Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
DNA vaccination wikipedia , lookup
Monoclonal antibody wikipedia , lookup
Molecular mimicry wikipedia , lookup
Lymphopoiesis wikipedia , lookup
Immune system wikipedia , lookup
Polyclonal B cell response wikipedia , lookup
Immunosuppressive drug wikipedia , lookup
Adaptive immune system wikipedia , lookup
Psychoneuroimmunology wikipedia , lookup
Adoptive cell transfer wikipedia , lookup
Cancer immunotherapy wikipedia , lookup
Immunology and Cell Biology (2012) 90, 1–2 & 2012 Australasian Society for Immunology Inc. All rights reserved 0818-9641/12 www.nature.com/icb OBITUARY Ralph Steinman and dendritic cells Immunology and Cell Biology (2012) 90, 1–2; doi:10.1038/icb.2011.91; published online 25 October 2011 O n the morning of 3 October, we were confronted with news evoking totally contradictory emotions. We celebrated that Ralph Steinman, along with Bruce Beutler and Jules Hoffman, had been awarded the 2011 Nobel Prize for Physiology and Medicine. At the same time we heard that Ralph had finally lost his 4-year battle against pancreatic cancer, sadly before he knew of the award. The entire Australasian Immunology Community and especially those who work on dendritic cells (DCs) extend their deepest sympathies to Ralph’s family, friends and work colleagues. Immunology has lost one of its finest scientists and inspirational leaders. Ralph Steinman has for many years rightly been considered the father of DC research. He was a Canadian, with a science degree from McGill, a medical degree from Harvard and further medical training from Massachusetts General Hospital. His extensive research on DCs was conducted during his long career at the Rockefeller University in New York, beginning as a post-doctoral fellow and progressing to be the Henry G Kunkel Professor and Editor of the Journal of Experimental Medicine. The modern concept of DCs as conductors of the immune orchestra1 owes much to Steinman’s work and leadership. We now consider DCs to be the crucial antigen-presenting cells that mediate between the innate and adaptive immune systems. DCs collect and process antigens for presentation on MHC molecules to T lymphocytes. DCs also sense the environment via innate receptors for inflammatory mediators, for damaged cells or for microbial products, and then direct an appropriate adaptive immune response from the T cells reactive with the presented antigen. In their quiescent state, the presentation of self-antigens by the DCs serves to maintain self-tolerance. Following pathogen invasion, the DCs are activated by the signals they receive via their innate receptors. T cells reactive with the foreign antigens presented by the DCs are then driven to an immune response tailored to the infection. The 2011 Nobel Prize reflects the development of this model, as Beutler and Hoffman discovered receptors that recognise microbial products and activate the innate immune system, including DCs. The current acceptance of this model belies the struggle in Steinman’s path to assigning DCs as the central cells. In 1973, Steinman, working with Zanvil Cohn, identified cells with a distinctive dendritic morphology as a rare component of a spleen cell suspension.2 The ‘veiled’ cells noted by others in lymph were, in retrospect, also DCs. However, few at that time were impressed by the particular morphology described in such reports, as other cells, including macrophages, can acquire a dendritic form. However, Steinman considered them a distinct cell type. He would need great courage of his convictions in this pursuit, as it took 10 years before the specialised antigen-presenting role of DCs was clearly established. The crucial finding was that almost all of the antigen-presenting, T-cell-stimulating function in mixed leucocyte reactions could be attributed to the small number of DCs present.3 Steinman and his research team then The image of Ralph Steinman was taken at the Australasian Society for Immunology 2010 Conference in Perth, Australia, where he was an invited speaker. The image is provided by and used with the permission of Alan Baxter, Comparative Genomics Centre, James Cook University, Townsville, Queensland 4811, Australia. led the rapidly expanding DC field: improving DC isolation procedures, developing monoclonal antibodies recognising DC surface components, analysing DC populations by flow cytometry and clarifying DC antigen-processing functions. Particularly important was his collaboration with scientists with a dermatology background, showing that epidermal Langerhans cells were a form of DC.4 Langerhans cells then served as the classic model of DCs as sentinels, collecting antigens in their immature state in the periphery, then migrating to lymph nodes as mature DCs to present the antigens to T cells. In addition to all his contributions to basic DC biology, Ralph Steinman was a passionate advocate for applying this new knowledge to the human immune system. His laboratory carried out many of the early studies on the interaction of HIV with DC during the development of AIDS. He believed that DCs could be manipulated for clinical benefit, either suppressing immune responses to reduce or prevent autoimmune pathology, or enhancing immune responses to improve vaccines against infectious disease or against tumours.5 Much publicity has now been given to the fact that Ralph himself tried a form of DC immunotherapy for his own pancreatic cancer. More publicity should be given to the approach he was developing of targeting antigens directly to DCs in situ, by injecting antigens coupled to antibodies against DC surface molecules. The series of papers on targeting DEC-205, from Steinman’s laboratory in collaboration with the laboratory of Michel Nussenzweig, attest to the promise of this new strategy, soon to be in clinical trials. Obituary 2 Ralph Steinman’s leadership of the DC research community was never more apparent than at the series of biennial International DC Symposia. His opening presentations and summing-up talks were clear, insightful and inspirational. His enthusiasm for the science was neither diminished by doubting criticism from others nor even by his severe illness. Some have observed that for Ralph the science and the people doing it were inextricably linked. His introduction of a speaker always involved some personal background, often with carefully researched slides. Certainly, most in the DC field believed that the first and essential step to introducing a new concept or finding was a quiet talk with Ralph. Probably everyone in the DC field has submitted a paper believing (rightly or not) that the key to the gate of acceptance or rejection was held by Ralph Steinman. So it may be worth noting the fate of a recent manuscript by Shklovskaya/Fazekas de St Groth averring that Langerhans cells are always tolerogenic, a view that was opposed by many and certainly contradicted earlier results from Steinman’s laboratory. Despite this, Ralph Steinman guided the manuscript through review such that one of his last actions was to authorise acceptance in Proceedings of the National Academy of Science, USA. Immunology and Cell Biology Ralph Steinman’s legacy is a thriving research field. Much of the detailed knowledge of DC biology needed for clinical applications is now available. We should follow through with the same dedication, resilience, enthusiasm and scientific solidity that characterised Ralph’s own remarkable research career. Ken Shortman Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Melbourne, Victoria 3052, Australia E-mail: [email protected] 1 Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998; 392: 245–252. 2 Steinman RM, Cohn ZA. Identification of a novel cell type in peripheral lymphoid organs of mice. J Exp Med 1973; 137: 1142–1162. 3 Steinman RM, Gutchinov B, Witmer MD, Nussenzweig MC. Dendritic cells are the principal stimulators of the primary mixed leucocyte reaction in mice. J Exp Med 1983; 157: 613–627. 4 Schuler G, Steinman RM. Murine epidermal Langerhans cells mature into potent allostimulatory dendritic cells in vitro. J Exp Med 1985; 161: 526–546. 5 Steinman RM, Banchereau J. Taking dendritic cells into medicine. Nature 2007; 449: 419–426.