Tumor necrosis factor (TNF) superfamily is a rapidly growing family
of cytokines that interacts with a corresponding superfamily of
receptors. Ligand-receptor interactions of this superfamily are
involved in numerous biological processes ranging from
hematopoiesis to pleiotropic cellular responses, including
activation, proliferation, differentiation, and apoptosis. The
particular response depends on the receptor the cell type, and the
concurrent signals received by the cell. Worldwide interest in the
TNF field surged dramatically early in 1984 with the cloning and
defining of the profound cellular effects of the first member of
this family, TNFa. Subsequently, the major influence of TNFa on the
development and functioning of the immune system was established.
Today, over 20 human TNF ligands and their more than 30
corresponding receptors have been identified. Few receptors still
remain orphans. What has emerged over the years is that most TNF
ligands bind to one distinct receptor and some of the TNF ligands
are able to bind to multiple TNF receptors, explaining to some
extent the apparent disparity in the number of TNF receptors and
ligands. Yet, in spite of some redundancy in TNF ligand/receptor
interactions, it is clear that in vivo spatial, temporal, and
indeed cell- and tissue-specific expression of both ligands and
their receptors are important factors in determining the precise
nature of cellular physiological and pathological processes they
control.
TNF superfamily has been the most highly investigated area of
basic medical research for over two decades. These investigations
have benefited from the enormous growth in our understanding of the
principal functions of theimmune system and the explosion in the
knowledge involved in regulation of normal and pathological immune
response. In addition, much has been learned about the molecular
mechanisms of programmed cell death and the escape of tumor cells
from apoptotic demise and from discovery of the key role played by
TNF ligands in this process. As the functioning of these
superfamily members is very complex, understanding TNF ligands and
their receptor biology requires a mA(c)lange of research activities
in many different disciplines including organ development,
molecular biology, experimental pathology, and immunology. As a
consequence of intensive studies in multiple areas over many years,
much has been learned. A key role of members of this superfamily in
normal functioning of the immune system, autoimmunity, and other
fundamental cellular process by which tumor cells develop has been
established. Many novel mechanisms involving TNF superfamily
members in the disease development process have been defined, and a
unified concept and new perspectives have also emerged. For
example, abrasions in the innate immune system, so far not
considered critical in autoimmunity, have found increasing
attention, and TNF-directed and not antigen directed therapy has
emerged as the most impressive therapeutic advance in managing
autoimmunity in humans. These findings provide a foundation for
novel drug design efforts that are poised to utilize newly acquired
knowledge. Several of these strategies have already materialized
into successful therapeutics such as use of TNF for cancers and
anti-TNFa antibodies and TNFR-Fc for autoimmune diseases, and many
have advanced to human clinical trials, while many more are
stillbeing tested in preclinical settings.
As in other rapidly evolving fields, these advances are not
necessarily congruent and are often difficult to organize into a
cogent whole. The aim of Therapeutic Targets of the TNF Superfamily
is to make readily available the major research important in the
exploitation of this family for developing therapeutic strategies
for human diseases, in a single volume. Under the auspices of
Landes Bioscience, I have undertaken the task to concisely
consolidate current knowledge of key TNF superfamily members
focusing on both basic aspects and their clinical application. In
this volume, a number of leading scientists in the field cover many
aspects of biology of TNF superfamily members, ranging from the
cloning and characterization of TNF ligands and their receptors,
through the use of animal models to study their functions in vivo
and their exploitation for human therapeutic use. Each chapter also
includes relevant background information and provides useful
bibliography for a more detailed analysis, making the study of TNF
ligands/receptors accessible at all levels of expertise.
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