
10:45 | Human Innate lymphoid in Health and Disease |
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Hergen Spits
University of Amsterdam, The Netherlands
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11:25 | IL-36 Ligands Regulate Intestinal Inflammation |
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Tim Denning
Associate Professor
Emory University School of Medicine
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| | The two most common forms of inflammatory bowel disease (IBD), Crohn’s disease and ulcerative colitis, affect approximately 1.4 million people in the United States. The etiology of IBD is unclear, yet aberrant innate and adaptive immune responses directed towards commensal microbiota are believed to underlie disease pathogenesis. With the knowledge that CX3CR1-expressing anti-inflammatory LP macrophages are abundant in the healthy intestine, while Ly6C-expressing pro-inflammatory LP macrophages dominate the inflamed intestine, we performed a DNA microarray analysis of these two subsets in order to identify candidate genes that may be targeted for therapeutic purposes. As a result of the microarray comparison, we identified the novel IL-1 family member IL-36g as the top most preferentially expressed cytokine in Ly6C+ LP macrophages. Several members of the IL-1 family of cytokines, including IL-1a, IL-1b, IL-18 and IL-33 are associated with the pathogenesis of experimental and human IBD, however the expression and function of IL-36g in the intestine is completely unexplored. Our data demonstrate that IL-36g promotes LP macrophage and DC activation and that blocking of IL-36 signaling during colitis ameliorates disease during the acute damage phase, but also dramatically inhibits wound healing in the recovery phase. Thus, further mechanistic insights defining the role of IL-36 during intestinal inflammation may contribute to the development of therapeutic strategies for the treatment of human IBD.
Benefits:
Understand the function of macrophages/monocytes during homeostasis and inflammation
Understand the function of IL-36 ligands in innate and adaptive immune cell activation
Understand the function of IL-36 ligands in regulating distinct phases of intestinal inflammation
Understand the signaling cascade between IL-36 and IL-22. |
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11:50 | A Critical Role for the IL-33/ST2 Axis in Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD) |
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Roland Kolbeck
Senior Director
Respiratory, Inflammation & Autoimmunity
MedImmune
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12:15 |
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George Pavlakis
Head, Human Retrovirus Section
Senior Investigator
NIH, Center for Cancer Research, National Cancer Institute
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12:40 |
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Xin Yu
Scientific Research Associate
Genentech
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1:05 | Closing Remarks & Conference Concludes |
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1:10 | Lunch Provided by GTC |