Ralph Marvin Steinman - 2011 Nobel Prize in Physiology

Ralph Marvin Steinman (January 14, 1943 – September 30, 2011) was a Canadian immunologist and cell biologist at Rockefeller University, who in 1973 coined the term dendritic cells while working as a postdoctoral fellow in the laboratory of Zanvil A. Cohn, also at Rockefeller University. Steinman was one of the recipients of the 2011 Nobel Prize in Physiology or Medicine.Ralph Steinman was born into an Ashkenazi Jewish family in Montreal, one of four children of Irving Steinman (d. 1995), a haberdasher, and Nettie Steinman (née Takefman, b. 1917). The family soon moved to Sherbrooke, where the father opened and ran a small clothing store "Mozart's". After graduating from Sherbrooke High School, Steinman moved back to Montreal where he stayed with his maternal grandparents Nathan and Eva Takefman. He received a Bachelor of Science degree from McGill University and received his M.D. (magna cum laude) in 1968 from Harvard Medical School. He completed his internship and residency at Massachusetts General Hospital.

On October 3, 2011, the Nobel Committee for Physiology or Medicine announced that he had received one-half of the Nobel Prize in Physiology or Medicine, for "his discovery of the dendritic cell and its role in adaptive immunity". The other half went to Bruce Beutler and Jules A. Hoffmann, for "their discoveries concerning the activation of innate immunity". However, the committee was not aware that he had died three days earlier, on September 30, from pancreatic cancer. This created a complication, since the statutes of the Nobel Foundation stipulate that the prize is not to be awarded posthumously. After deliberation, the committee decided that as the decision to award the prize "was made in good faith", it would remain unchanged.

Steinman's daughter said that he had joked the previous week with his family about staying alive until the prize announcement. Steinman said: "I know I have got to hold out for that. They don't give it to you if you have passed away. I got to hold out for that."

Steinman had received numerous other awards and recognitions for his lifelong work on dendritic cells, such as the Albert Lasker Award For Basic Medical Research (2007), the Gairdner Foundation International Award (2003), and the Cancer Research Institute William B. Coley Award (1998). In addition, he was made a member of Institute of Medicine (U.S.A.; elected 2002) and the National Academy of Sciences (U.S.A.; elected 2001).

1998 – William B. Coley Award

1999 – Robert Koch Prize

2003 – Gairdner Foundation International Award

2006 – Debrecen Award for Molecular Medicine

2007 – Albert Lasker Award for Basic Medical Research

2009 – Albany Medical Center Prize (Shared with Charles A. Dinarello and Bruce Beutler; )

2010 – Heineken Prizes

2011 – Nobel Prize in Physiology or Medicine (shared with Bruce Beutler and Jules A. Hoffmann)

Immunology tries to understand resistance to infection. Infections are first resisted by innate immunity, followed by adaptive immunity which has memory and so can prevent reinfection. Two questions that Immunologiests ask: 1) what mechanism do innate and adaptive resistance come about? 2) how do these mechanisms contribute to other fields of medicine such as cancer, allergy, autoimmunity etc.? In the 20th century, he came up with two theories: 1) macrophages mediate innate resistance through phagocytosis and intracellular killing 2) Ab mediate adaptive resistance by neutralizing microbial toxins. Steinman discovered that dendritic cells link innate to adaptive immunity, including adaptive Tcell-mediated immunity.

He studied the initiation of antibody responses in tissue culture in the laboratory. As shown, he found out that antigens, lymphocytes and "accessory cells" together create immune responses. Accessory cells contain a new cell type with probing cell process or "dendrites". These cells proved to be the missing link between innate and adaptive immunity.

Several features were used to identify and purify dendritic cells from mouse spleen. Because dendritic cells were discovered amongst "adherent" accessory cells (i.e. those that attach to tissue culture surfaces), they had to be distinguished from macrophages, whose hallmarks were persistent phagocytosis and adherence to tissue culture surfaces. However, Steinman found that dendritic cells (blue) had different morphology and expressed different molecules from macrophages. For example, they did not express FcR- receptors but did express major components of the Major Histocompatibility Complex II and did not adhere to surfaces or exploit phagocytosis. Macrophages on the other hand showed the opposite characteristics. The study was carried out in collaboration with Zanvil A. Cohn, who studied resistance to infectious diseases especially the biology of macrophages.

Some general features of T cell responses that are initiated by dendritic cells: - adaptive immunity develops in two stages: DCs present antigens and initiate the afferent limb, while the other APC mediate the effectors to eliminate the antigen or infection - in tissue cultures, immunity develops in clusters of DC and lymphocytes. You can actually observe the onset of adaptive immunity in vitro. Dendritic cells were therefore considered "nature's adjuvants" for T cell immnunity, meaning they helped induce T cells. DCs can produce protective substances like cytokines, interferons, chemokines, anti-microbial peptides DCs can mobilize innate lymphocyltes such as natural killer cells (which in turn produce cytokines or kill target cells upon recognition) However, unlike macrophages, DCs do not phagocytose or kill microbes

DCs capture, process and present antigens: - some receptors such as FcR death receptor can activate/inhibit DC function - Antigen processing and presentation of proteins and lipids seems efficient and can include cross presentation on MHC I and CD1 - Uptake and processing are regulated by environmental stimuli - In vivo, dendritic cells process antigens to form peptide-MHC complexes in the steady state, especially in lymphoid organs - Most DCs in vivo in the steady state are immature, able to take up and present antigens, but unable to adaptive T cell immunity - Environmental stimuli, e.g., microbial products, alter or mature DCs and/or act together with DCs to control the formation of different types of helper, cytotoxic and regulatory types of T cells - Maturing dendritic cells also carry out innate responses, particularly the formation of cytokines and chemokines - Maturation links innate to adaptive immunity; it controls the quality of the response that develops in DCs and in lymphocytes that recognize presented antigens - "subset" refers to distinct DC with different receptor for antigen uptake and maturation, and distinct functions in innate and adaptive immunity. they reside in the peripheral organs and induce different forms of antigen-specific peripheral tolerance. Antigens from the periphery are captured by DC in lymphoid tissues, even in steady (not matured) state. In steady state, DC induce tolerance so that DC maturation can lead to immunity to microbial antigen - However, maturing DC capture microbial as well as self, dying cells, thus resulting in autoreactivity and chronic inflammation.