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Inflammation & Allergy -
Drug Targets
(Formerly 'Current Drug Targets - Inflammation & Allergy')
ISSN: 1871-5281
Inflammation & Allergy
- Drug Targets
Volume 6, Number 4, December 2007
Contents
Therapeutic Implications of Immunoparalysis in Critically
Ill Patients Pp. 191-196
Guillermo M. Albaiceta, Paula R. Pedreira, Emilio García-Prieto
and Francisco Taboada
[Abstract]
Gastrin-Releasing Peptide Receptor as a Molecular
Target for Inflammatory Diseases Pp. 197-200
Fabricia Petronilho, Rafael Roesler, Gilberto Schwartsmann
and Felipe Dal Pizzol
[Abstract]
The Role of Coagulation in Pulmonary Pathology Pp.
201-209
Morohunfolu E. Akinnusi and Ali A. El Solh
[Abstract]
Therapeutic Targeting of Leukocyte Trafficking Across
the Blood Brain Barrier Pp. 210-222
Caroline Coisne, Ruth Lyck and Britta Engelhardt
[Abstract]
TLR7/9 Antagonists as Therapeutics for Immune-Mediated Inflammatory
Disorders Pp. 223-235
Siquan Sun, Navin L. Rao, Jennifer Venable, Robin Thurmond
and Lars Karlsson
[Abstract]
Innate and Adaptive Immune Responses in Allergic Contact
Dermatitis and Autoimmune Skin Diseases Pp. 236-244
Fanny Edele, Philipp R. Esser, Christian Lass, Melanie
N. Laszczyk, Eva Oswald, Christian M. Strüh, Anne Rensing-Ehl
and Stefan F. Martin
[Abstract]
Abstracts
[Back to top]
Therapeutic Implications of Immunoparalysis
in Critically Ill Patients
Guillermo M. Albaiceta, Paula R. Pedreira, Emilio García-Prieto
and Francisco Taboada
In opposite to the classic view of the systemic inflammatory
response, there is increasing evidence that, during critical
illness, there is a systemic antiinflammatory state intended
to avoid the spread of the local proinflammatory response.
The resulting immunosupression increases the risk of nosocomial
infections, and has been related to an increase in morbidity
and mortality in critically ill patients. Monocytes play a
key role in orchestrating the inflammatory response, and a
functional impairment of this population is the responsible
for these phenomena. The decreased surface expression of class
II molecules of the Main Histocompatibility Complex is both
a marker of this state and a pathogenetic mechanism, as it
decreases the antigen presentation capabilities of the mononuclear
phagocytes. There are some therapeutic strategies to overcome
this situation. Cytokines like IFNγ
or GM-CSF have been tested in animal models and patients,
but there are no conclusive data. Other drugs like Flt3, AS101
or antibodies against IL-10 have been tested only in experimental
models. The development of a new framework on the inflammatory
response, the need for a consensus in immune monitoring and
the development of experimental and clinical trials are required
to improve the outcome of severe patients with systemic injuries.
[Back to top]
Gastrin-Releasing Peptide Receptor as a Molecular
Target for Inflammatory Diseases
Fabricia Petronilho, Rafael Roesler, Gilberto Schwartsmann
and Felipe Dal Pizzol
Bombesin-like peptides (BLP) and its receptors are widely
distributed in mammalian peripheral tissues and in the central
nervous system. Recently, effects of these peptides on the
production and release of cytokines were described both in
animal models and humans with inflammatory diseases. Some
pathological conditions such as exposure to tobacco smoke,
chronic obstructive pulmonary diseases and eosinophilic granuloma
have recently been found to be associated with an increase
of pulmonary BLP-producing cells. Proinflammatory neuropeptides
have a key role in the pathogenesis and maintenance of rheumatoid
arthritis and sepsis. Together, these findings support the
view that the GRPR should be considered a therapeutic target
for a subset of inflammatory diseases.
[Back to top]
The Role of Coagulation in Pulmonary Pathology
Morohunfolu E. Akinnusi and Ali A. El Solh
Understanding mechanisms that underlie lung disorders is crucial
to achieving optimum care and improved outcomes in pulmonary
medicine. Extensive investigations have revealed that inflammation
displays an active role in the pathogenesis of these diseases.
The byproduct of these inflammatory reactions has been shown
to propagate pulmonary disease in consonance with alteration
in haemostatic balance. It is now apparent that the two phenomena
constitute an interwoven relationship with protective but
damaging effects, when dysregulated. However, the precise
role of coagulation abnormalities in pulmonary pathology is
still evolving. A large body of evidence suggests that an
imbalance in intra-alveolar procoagulant and fibrinolytic
activities occurs in a variety of lung conditions. This imbalance
may even herald a number of pulmonary diseases. Its sequelae
have been observed in lung parenchyma of humans and in animal
models of lung inflammation. As the pathogenesis of coagulation-related
lung diseases continues to be unraveled, therapeutic measures
to mitigate pulmonary disease-specific coagulopathy are emerging.
