jps.21523

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effectiveness,97,248 formulations such as degrad- translate to other species. Numerous studies
able polymer microspheres may provide sustained have highlighted differences in mouse and
exposure to antigens, obviating the need for human immune systems including differences
multiple administrations. Practical considera- in complement reactivity,251 induction of Th17
tions such as stability and cost may preclude cells,252 or response to a vaccine based on particle
the widespread use of some otherwise potent size.70
protein adjuvants such as cytokines.64,244 In 2006, the National Research Council con-
Thus, we can summarize the ideal vaccine vened a Workshop on Immunomodulation253
adjuvant as one which selectively targets the which made several recommendations to improve
antigen to the desired population of APCs, vaccine design including (1) an improved mole-
minimizes the amount of antigen required, cular level understanding of the innate immune
induces the desired adaptive immune response system, (2) the need for effective delivery mechan-
while minimizing the innate immune response, is isms, (3) the identification of potential molecular
minimally toxic, low-cost, stable for long-term targets to modulate innate immunity without
storage, and provides protective immunity in a undesirable side effects, and (4) new strategies to
single dose via a convenient delivery route. target DCs and optimize antigen presentation. A
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 4, APRIL 2009 DOI 10.1002/jps
VACCINE ADJUVANTS 1305
key need that was identified by this panel was that remain with regard to fully realizing the health
in order to solve these important problems, it is benefits of active immunization programs. Some
critical for researchers from multiple disciplines of these obstacles include the implementation of
to work together. These fields may include improved adjuvants, development of single dose
biochemistry, immunology, materials science, cell vaccines, methods to overcome the poor immuno-
biology, computational biology/materials science, genicity of recombinant and subunit immunogens,
pathology, oncology, microbiology, and combina- and the ability to rapidly and rationally develop
torial science. It is important to combine expertise vaccines against emerging pathogens. In this
from antigen biochemistry, cell biology, and regard, the mechanisms underpinning the effec-
immunology to understand the mechanism of tive modulation of cellular and molecular events
immunogenicity and how the preservation of associated with adjuvant enhancement of immune
various epitopes contributes to immunogenicity. responses are still largely unknown. There is
As these antigens are combined with adjuvants, it growing interest in the development of vaccine
is important for materials scientists to work delivery systems based on micro- and nano-scale
closely with immunologists to understand how devices composed of biodegradable polymers,
protein antigens can be stabilized during encap- because they have the potential to act as effective
sulation and delivery and how adjuvants interact adjuvants by encompassing all three of the
with APCs. As these adjuvanted systems enter the classical adjuvant properties: providing an anti-
body, they encounter plasma proteins that may genic depot with a tailored and pulsatile release of
adsorb on to the surface of the adjuvant. How this the antigen over time, directing particulate
affects the release of the antigen and how this antigens to the APCs and modulating the activa-
influences APC activation or antigen processing is tion of innate immunity by altering polymer
of great significance to the initiation of the desired chemistry.95 However, the mechanism of adju-
immune response. Finally, the use of the appro- vanticity and the ability of adjuvant chemistry
priate animal models to study these phenomena is to selectively modulate the immune response
critical and immunohistochemical methods are are still largely unknown. In order to address
needed to study how these adjuvants affect the these challenges, it is important to perform
local tissue response. fundamental and systematic studies of the role
In this regard, the authors, who belong to of polymer chemistry in regulating activation
chemical engineering and veterinary microbiology of APCs (e.g., DCs), antigen uptake, processing,
departments have worked towards providing a and presentation, migration to the draining
highly cross-disciplinary research environment lymph node, and modulation of the immune
for students and postdoctoral researchers in their response.
respective groups. The chemical engineering The mechanisms by which adjuvants enhance
graduate students have the opportunity to take and/or redirect the immune response (e.g., for-
courses on immunology and molecular biology mation of high titer antibodies, CD4� helper T
techniques, participate in journal clubs, and lymphocytes and/or CD8� T lymphocytes) in order
several of them have completed an immunobiology to establish long-term immunologic memory are
certificate program on their way to a Ph.D. poorly understood. Upon antigen stimulation,
Likewise, the microbiology students have the T cells differentiate into two distinct populations
opportunity to take courses on polymeric bioma- described as Th1 and Th2 type immune
terials and nanotechnology. Such an approach has responses.254 Furthermore, Th1- and Th2-related
immensely benefited students from both disci- cytokines (IFNg or IL-4/IL-13 respectively) can
plinary groups and has prepared them to address impact both the quality and magnitude of humoral
diverse research problems with new and inno- and cell-mediated immunity. Humoral immunity,
vative perspectives. Similar examples of cross- characterized by the activation of B cells that
disciplinary research groups exist and are much differentiate into antibody secreting plasma cells,
needed as scientists embark on new therapies for is effective at neutralizing toxins, viruses, com-
diseases such as cancer, HIV, and respiratory plement fixation, and opsonization of extra-
infections. cellular pathogens whereas the cell-mediated
Over the last 200 years, the use of vaccines has immunity (i.e., activation of cytotoxic T cells
proven to be one of the most successful medical and macrophages) are crucial for protection
interventions in the reduction of disease caused by against intracellular pathogens.255 The balance
infectious agents.1 However, many challenges still of humoral and cell-mediated immune responses
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 4, APRIL 2009
1306 WILSON-WELDER ET AL.
has been shown to be important in the favorable Finally, in order to understand the cellular and
outcome of many disease states. In this regard, molecular mechanisms that establish immuno-
vigorous and inappropriate cell-mediated immune logic memory, it is very important to correctly [ Pobierz całość w formacie PDF ]

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