Biomedical Engineering Reference
In-Depth Information
information back to both the research and the clinical scientists, such as additional
details regarding mechanism of action, or disease-specific diagnostic or prognostic
biomarkers.
Examples of the translational medicine approach are evident in the development of
therapeutic compounds that target components of the immune system in diseases that
encompass an inflammatory component. A recent review of the development of anti-
TNF treatment provides an elegant illustration of this approach [8]. The process
begins in the laboratories conducting basic research in immunology where the
increasingly more complex mysteries of immune system continue to be elucidated:
new cytokines, receptors, signaling pathways, transcription factors, cellular subsets,
and functional activities are identified and characterized at a rapid rate (Figure 9.3).
There are three major phases to translational medicine: basic science, clinical
research, and drug development.
Historically, in the first phase, discoveries in immunology were achieved using
elegant in vivo and in vitro murine models that first employed inbred mouse strains
and adoptive transfer experiments, and later molecular manipulations involving gene
knockouts and gene transfer systems. In vitro cellular systems and molecular tools
were then used to verify and refine the findings in the human system. Even though
these highly controlled experimental approaches fall short of fully translating to the
complex realities of the whole, the basic premises are valid. Critical information such
as defining the key cellular components, soluble factors, molecular pathways, and
rate-limiting steps in the immune system has been gained through the use of these
models. In addition, these experimental models provide insight into potential new
drug targets.
In the next phase, clinical research scientists help to characterize the pathogenesis
of immune abnormalities by conducting extensive case studies in which known
immune parameters are observed and analyzed in patients with immunological
disorders. This extensive immunological characterization in patient populations
provides insights into potential disease-specific biomarkers.
In the last phase, pharmaceutical scientists translate all of this information into
drug development. Information on the need for new compounds comes from clinical
research. Direction for selection of PD biomarker would most likely be obtained from
the case study reports. Potential PD biomarkers will also come from basic research
and experimental modeling.
If the PD biomarker is a cellular component of the immune system, flow
cytometry represents the most useful analytical tool for both extensive phenotypic
and functional analyses. Discrimination and enumeration of the cellular compo-
nents of the immune system, and the ever-increasing number of distinct subsets,
require simultaneous evaluation of multiple surface and/or intracellular character-
istics. Multiparametric flow cytometry is the ideal (and perhaps the only) tech-
nology to obtain these measurements because of the number of data points that can
be simultaneously captured. Data can be collected with relatively high throughput
and good precision. Moreover, functional assays such as cytokine production,
antigen-specific proliferation, apoptosis, and even cytotoxicity can be assessed
with flow cytometry.
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