Current efforts are directed at depicting multifaceted molecules
capable of selective but simultaneous interference with relevant
aspects of the dual coagulation-fibrinolytic pathway.
[Back to top]
Therapeutic Targeting of Leukocyte Trafficking Across
the Blood Brain Barrier
Caroline Coisne, Ruth Lyck and Britta Engelhardt
The central nervous system (CNS) has long been regarded as
an immune privileged organ implying that the immune system
avoids the CNS not to disturb its homeostasis, which is critical
for proper function of neurons. Meanwhile, it is accepted
that immune cells do in fact gain access to the CNS and that
immune responses are mounted within this tissue. However,
the unique CNS microenvironment strictly controls these immune
reactions starting with tightly regulating immune cell entry
into the tissue. The endothelial blood-brain barrier (BBB)
and the epithelial blood-cerebrospinal fluid (CSF) barrier
control immune cell entry into the CNS, which is rare under
physiological conditions. During a variety of pathological
conditions of the CNS such as viral or bacterial infections,
or during inflammatory diseases such as multiple sclerosis
(MS), immunocompetent cells readily traverse the BBB and subsequently
enter the CNS parenchyma. Most of our current knowledge on
the molecular mechanisms involved in immune cell entry into
the CNS has been derived from studies performed in experimental
autoimmune encephalomyelitis (EAE), an animal model for MS.
Thus, a large part of our current knowledge on immune cell
entry across the BBBs is based on the results obtained in
this animal model. Similarly, knowledge on the benefits and
potential risks associated with therapeutic targeting of immune
cell recruitment across the BBB in human diseases are mostly
derived from such treatment regimen in MS. Other mechanisms
of immune cell entry into the CNS might therefore apply under
different pathological conditions such as bacterial meningitis
or stroke and need to be considered.
[Back to top]
TLR7/9 Antagonists as Therapeutics for Immune-Mediated Inflammatory
Disorders
Siquan Sun, Navin L. Rao, Jennifer Venable, Robin Thurmond
and Lars Karlsson
There is an increasing interest in ligands of nucleic acid-sensing
Toll-like receptors (TLR), especially TLR7 and TLR9, for pharmacological
intervention in various diseases. The TLR7 agonist imiquimod
is currently used as a topical treatment for genital warts
caused by human papillomavirus (HPV), actinic keratosis (AK)
and superficial basal cell carcinoma. Oligodeoxynucleotides
(ODN) TLR9 agonists are currently in clinical trials for use
in lung cancer, as anti-viral therapy, as adjuvants and as
immune modulators in asthma and allergies. TLR7/9 antagonists,
such as the anti-malaria drugs chloroquine, hydroxychloroquine
and quinacrine, have been used since the 1950s to treat immune-mediated
inflammatory disorders (IMID) such as rheumatoid arthritis
(RA), systemic lupus erythematosus (SLE) and Sjögren’s
syndrome. However, the use of these anti-malarials in IMID
is limited due to the side effects or suboptimal efficacy.
Pre-clinical animal models as well as genetic linkage studies
have indicated that TLR7/9 play a pivotal role in the aforementioned
as well as other IMID such as multiple sclerosis (MS), inflammatory
bowl disease (IBD)/colitis and psoriasis. Recent evidence
has suggested that selective, specific antagonists for TLR7
and/or 9 might be more beneficial in certain diseases, such
as SLE. Thus, the use of suppressive ODN or novel small molecule
TLR7/9 inhibitors with a larger safety window and differentiated
selectivity may potentially have significant clinical utility
in these IMID. Herein, we review efforts to develop novel
TLR7/9 antagonists and the rationale for the use of such therapeutics
in a variety of IMID.
[Back to top]
Innate and Adaptive Immune Responses in Allergic Contact
Dermatitis and Autoimmune Skin Diseases
Fanny Edele, Philipp R. Esser, Christian Lass, Melanie
N. Laszczyk, Eva Oswald, Christian M. Strüh, Anne Rensing-Ehl
and Stefan F. Martin
Allergic contact dermatitis is induced by chemicals or metal
ions. A hallmark of this T cell mediated skin disease is the
activation of the innate immune system by contact allergens.
This immune response results in inflammation and is a prerequisite
for the activation of the adaptive immune system with tissue-specific
migration of effector and regulatory T cells. Recent studies
have begun to address in detail the innate immune cells as
well as the innate receptors on these cells and the associated
signaling pathways which lead to skin inflammation. We review
here recent findings regarding innate and adaptive immune
responses and immune regulation of contact dermatitis and
other skin diseases as well as recent developments towards
an in vitro assessment of the allergenic potential
of chemicals. The elucidation of the innate inflammatory pathways,
cellular components and mediators will help to identify new
drug targets for more efficient treatment of allergic contact
dermatitis and hopefully also for its prevention.
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