Abstract: methods by which the immune response was initiated

Abstract: 2011 Ralph
Marvin Steinman (1943-2011) “for his discovery of the dendritic cell and
its role in adaptive immunity”

The complexity of the immune system can be attributed to the
immense variety of cell types involved in mediating immune responses. Many
immunologists have spent time familiarizing themselves with the several leukocyte
subsets involved in immunity and have attempted to understand their respective specialized
functions in the immune system. In 1973, the discovery of the dendritic cell
(DC) was a major breakthrough in the classification of cells in immunology, for
which scientist Ralph Steinman (1) was awarded the Nobel Prize in Physiology
and Medicine in 2011. Before Steinman’s discovery, immunology focused on the presence
of antigens and lymphocytes (2). But the discovery of the DC system shed light on
the methods by which the immune response was initiated and modulated. Langerhans
cells (LCs) were first visualized in the skin, however there was prolonged
speculation as to what function or purpose they served. It would later be known
that LCs were members of the DC family (3). During his research, Steinman identified
a novel cell type in the spleen and other peripheral lymphatic organs of mice (1).

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The term dendritic cell was coined after these cells’ distinct morphological
features. At the time of DC discovery, a link between activation of the innate
immune system and the subsequent priming of cells of the adaptive immune system
was still missing. Several experiments conducted on DCs derived from lymphoid
tissues bridged this gap, establishing DCs as potent stimulators of primary
immune responses (4). Among antigen presenting cells, DCs, unlike B lymphocytes
and macrophages, are the only cells able to stimulate both naïve and memory T
lymphocytes, ultimately inducing a primary immune response (5). Therefore, DCs
play a central role in the initiation of immune responses, creating
possibilities for their use in the development of therapeutic strategies
against tumors and other immunological diseases (6).

 

 

Annotated Bibliography:

(1)  Steinman R. M., Cohn Z. A. Identification of a
novel cell type in peripheral lymphoid organs of mice. I. Morphology,
quantitation, tissue distribution. The Journal of Experimental Medicine. 1973;137(5):1142–1162. Available from: doi:10.1084/jem.137.5.1142. 

 

This paper was the first to coin the term dendritic cell to a
novel cell type initially discovered in the peripheral lymphoid organs of mice.

On the basis of morphological criteria, large stellate cells were observed to
have properties that were distinct from known cell types including mononuclear
phagocytes, granulocytes and lymphocytes. The discovery of dendritic cells,
followed later by the identification of their function, helped scientists
understand the process by which the innate and adaptive immune system was
moderated.

 

 

 

(2)  Banchereau J., Steinman R. M. Dendritic cells and
the control of immunity. Nature. 1998;392, 245-252. Available from: doi:10.1038/32588.

 

This paper describes the function of dendritic cells and
further elaborates to convey their purpose and importance in the immune system.

Previously, studies of pathogenesis were often focused on immunology solely pertaining
to the interactions between antigens and lymphocytes. However, the details
presented in this paper placed a new emphasis on dendritic cells (DC) and their
significant role in controlling immunity. Ultimately due to their central role
in controlling immune responses, DCs have seen to be promising targets for
clinical situations that involve T cells, including transplantation, allergy, tumors,
vaccines and autoimmune diseases.

 

 

 

(3)  Schuler G., Steinman R.M. Murine
epidermal Langerhans cells mature into potent immunostimulatory dendritic cells
in vitro. The
Journal of Experimental Medicine.

1985;161(3):526–546. Available
from: doi:10.1084/jem.161.3.526

 

Langerhans cells (LC) were first described in 1868 by Paul
Langerhans as “nerves of the human skin.” LCs were the first dendritic cell
subset to be discovered, despite the fact that the existence or function of
dendritic cells (DC) was not clear at the time. This paper published in 1985 by
Schuler and Steinman recognized that LCs were not nerve cells, but indeed
belonged to the larger DC family. Most of the early DC research was carried out
using LC ex vivo and in vitro, ultimately allowing researchers to use LCs as
methods to understand and establish the crucial function of DCs – the most
potent inducers of T-cell immunity. This discovery shaped the future of
immunological research and led to the investigation of DCs as the novel cell
type responsible for moderating immunity.

 

 

 

 

(4)  Steinman
R. M., Witmer M. D. Lymphoid dendritic cells are potent stimulators of the
primary mixed leukocyte reaction in mice. Proceedings of the National
Academy of Sciences of the United States of America. 1978;75(10):5132-5136.

Available from: doi:10.1073/pnas.75.10.5132

 

This paper exemplifies one of the many experiments
carried out to suggest that dendritic cells are potent stimulators of the
primary mixed leukocyte reaction (MLR) used to assess how T-cells react to
external stimuli. Dendritic cells (DC) were shown to participate in the MLR. The
findings presented in the paper suggest that DCs were at least 100 times more
effective than other major cell subclasses (B and T lymphocytes and
macrophages) in stimulating an immune response. By recognizing that DCs played
a central role in stimulating MLR, it was suggested that DCs – and not
macrophages – may prove to be critical accessory cells required in the
generation of a variety of immune responses.

 

 

 

(5)  Inaba
K., Metlay J. P., Crowley M. T., Steinman R. M. Dendritic cells pulsed with
protein antigens in vitro can prime antigen-specific, MHC-restricted T cells in
situ. The Journal of
Experimental Medicine. 1990;172(2):631-640. Available from:
doi:10.1084/jem.172.2.631 

 

This
paper describes a dendritic cells (DC) unique capacity to stimulate naïve T
cells. The immunological activity of a T lymphocyte is correlated to its
respective antigen presented by major histocompatibility complex (MHC)
molecules on the surface of antigen-presenting cells. While many cell types are
capable of generating MHC-peptide complexes and presenting these to primed T
cells, the experiment conducted by the authors in this paper assess the
capacity of DCs to sensitize the T cells of unprimed mice.  Ultimately, the findings of the paper suggest
that DCs are uniquely capable of stimulating naïve T cells in situ. This is a
finding that paves the way for research focusing on DCs pivotal role in
regulating the balance between immunity and tolerance of the immune system.

 

 

 

(6)  Banchereau
J., Palucka A. K., Dhodapkar M., Burkeholder S., Taquet N., Rolland A., Taquet
S., Coquery S., Wittkowski K. M., Bhardwaj N., Pineiro L., Steinman R. M., Fay
J. Immune and clinical responses in patients with metastatic melanoma to
CD34(+) progenitor-derived dendritic cell vaccine. Cancer Research.

2001;61(17):6451-6458. Available from: http://cancerres.aacrjournals.org/content/61/17/6451.long

 

This
paper is one of the many studies that investigates the use of dendritic cells (DC)
in the development of therapeutic strategies against immunological diseases.

The authors examined the ability of DCs to elicit an immune response to
multiple tumor antigens, specifically of antigen-bearing CD34-DCs in patients
with stage IV melanoma. Similar studies investigating the safety and immunogenicity
of DCs in a therapeutic environment may propose newer methods of targeting tumors
and immunological diseases. These findings serve to prove that dendritic cells
in therapy may be a novel method to address immunological diseases in the near
future. 

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