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1 HARVARD MEDICAL SCHOOL - PORTUGAL PROGRAM // 4TH INTERNATIONAL SYMPOSIUM: IMMUNOMEDICINE WELCOME MESSAGE Welcome to the Fourth International Symposium on Immunomedicine of the Harvard Medical School – Portugal Program in Translational Research and Information. This year’s symposium will be held on 12-13th April 2013, at the Faculty of Health Sciences of the University of Coimbra (Coimbra, Portugal). During the two days of the Symposium there will be seven great talks from invited speakers from Portugal and Boston, covering many exciting areas in the field of Immunology. We invite you to join the speakers and the Portuguese and Harvard Medical School Directors of the Program, whom will be fully available for informal discussions throughout the duration of the Symposium. We look forward to seeing you all. _____________________________ ______________________________ Maria Carmo-Fonseca Tom Kirchhausen Program Director in Portugal Program Director at Harvard Medical School 2 HARVARD MEDICAL SCHOOL - PORTUGAL PROGRAM // 4TH INTERNATIONAL SYMPOSIUM: IMMUNOMEDICINE KNOW THE SCHEDULE FRIDAY, 12TH APRIL 2013 4.30pm - 5.30pm Registration 5.30pm - 6.00pm Welcome 6.00pm - 7.00pm Lecture 1: Michael Starnbach Harvard Medical School Bacterial Pathogens Modify Host Immunity and Host Cells 7.00pm - 8.00pm Lecture 2: Margarida Correia-Neves Escola de Ciências da Ssaúde, ECS UM Should we care about the thymus during infection by mycobacteria? 8.20pm Dinner for all those previously registered 3 HARVARD MEDICAL SCHOOL - PORTUGAL PROGRAM // 4TH INTERNATIONAL SYMPOSIUM: IMMUNOMEDICINE day 1 KNOW THE SCHEDULE day 2 SATURDAY, 13TH APRIL 2013 9.30am - 10.30am Lecture 3: Nuno Alves Institute for Molecular and Cell Biology, IBMC UP The Quest for the Thymus: Molecular and Cellular Mechanisms required for Thymus Development and Function 10.30am - 11.30pm Lecture 4: Jonathan Kagan Boston Children's Hospital, Harvard Medical School Innate immunity from insects to man 11.30am - 12.00pm Coffee Break 12.00pm - 1.00pm Lecture 5: Bruno Silva-Santos Institute of Molecular Medicine, IMM UL T cells in cancer and autoimmunity 1.00pm - 2.30pm Round tables with speakers, including lunch for all those previously registered 2.30pm - 3.30pm Lecture 6: Margarida Souto-Carneiro Center for Neurosciences and Cell Biology, CNC UC B is for Bad: Altered B cell response in primary Immunodeficiencies and Neurodegeneration 3.30pm - 4.30pm Lecture 7: Sung-Yun Pai Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Med. School Translational Investigation in Congenital Immunodeficiency 4.30pm - 5.00pm Coffee Break 5.00pm - 6.45pm Research as a Career in Biomedicine: Why it is Fun Open Discussion with Speakers and HMS-PT Directors 6.45pm - 7.00pm Farewell 4 HARVARD MEDICAL SCHOOL - PORTUGAL PROGRAM // 4TH INTERNATIONAL SYMPOSIUM: IMMUNOMEDICINE MEET THE SPEAKERS lecture 1 MICHAEL STARNBACH Bacterial Pathogens Modify Host Immunity and Host Cells Research in my lab uses a combination of cellular and molecular approaches in the analysis of cellular immune responses to pathogens that cause chronic bacterial infections. Many virulence factors have been identified that allow bacteria to survive and replicate within the mammalian host and often within host cells. I have focused on the immune consequences of these survival strategies, specifically asking the following questions: What are the pathways for recognition of antigens from intracellular bacterial pathogens? How do bacterial virulence factors subvert or inhibit cellular immune responses allowing for chronic infection? How can we promote the recognition of bacterial antigens that may or may not be recognized in the context of natural infections? What are the key host effector cells and pathways needed for protective immune responses to intracellular bacterial pathogens and their products? 