The Nobel Prize–Winning Work of Ralph Steinman (1943–2011) and Its Relevance to Transplantation

Ralph Marvin Steinman, whose seminal discovery of dendritic leukocytes and their potent ability to stimulate adaptive T-cell responses launched a new field and invigorated almost all branches of basic and clinical immunology, died on September 30, 2011, 2 to 3 days before being awarded the Nobel Prize in Physiology and Medicine (shared with Bruce Beutler and Matthais Hoffman for their discovery of receptors that recognize microbial products and activate the immune system). Ralph Steinman grew up in Sherbrooke, Quebec, Canada, and obtained a science degree from McGill University, Montreal, in 1963 and an MD from Harvard Medical School in 1968. While a young physician at Massachusetts General Hospital in the late 1960s, he became fascinated by immunology and, in particular, by the work of Burnet, Medawar, and Gowans that raised the fundamental question of how lymphocyte-mediated immune responses (particularly those to transplanted tissue) were initiated. In 1970, he embarked on postdoctoral studies with Zanvil Cohn and James Hirsch at The Rockefeller University in New York—already a center of excellence in cell biology. Initially, he examined how macrophages capture and present antigens to initiate immune responses. Dismissive of macrophages as accessory or antigen-presenting cells, he looked for more effective “accessory cells” in mouse spleen, where, as it had been shown, antibody responses were initiated. Therein, he and Cohn identified rare, large, low-density “stellate cells” with distinct properties that they named “dendritic cells (DC)” (1). The biologic significance of such rare cells was doubted by many, including those deterred by the cumbersome enrichment procedures. It was not for several years, until Steinman and Witmer-Pack demonstrated that DC were 100-fold superior to macrophages in activating allogeneic T cells in mixed leukocyte reactions (2), that their immunologic role became more widely recognized. Further effort was required to prove that DC could capture, process, and present external/foreign antigens and induce T-cell activation. Many crucial developments followed. Working with Steinman, Schuler, and Romani showed that epidermal Langerhans cells that could pick up antigen were a type of DC and that their migration was associated with maturation into potent T-cell stimulatory cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) was shown to be necessary for DC maturation. In addition, with Steinman, Nussenzweig developed the first DC-specific antibody, a development that greatly aided their purification, whereas Inaba showed that DC could induce T helper–cell development. In Europe, Lechler and Batchelor demonstrated in vivo immunogenicity of DC in rat renal allograft “parking” experiments, whereas Steinman’s work with Faustman showed that depletion of DC in pancreatic islet allografts prolonged their survival in diabetic hosts. Following studies with Steinman of DC migration from skin allografts, Larsen, Austyn, and Morris in Oxford reported the trafficking of donor major histocompatibility complex II+ DC from heart allografts to host secondary lymphoid tissue, implicating DC as inducers of rejection. However, in Pittsburgh, Lu, Demetris, and Thomson demonstrated similar trafficking patterns of liver-derived DC associated with the induction of spontaneous liver allograft tolerance and the ability of immature liver-derived or bone marrow-derived DC to prolong allograft survival. Collectively, these studies showed the pluripotential ability of DC to regulate alloimmune responses in vivo (3, 4). In addition, transplantation provided the basis for studying the role of DC in direct and indirect allorecognition. In 1992, a major breakthrough occurred when Inaba, Steinman, and colleagues propagated DC from hematopoietic progenitors using GM-CSF. The ability to generate large numbers of these previously rare, difficult-to-isolate cells, including those from humans, resulted in a rapid change in momentum and an explosive development of basic and applied DC biology. This new ease of DC propagation facilitated a demonstration of the ability of antigen-loaded mature DC to serve as immunological adjuvants able to immunize mice and humans. The molecular basis of DC antigen-processing and presentation functions begun to be clarified, and the role of the decalectin DEC-205 on DC in enhancing antigen presentation efficiency was identified. Later, the progenitors of DC in bone marrow were identified, and their critical dependence on the cytokine fms-like tyrosine kinase-3 ligand for lineage development was revealed. Reflecting his strong, enduring commitment to human subject immunology research, Steinman’s laboratory performed early studies on the interaction of DC with human immunodeficiency virus, showing that DC could transmit vigorous cytopathic infection to CD4+ T cells. In human cancer, early work showed that antigen-loaded mature DC could immunize patients to cancer antigens. Over time, objective responses using DC cancer vaccines have been modest, but it must be noted that limited tumor target antigens and the requirement to test DC vaccines in immunocompromised patients with advanced disease have contributed to these limited outcomes. Future success may depend on the use of fully activated DC loaded with multiple tumor-specific antigens given to patients with minimal residual disease and the control of mechanisms underlying peripheral tolerance. The recent approval of a novel DC-based vaccine for prostate cancer is a promising development in this direction. The growing understanding that DC maturation was associated with transition from immature DC with tolerogenic properties led to increasing interest in the role of immature DC (tolerogenic DC) in central and peripheral tolerance in the steady state. Steinman realized the potential of targeting antigen to these immature DC in situ with DC-specific antibody (anti-DEC [CD] 205) to promote tolerance—a strategy soon to be in clinical trials. Moreover, he and Dhodapkar demonstrated the ability of injected immature DC to inhibit antigen-specific effector T cells and induce antigen-specific regulatory T cells (Treg) in vivo in humans—a property now being tested in autoimmune disease and transplantation, including the imminent testing of tolerogenic DC in human renal transplantation as part of “The One Study” (a unified, co-operative approach to cell therapy in clinical organ transplantation). Steinman’s demonstration of the ability of DC to expand or induce antigen-specific Treg in vitro with efficacy as adoptive cell therapy in experimental autoimmune disease, or for suppression of graft-versus-host disease following bone marrow transplantation, offers further evidence of the therapeutic potential of tolerogenic DC. This potential is exemplified by DC with transforming growth factor-β1-induced, alloantigen-specific Treg protecting islet allografts in a stringent transplantation model in which naturally occurring Treg are relatively ineffective (5). Developments in basic and applied DC biology have been discussed in a succession of international and Keystone symposia over the past 20 years. Steinman’s leadership and his insightful and inspiring opinions were keenly sought. Now, almost 40 years from the discovery of the rare “stellate cells” in mouse spleen, DC are recognized as heterogeneous and highly specialized major players in the regulation of innate and adaptive immunity. Steinman (Fig. 1) was not only a stellar scientist but also an exceptional colleague and a gentleman to the core. One of us (M.S.) had the extreme good fortune of both scientific exchanges and informal luncheons with Steinman over the years. In these days of “patent before publish”, many ideas were freely discussed, laboratory meetings were wide open to each other’s post docs, and unpublished data were shared without any concern of being scooped. There was never discussion about first or senior authorship and the ultimate grace of never taking undue credit. A stickler for precision—unfailingly changing mixed lymphocyte reaction to mixed leukocyte reaction every time it appeared in one of our manuscripts—Steinman taught immunology, from students to professors, with humility and uncommon openness to new ideas.FIGURE: Ralph M. Steinman, M.D. Photo credit: Zach Veilleux, The Rockefeller University, New York.Shortly before his death, Ralph Steinman expressed his strongly held view (6) that DC would provide the basis of many future medical advances. His excitement in their clinical potential remained unabated. His enduring legacy would be the full realization of this vision and, for a wide range of patients—from those afflicted with immunodeficiency to organ graft recipients—the benefit of a fuller life.

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