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Inflammation
& Allergy - Drug Targets
(Formerly 'Current Drug Targets - Inflammation & Allergy')
ISSN: 1871-5281
Inflammation & Allergy
- Drug Targets
Volume 7, Number 2, June 2008
Contents
HLA-G and Inflammatory Diseases Pp.
67-74
Olavio R. Baricordi, Marina Stignani, Loredana Melchiorri
and Roberta Rizzo
[Abstract]
Intravenous Immunoglobulin Therapy in Dermatologic
Disorders Pp. 75-84
Seray Külcü Çakmak, Ülker Gül,
Müzeyyen Gönül, Arzu Kiliç
and Seçil Soylu
[Abstract]
Anti-Selectin Therapy for the Treatment of Inflammatory
Diseases Pp. 85-93
Barbara Rossi and Gabriela Constantin
[Abstract]
Polarization of Cytokine Profile from Th1 into
Th2 Along Colorectal Adenoma-Carcinoma Sequence: Implications
for the Biotherapeutic Target? Pp. 94-97
Guanglin Cui and Jon Florholmen
[Abstract]
HTLV-1-Associated Myelopathy/Tropical Spastic
Paraparesis (HAM/TSP) Inflammatory Network Pp. 98-107
Denise U. Goncalves, Fernando A. Proietti, Edel F. Barbosa-Stancioli,
Marina L. Martins, João G. Ribas, Olindo A. Martins-Filho,
Andrea Teixeira-Carvalho, Vanessa Peruhype-Magalhães
and Anna B. Carneiro-Proietti
[Abstract]
ADAM8 in Allergy Pp. 108-112
Osamu Matsuno, Toshihide Kumamoto and Yasunori Higuchi
[Abstract]
Helminth Products as a Potential Therapeutic
Strategy Inflammatory Diseases Pp. 113-118
Maria Fernanda de Macedo Soares and Claudia A. Araújo
[Abstract]
The Treatment Targets of Asthma: From Laboratory
to Clinic Pp. 119-128
Cailong Fang, Chris J. Corrigan and Sun Ying
[Abstract]
Abstracts
[Back to top]
HLA-G and Inflammatory Diseases
Olavio R. Baricordi, Marina Stignani, Loredana Melchiorri
and
Roberta Rizzo
HLA-G antigens are non classical HLA-class I molecules
characterized by a low allelic polymorphism, a limited tissue
distribution and the presence of membrane bound and soluble
isoforms. The HLA-G antigens were firstly detected in cytotrophoblast
cells at the feto-maternal interface where they maintain a
tolerogenic status between the mother and the semiallogenic
fetus. Recently a variable expression of HLA-G molecules has
been documented in several autoimmune diseases, viral infections,
cancer diseases and transplantation. Overall the presence
of HLA-G molecules in both membranes bound and soluble isoforms
was associated with tolerogenic functions against innate and
adaptative cellular responses. HLA-G antigens are able to
affect the cytotoxicity of natural killer and CD8+ T cells,
CD4+ T lymphocyte functions and dendritic cell maturation.
In addition to the allelic polymorphism the HLA-G gene shows
a deletion/insertion polymorphism of a 14 base pairs sequence
(14bp) in the exon 8 at the 3’ untranslated region.
Several reports have associated the presence of the 14bp insertion
allele (+14bp) to an unstable mRNA and a lower sHLA-G protein
production, suggesting a different ability to counteract inflammation
between genotypes.
We reviewed the literature on the expression of HLA-G antigens
in autoimmune and allergic diseases and the possible functional
role of these molecules in counteracting inflammation.
[Back to top]
Intravenous Immunoglobulin Therapy in Dermatologic Disorders
Seray Külcü Çakmak, Ülker Gül,
Müzeyyen Gönül, Arzu Kiliç and Seçil
Soylu
Intravenous immunoglobulin (IVIG) is sterilized and purified
human plasma which contains supra-physiologic levels of immunoglobulin
G. IVIG is currently used in the treatment of immunodeficiency
syndromes, inflammatory disorders and infectious diseases.