5 HARVARD MEDICAL SCHOOL - PORTUGAL PROGRAM // 4TH INTERNATIONAL SYMPOSIUM: IMMUNOMEDICINE MEET THE SPEAKERS lecture 2 MARGARIDA CORREIA-NEVES Should we care about the thymus during infection by mycobacteria? The ability of the immune system to mount an efficient immune response to pathogens depends, among others, on its capacity to establish and maintain a functional and diverse repertoire of T lymphocytes. T lymphocytes differentiate within the thymus, in a complex process that depends on three key features: thymic structure, antigens encountered within the thymus and the milieu surrounding the differentiating cells. The thymus is extremely active and establishes a diverse repertoire of T cells quite early in life, which suggested a role for the thymus mostly during infancy. It is now clear, however, that the process of T cell differentiation and export to peripheral organs is important also during adulthood. Of interest, the thymus was, for long, considered somehow protected from infection, or at least, not clearly affected by infection. We and others have recently shown that infection influences T cell differentiation, either directly or indirectly (through systemic increase in the levels of corticosteroids and of pro-inflammatory cytokines), which opens new questions on the role of the thymus throughout life. Of relevance in the context of infection by Mycobacteria, is the alteration of thymic structure and function. Specifically, mycobacterial infections alter T cell differentiation, which impacts on the ability of the host to fight against infection. Maintaining a functional thymic environment is essential to maintain T cell differentiation and prevent the emergence of central tolerance to the invading pathogens, which will be discussed. 6 HARVARD MEDICAL SCHOOL - PORTUGAL PROGRAM // 4TH INTERNATIONAL SYMPOSIUM: IMMUNOMEDICINE MEET THE SPEAKERS lecture 3 NUNO ALVES The Quest for the Thymus: Molecular and Cellular Mechanisms Required for Thymus Development and Function The production of T lymphocytes by the thymus, also known as thymopoiesis, is not constant during life and deficits in thymic function arise in several physiopathological settings ranging from aging to infection and myeloablative conditioning regimens prior to allogeneic hematopoietic transplantation. Thus, the development of approaches to regenerate thymic activity in disease is an emergent clinical goal. In the thymus, essentially all steps of thymopoiesis require interactions between T lymphocyte precursors (thymocytes) and thymic epithelial cells (TECs). TECs are classically divided into two specialized subsets, cortical (cTECs) and medullary (mTECs), which derived from a common bipotent epithelial progenitor. Whereas cTECs are important at early stages of thymopoiesis, mTECs regulate later phases of T cell development. The identification of thymic epithelial progenitor cells (TEPCs) has been a quest in the recent years given the possibility of developing cell-based therapies to alter thymic function. Recent findings suggest that TEC differentiation proceeds through compartment-specific progenitors for cTECs and mTECs, although the details of precursor-progeny relationship are unresolved. The partitioning of TEPCs into cTECs and mTECs requires reciprocal instructive signals from thymocytes, a symbiotic process known as “thymic crosstalk”. While the molecular basis of mTEC maturation has been partially elucidated, our understanding about the differentiation pathway of cTECs remains largely undisclosed. I will discuss our recent findings on the cellular and molecular pathways involved in cTEC differentiation in normal and pathological conditions. We aim to provide with a detailed framework for cTEC development and function that may be integrated into therapeutics to improve thymic functioning in acquired and congenital immunodeficiencies. 7 HARVARD MEDICAL SCHOOL - PORTUGAL PROGRAM // 4TH INTERNATIONAL SYMPOSIUM: IMMUNOMEDICINE MEET THE SPEAKERS lecture 4 JONATHAN KAGAN Innate Immunity from Insects to Man I have been studying Pattern Recognition Receptor signaling pathways as a means of understating the earliest events that initiate immunity to infection. Our work initiated with studies of the Toll-like Receptor (TLR) signaling networks, which mainly operate in professional phagocytes and function to detect microorganisms that enter our bodies. The organizing principles that govern TLR signaling are entirely unknown and their elucidation will likely reveal answers to several fundamental questions that apply to the study of vaccine design. My research has focused primarily on defining the subcellular sites of TLR signal transduction. We have established that TLR adaptor proteins function as pairs of sorting and signaling adaptors, where the sorting adaptor functions to recruit the signaling adaptor to a subcellular site that contains an activated TLR. Our work provided the first in vivo evidence that the localization of these adaptor proteins in important for controlling microbial infections. In addition, we have defined a new signal transduction pathway activated when mammalian cells are exposed to bacterial LPS. This new pathway is most notable in that signal transduction is not