Ralph Steinman and the Discovery of Dendritic Cells

Ralph M. Steinman

Ralph Steinman

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Introduction

The mechanism by which our body combats invading pathogens and infections has always been an area of interest for researchers. Many scientists have rolled in various theories and discoveries. However, Ralph Steinman and his work stands out effortlessly in this context.
Ralph Steinman who studied immunity at Harvard Medical school, wanted to discover immune initiation and the relation between innate and adaptive. His discovery of dendritic cells cleared this dilemma for the med-community.

In vitro study revealed that lymphocytes were not enough to produce an immune response, some accessory cells were required for initiation whose function was to present antigen to the lymphocytes. (1)

The accessory cell was assumed to be a macrophage. Steinman joined Physician-scientist Zanvil A.Cohn and James G. Hirsch. His first assignment was to explore macrophages as accessory cells by using horseradish peroxidase and immune complexes. There was no antigen found within macrophages leading to failure but an important clue that the uptake of antigen was so rapid that macrophages must be constantly recycling their membranes was found. (1)

The Branched Cell

With the help of Rockefeller colleagues in fixation, electron microscopy and centrifugation, Steinman and Cohn studied mouse spleen cells, they discovered a cell with dendritic processes and no phagocytic vacuoles. The cells were called dendritic cells meaning tree. This won the Nobel Prize in Physiology in 2011.

A Victorious Experiment

In 1978, Steinman and his student Michael Nussenzweig developed an assay based on haptens being used as antigens. The assay involved modifying cells with the nitrophenyl moiety and measuring the cytotoxic or killer T-lymphocytes formed. Dendritic cell responses were compared to macrophages’ response. Dendritic cells were confirmed as the accessory cells. The principle of accessory cells presenting antigens to T-cells for initiating immune response was made. (2)

The initial fruitless efforts of segregating dendritic cells from a mixture and locating them in the organism were turned fruitful with Nussenzweig monoclonal antibody 33D1. It visualized dendritic cells in tissues and separated them from mixtures with immune response decreasing with it.
Important contributions were made by Wes Van Voorhis, who studied the presence of dendritic cells in blood and them being different from monocytes and Kayo Inaba who showed a non-macrophage in the spleen could function as an accessory cell. Comparison of both cells showed dendritic cells being more superior. (2)

Immunotherapy

Even more praiseworthy was his experiment with antiviral and anti-tumor activities of dendritic cells, these were removed from the mouse and loaded with antigen, placed again and that gave strong immunity. This method introduced immunotherapy. (3) This was used for therapy with the first drug Provenge for the treatment of prostate cancer and Steinman’s pancreatic tumor.

Experiments found that dendritic cells are present in airway epithelium, skin, mucosa, spleen, thymus, lymph nodes and tonsils. The link between dendritic cells and macrophages was found to be myeloid precursors. Both were derived out of it.

Two States of Dendritic Cells

Steinman and colleagues Gerold Schuler and Nikolaus Romani discovered that dendritic cells exist in two states. The inactive state which turns to an active state once they are exposed to toll receptor ligands and cytokines. This process called maturation. With maturation, dendritic cells mobilized MHC II from lysosomes to their surface and started acting as antigen-presenting cells (3).

Development Of Tolerance

Daniel Hawiger tested dendritic cell function in vivo by delivering antigen. He engineered a monoclonal antibody that carried antigen to dendritic cells. This experiment unexpectedly found that antigen delivered with maturation signal, resulted in strong immunity but without stimulus, the T-cells were deleted or turned to regulatory t cells. (1) This protected bodies own cells.

Immunisations

Steinman formed the framework of new vaccines. Antigens of Tb, HIV etc. bind to antibodies and are introduced to dendritic cells with adjuvants for activation (4).
Steinman’s work opened up new prospects for the field of immunology. His work without doubt provides better understanding of immune phenomena and paves a way for redefining disease occurrence and mortality by bringing in vaccine mediated specific and general health protection.

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Immucura identifier : BGI21-00X

References:

1. Steinman RM. Dendritic cells: understanding immunogenicity. Eur J Immunol. 2007 Nov;37 Suppl 1:S53-60.
2. Inaba K, Inaba M, Romani N, Aya H, Deguchi M, Ikehara S, et al. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med. 1992 Dec;176(6):1693–702.
3. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998 Mar;392(6673):245–52.
4. Ljunggren H-G. Dendritic cells, dendritic cell-based vaccines and Ralph Steinman. Vol. 271, Journal of internal medicine. England; 2012. p. 174–6.

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