Although numerous immunomodulatory mechanisms have been suggested,
the exact mechanisms of action are poorly understood. There
is also accumulating evidence that high-dose IVIG is efficacious
in the treatment of some skin diseases, despite the lack of
evidence from randomized, double-blind, placebo-controlled
trials. Though in most cases, IVIG is only effective in combination
with other immunomodulating strategies, it offers new hope
for the treatment of many severe dermatologic conditions.
This article focuses on the efficacy and safety of IVIG therapy
in skin diseases.
[Back to top]
Anti-Selectin Therapy for the Treatment of Inflammatory Diseases
Barbara Rossi and Gabriela Constantin
Leukocyte migration into the tissues represents a key
process in the pathogenesis of inflammatory diseases. Data
obtained in clinical trials have convincingly shown that inhibition
of leukocyte migration into the target organs represents an
effective therapeutic approach for diseases in which inflammation
has a noxious effect. Leukocyte tethering and rolling are
the earliest steps of leukocyte adhesion cascade in inflamed
vessels. Selectins are type I transmembrane glycoproteins
that bind sialylated carbohydrate structures in a calcium-dependent
manner and are involved in the tethering and rolling of leukocytes
under physiological and pathological conditions. Three selectins
have been identified: L-, P- and E-selectin. Current understanding
of the glycosylation-dependent selectin function reveals a
complex role for selectins and their ligands during inflammatory
diseases. Among selectin ligands, mucin P-selectin glycoprotein
ligand-1 (PSGL-1) binds all three selectins and has a well-documented
role in organ targeting during inflammation in animal models.
However, although inhibition of selectins and their ligands
in animal models of inflammatory diseases has proven the validity
of this approach in vivo, only a limited number of
anti-selectin drugs have been tested in humans. Recent results
obtained in clinical trials for asthma and psoriasis show
that, although very challenging, the development of selectin
antagonists holds concrete promise for the therapy of inflammatory
diseases.
[Back to top]
Polarization of Cytokine Profile from Th1 into Th2 Along Colorectal
Adenoma-Carcinoma Sequence: Implications for the Biotherapeutic
Target?
Guanglin Cui and Jon Florholmen
The development of colorectal carcinoma (CRC) has been
hypothesized to be raised mostly from the precancerous lesion
of colorectal adenoma (CRA) through a multistep process and
defined as the adenoma-carcinoma sequence. In response to
the tumorigenesis, host cellular immunity acts as the most
important defense factor with cytokines as the main regulator
molecules. Therefore, changes of cytokines of the T helper
1 (Th1)/T helper 2 (Th2) type immune responses along this
sequence may therefore reflect a functional switch of host
anti-tumor immunity. This minireview focused on the recent
knowledge of the Th1/Th2 balance in the adenoma-carcinoma
sequence and its potential clinical and therapeutical significance.
[Back to top]
HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis
(HAM/TSP) Inflammatory Network
Denise U. Goncalves, Fernando A. Proietti, Edel F. Barbosa-Stancioli,
Marina L. Martins, João G. Ribas, Olindo A. Martins-Filho,
Andrea Teixeira-Carvalho, Vanessa Peruhype-Magalhães
and Anna B. Carneiro-Proietti
HTLV-1 associated myelopathy/ tropical spastic paraparesis
(HAM/TSP) is a systemic immune-mediated inflammatory disease
and tissues other than nervous can be damaged, mainly ocular,
rheumatic and dermatologic. Over 90% of HTLV-1-infected individuals
remain lifelong asymptomatic and this retrovirus persists
indefinitely in their CD4+ T-lymphocytes. The infection is
maintained due to the proliferation of lymphocytes that harbor
a provirus and express HTLV-1 proteins, particularly Tax,
promoting an active and selective expansion of infected T
cells. High proviral load is related to disease progression,
which is correlated to disequilibrium between host and virus.
