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Home HITV Cancer Therapy What is Cancer Immunotherapy The Discovery and Role of Dendritic Cells

Thursday29 June 2017

The Discovery and Role of Dendritic Cells

The Discovery and Role of Dendritic Cells in Cancer Immunotherapy

Ralph Steinman
The late Mr. Ralph Steinman was awarded the Nobel Prize in Physiology/Medicine 2011 for his discovery of the dendritic cell and its role in adaptive immunity

Dendritic cells were discovered in 1973 by Ralph Steinman and the late Zanvil A. Cohn at the Rockefeller University. At the time, Steinman and Cohn were studying spleen cells to understand the induction of immune responses in a major lymphoid organ of the mouse. They were aware from research in other laboratories that the development of immunity by mouse spleen required both lymphocytes and "accessory cells," which were of uncertain identity and function.

The accessory cells were thought to be typical macrophages, but despite extensive laboratory experience with macrophages, Steinman and Cohn encountered a population of cells with unusual shapes and movements that had not been seen before. Because the cells had unusual tree-like or "dendritic" processes, Steinman named them "dendritic cells."

Dendritic Cell
How the Dendritic Cell looks like

When Steinman evaluated this population of cells, they had little, if any, resemblance to the well-known macrophages. Dendritic cells lacked an abundant membrane enzyme that was typical of macrophages. In contrast to macrophages, the dendritic cells detached from culture surfaces, had poor viability, and their turnover in spleen was rapid.

Also unlike macrophages, dendritic cells had few digestive bodies or lysosomes, lacked the key receptors for antibody-coated particles (Fc receptors), and were poorly phagocytic in vivo and in vitro. Accordingly, the research experience of the Cohn-Steinman laboratory with the cell biology of macrophages enabled the confident identification of dendritic cells as novel cells having distinct properties and, eventually, functions.

Functional studies revealed their potent stimulatory role in immune function. Subsets of dendritic cells were identified, each having its own surface markers. Dendritic cells were seen in the T-cell areas of organs of the lymph system, the ideal location for initiating immunity. Laboratories worldwide started to study dendritic cells and demonstrate their potent immune stimulatory functions.

Dendritic Cell Engulfing Ca Cell
A Dendritic Cell engulfing a cancer cell
[ Image courtesy of The Medical City, Philippines ]

Dendritic cells exist throughout the body. As seen in the tissues of skin, airway, and lymphoid organs, the cells are shaped like stars. When isolated and spun onto slides, they display numerous fine branches. When looked at with an electron microscope, these branches are long and thin and can appear spiny or sheet-like. When alive and viewed by phase-contrast microscopy, dendritic cells extend large, delicate, sheet-like processes that can drape around the cell bodies of lymphocytes, which can bind to dendritic cells in large numbers. The processes of dendritic cells continually form, bend, and retract. The tentacular shape and constant movement of dendritic cells fit precisely with their functions: to snatch invaders, embrace other cells of the immune system, and deliver the antigens and other signals that are needed to initiate vigorous responses.

Dendritic cells are stellate or tree-like cells (Greek, dendron, tree) that are found in lymphoid or immune organs, and at the interfaces between our bodies and the environment. The epidermal layer of the skin has a rich network of dendritic cells, which were first described in 1868 by a medical student in Germany, Paul Langerhans, who thought they were part of the nervous system. In addition, dendritic cells line the surfaces of the airway and intestine, where they function as sentinels that sample proteins and particulates from the environment. It took until 1973 for Ralph Steinman and Zanvil Cohn to begin the modern era of dendritic cell science by showing that dendritic cells are a new class of white blood cells with a number of distinctive features and functions.

Dendritic cells arise from proliferating progenitors, primarily in the bone marrow, a process driven by chemical messengers, to become precursors such as the monocytes in blood, and these in turn give rise to immature dendritic cells. The cells develop further or mature as they capture, process antigens, and migrate under the influence of other chemical messengers to tissues such as spleen and lymph nodes. There they attract and stimulate T and B cells to produce strong immune responses. The dendritic cells die unless they receive signals from the activated T cells to prolong their life span.

Research following the discovery of dendritic cells thirty five years ago is profoundly changing the science of immunology and its many interfaces with medicine. These previously unknown cells are now recognized as controllers that both create and curtail immunity.

In the steady state, and when the body is challenged by injury and infection, dendritic cells travel from body surfaces to immune or lymphoid tissues, where they home to regions rich in T cells. There, dendritic cells deliver two types of information: they display antigens, the substances that are recognized by T cells, and they alert these lymphocytes to the presence of injury or infection. This directs the T cells to make an immune response that is matched to the challenge at hand.

Dendritic cells are a critical, and previously missing, link in the immune system. As sentinels, dendritic cells patrol the body seeking out foreign invaders, whether these are bacteria, viruses, or dangerous toxins. After capturing the invaders, often termed antigens, dendritic cells convert them into smaller pieces and display the antigenic fragments on their cell surfaces. The dendritic cells then travel to lymph nodes or the spleen where they stimulate other cells of the immune system to make vigorous responses, in particular, the B cells that make antibodies to neutralize the invaders and killer T cells that launch specific attacks to destroy them.

New research is showing that dendritic cells are equally responsible for a seemingly opposite role in health called immune tolerance, which silences dangerous immune cells and prevents them from attacking innocuous materials in the body or the body's own tissues.

Given these functions of dendritic cells, it is not surprising that they are the subject of much research in medicine. During infection and cancer, microbes and tumors exploit dendritic cells to evade immunity, but dendritic cells also can capture infection and tumor-derived protein and lipid antigens and generate resistance, including new strategies for vaccines. During allergy, autoimmunity and transplantation, dendritic cells instigate unwanted innate and adaptive responses that cause disease, but dendritic cells also can suppress these conditions. In other words, dendritic cells because they orchestrate innate and adaptive immune responses, are an unavoidable target in studying disease and in designing treatments.

In summary, studies of immunology and disease have long focused on antigens and lymphocytes (B cells, T cells, NK cells) as the mediators of immune responses. However, accumulating evidence shows that dendritic cells provide vital links between antigens and all types of lymphocytes.

HITV Lab

HITV Lab is involved in cell-based biotechnology medical applications with special focus on Dendritic Cell-Based Immunotherapy for cancer. HITV Lab is committed to support an international collaboration in the FDA clinical trial of HITV Therapy in late-stage cancer patients led by the University of Maryland, USA.

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