initiated by the classic LPS receptor TLR4, but is rather triggered by the LPS binding protein CD14. Upon encountering LPS, CD14 triggers a signaling response that internalizes TLR4 into endosomes, where the classic TRIF-mediated signaling events that lead to interferon expression are activated. These studies provide the first evidence that TLR4 does not control all cellular responses to bacterial LPS, an observation that may have broad implications for the understanding of signal transduction in general. Recently, we have extended our work to the cytosolic pattern recognition receptors of the RIG-I like receptor (RLR) family, which functions in all mammalian cells to detect viral infections. Using a similar logic that we have applied to the TLR network, we have discovered a new subcellular site of antiviral signal transduction. In addition to the previously described mitochondria, RLR signaling also occurs from peroxisomes, an organelle never before implicated in innate immunity. This work has allowed a new area of my research to emerge, and we will focus on extending our initial studies of the RLR signaling network to further define the role of peroxisomes in antiviral immunity. 8 HARVARD MEDICAL SCHOOL - PORTUGAL PROGRAM // 4TH INTERNATIONAL SYMPOSIUM: IMMUNOMEDICINE MEET THE SPEAKERS lecture 5 BRUNO SILVA-SANTOS T cells in cancer and autoimmunity T lymphocytes are critically involved in both preventing and causing pathology. Whereas they play protective roles against infectious microrganisms and tumors, they can be highly pathogenic in autoimmunity and chronic inflammatory diseases. For example, T cells producing interleukin-17 (T17) are required to fight bacterial and fungal infections, but they are also major drivers of type 1 diabetes, multiple sclerosis and psoriasis. Moreover, recent data has highlighted a diversity of T cell subsets that can be involved in such processes, often playing antagonistic roles. For instance, the pro-inflammatory action of T17 cells is counteracted by the anti-inflammatory function of regulatory T (Treg) cells. In my laboratory we investigate the molecular mechanisms underlying the differentiation and activation of key T cell subsets. We have identified various new molecular players, such as the tumor necrosis factor superfamily member CD70 and its receptor CD27, which promote Treg development while inhibiting T17 differentiation and function. This makes CD70/ CD27 a promising candidate pathway for intervention in autoimmunity and chronic inflammation. On the other hand, we also study T cell responses to tumors, and have dissected the molecular mechanisms of tumor cell recognition by gamma-delta T cells, a highly cytotoxic T cell subset that is being evaluated in cancer clinical trials. We have identified the Natural Killer receptors NKG2D and NKp30 as major determinants of leukemia/ lymphoma targeting by human gamma-delta T cells. We are now building on these findings toward the development of novel immunotherapy protocols against cancer. 9 HARVARD MEDICAL SCHOOL - PORTUGAL PROGRAM // 4TH INTERNATIONAL SYMPOSIUM: IMMUNOMEDICINE MEET THE SPEAKERS lecture 6 MARGARIDA SOUTO-CARNEIRO B is for Bad: Altered B cell response in primary Immunodeficiencies and Neurodegeneration B lymphocytes and plasma cells play a central role in the immune response both as regulators (cytokine production; antigen presentation; cell-cell interaction) and as antibody-producing cells. Dramatic functional alterations in peripheral blood B lymphocytes subsets are a hallmark of chronic inflammatory diseases, in particular those with an autoimmune basis. In chronic autoimmune inflammation B cells exhibit abnormal proliferation, maturation and apoptosis, and produce antibodies against self-antigens, which enter the antigen processing pathway after pathogenic tissue and/or cell destruction. The precise mechanisms underlying this auto-reactivity are still ill understood. We will discuss two questions about autoantibodies and abnormal B cell responses in contexts usually not associated with “classical” autoimmune diseases: 1) How do reactive oxygen species (ROS) control B cell tolerance, and prevent chronic inflammation? Using a combination of human samples from patients with chronic granulomatous diseases –a primary immunodeficiency- and the corresponding mouse model, we will debate how mutations in the NADPHoxidase complex and deficient production of ROS leads to autoantibody production through type I Interferon pathway (even in germ-free conditions); how DSS-induced colitis is exacerbated; how the development of memory B cells in a secondary immune response is impaired; and how the response to Candida albicans is deficient. 