Cytotoxic T lymphocytes are abundant and chronically activated
in asymptomatic carriers and in HAM/TSP patients. The asymptomatic
carriers were shown to have a high frequency of pro-inflammatory
monocytes and anti-inflammatory IL-10+CD4+ and IL-10+CD8+
T-cells, as an immunoregulatory mechanism to counterbalance
the monocyte-derived TNF-alpha. A putative immunomodulatory
event would be the key to control their overall immunological
status. In HAM/TSP, a pro-inflammatory microenvironment is
the hallmark of the immunological profile. Enhanced frequency
of activated CD8+ T-cells (HLA-DR+) in combination with high
CD18 surface expression has been seen. In blood and cerebrospinal
fluid, increased levels of Type-1 cytokines, as interferon-(IFN)-gamma,
Tumor Necrosis Factor (TNF)-alpha, Interleukin (IL)-2, and
pro-inflammatory IL-6, can be found. Concerning the progression,
HLA polymorphisms may influence HAM/TSP and the allele HLA-A*2
has been associated with protection. The authors showed that
HAM/TSP is strongly associated with a decreased percentage
of B-cells, with enhanced T/B-cell ratio and activated CD8+
T-cells. These immunological parameters have been proposed
as a prognostic biomarker for HAM/TSP.
[Back to top]
ADAM8 in Allergy
Osamu Matsuno, Toshihide Kumamoto and Yasunori Higuchi
ADAM (a disintegrin and metalloprotease) family members
are membrane-anchored proteins with wide ranging functions,
including proteolytic cleavage of cell surface molecules,
cell fusion, cell adhesion and intracellular signaling. ADAM8,
also known as CD156a, is expressed mainly in cells of the
immune system, such as monocytes, neutrophils, eosinophils,
dendritic cells, and B cells. It can cleave a variety of substrates
and is a sheddase for CD23 and L-selectin. ADAM8 has an important
role in allergic inflammation.
ADAM8 mRNA expression is increased with disease progression
in asthma. ADAM8 is strongly induced by allergens and Th2
cytokines in the lung in experimental asthma. Soluble ADAM8
is elevated in the bronchoalveolar lavage fluid of patients
with eosinophilic pneumonia and has a physiologic role in
protecting against allergic pulmonary disease in experimental
murine asthma. Together, these findings support the view that
ADAM8 might be a therapeutic target for allergic respiratory
diseases. This review discusses novel strategies for immune
intervention in allergic respiratory disease.
[Back to top]
Helminth Products as a Potential Therapeutic Strategy for
Inflammatory Diseases
Maria Fernanda de Macedo Soares and Claudia A. Araújo
Helminths secrete several molecules that can modulate
the immune responses, favoring their evasion and perpetuate
their survival in the host. These molecules interfere with
antigen presentation, cell proliferation and activation, antibody
production, cause cell death, and stimulate regulatory responses.
Here, we focus on some helminth products and address their
immunomodulatory effects in the host immune system and, also,
we describe some anti-inflammatory properties of an Ascaris
suum-derived immunomodulatory molecule, named PAS-1.
This protein is a 200-kDa molecule isolated by affinity chromatography
using MAIP-1 (monoclonal antibody which recognizes PAS-1),
coupled to Sepharose 4B. It suppresses the inflammatory responses
in murine models of delayed-type hypersensitivity, lung allergic
inflammation and LPS-induced inflammation into air pouches.
PAS-1 also stimulates the secretion of regulatory cytokines
such as IL-10 and TGF-β
and primes IFN-γ-secreting
CD8+ and IL-10/ TGF-β-secreting
CD4+CD25+ cell clones that avoid the lung inflammation. Thus,
this protein is a potent immunomodulatory component that may
be used for therapeutic interventions in inflammatory diseases.
[Back to top]
The Treatment Targets of Asthma: From Laboratory to Clinic
Cailong Fang, Chris J. Corrigan and Sun Ying
Asthma is a chronic disease characterised by airways
hyperresponsiveness, airways inflammation, airways remodelling
and reversible airways obstruction. Airway structural cells,
recruited inflammatory cells and many mediators such as cytokines,
chemokines and adhesion molecules are involved in the pathogenesis
of asthma. Although asthma is treatable in most, but not all
patients by currently available drugs, no treatment is preventive
or curative and the disease has reached epidemic proportions
worldwide and its incidence is continuing to increase. Many
thousands have chronic, severe asthma and suffer daily symptoms
making it imperative that we continue to improve our understanding
of the mechanisms of asthma particularly related to airway
inflammation and remodelling, the hallmarks of asthma, and
to identify new therapeutic targets. In this review we will
discuss current drugs and potential targets in the treatment
of asthma.
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