2) Is there evidence for chronic inflammation in neurodegeneration leading to movement impairment? Using blood B cells from Parkinson’s Disease patients we study how B cell-derived regulatory T cell formation is impaired and how the production of autoantibodies is increased, under conditions where B cell function and intracellular signaling pathways are altered. 10 HARVARD MEDICAL SCHOOL - PORTUGAL PROGRAM // 4TH INTERNATIONAL SYMPOSIUM: IMMUNOMEDICINE MEET THE SPEAKERS lecture 7 SUNG-YUN PAI Translational Investigation in Congenital Immunodeficiency The study of congenital disorders of the immune system have led to seminal discoveries about the genes that control immune cell development and function. A veritable explosion in gene discovery in this field has led to the identification of ~150 genes that cause congenital immunodeficiency in humans. Simultaneously, medical advances in the treatment of these rare disorders has made allogeneic hematopoietic stem cell transplantation the standard therapy and ultimately paved the way for the use of somatic gene therapy. My laboratory focuses on translational investigations in congenital immunodeficiency and its treatment. We gather samples from children with rare immunodeficiencies including severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome and others, and investigate the effects of the various genes responsible and specific mutations on immune development and function. We were involved in the development and implementation of a universal newborn screening program to detect SCID in newborn dried blood spots at birth and have uncovered interesting and unexpected phenotypes of SCID in the process. We are examining the effect of different types of allogeneic transplantation methods on the immune reconstitution of SCID patients, particularly with regards to B cell function and dysregulation. Finally, we are conducting gene therapy trials in the X-linked form of SCID (due to mutations in IL2RG) and in Wiskott-Aldrich syndrome in collaboration with colleagues in the US and Europe. Through these investigations we aim to understand the mechanisms underlying these genetic disorders, improve diagnostic techniques, and ultimately advance the field by improving outcomes of both standard and experimental therapeutic approaches. 11 HARVARD MEDICAL SCHOOL - PORTUGAL PROGRAM // 4TH INTERNATIONAL SYMPOSIUM: IMMUNOMEDICINE ABOUT HARVARD MEDICAL SCHOOL – PORTUGAL PROGRAM The HMS-PT Program is a wide-ranging initiative, involving professors, researchers and students from all 8 schools of Medicine in Portugal, as well as the country's main biomedical research laboratories. It aims at modernizing and improving the quality of medical education in Portugal, whilst also broadening the scope of cooperation between Portuguese medical schools and associated laboratories in such a way as to spur the creation of a truly competitive level of training at the international level. The translational research activities are designed to help populate Portuguese research institutions with an increasingly sophisticated clinical and translational research capacity, and to expand the rate and quality of Portuguese clinical and translational research contributions to the international community. The program is also designed to foster long-lasting collaborative ventures, both within Portugal and between Portuguese and Harvard research groups. COIMBRA AND UNIVERSITY OF COIMBRA Sometimes referred to as a town of students, Coimbra is one of the three main urban centres in Portugal. The town nowadays covers an area of 319,41 km², with a total population of about 144,000 people. The Mondego river crosses through the city. The richness of Coimbra rests mostly on the University of Coimbra, one of the oldest in Europe, with about 20,000 students – the city has a total of 35,000 higher education students distributed across a multiplicity of graduation courses, awarding all academic degrees in fields ranging from medicine and biomedical sciences to aeronautical engineering and mathematics. THE VENUE Auditório da Unidade Central da Faculdade de Medicina da Universidade de Coimbra Unidade Central, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, Celas CONTACTS For more information please visit www.hmsportugal.pt Please direct all further enquiries to [email protected] 12 HARVARD MEDICAL SCHOOL - PORTUGAL PROGRAM // 4TH INTERNATIONAL SYMPOSIUM: IMMUNOMEDICINE