|
Inflammation & Allergy -
Drug Targets
(Formerly 'Current Drug Targets - Inflammation & Allergy')
ISSN: 1871-5281
Inflammation & Allergy
- Drug Targets
Volume 7, Number 1, March 2008
Contents
Mesalamine for Inflammatory Bowel Disease: Recent
Reappraisals Pp. 1-5
Giovanni C. Actis, Paola Pazienza and Floriano Rosina
[Abstract]
Liver Tolerance and the Manipulation of Immune Outcomes
Pp. 6-18
Lauren E. Holz, Geoffrey W. McCaughan, Volker Benseler,
Patrick Bertolino and David G. Bowen
[Abstract]
Inflammatory Aspects of Depression Pp. 19-23
Ubiratan C. Adler, Andrea H. Marques and Helena M. Calil
[Abstract]
Role of Transglutaminase-Catalyzed Reactions in the
Post- Translational Modifications of Proteins Responsible
for Immunological Disorders Pp. 24-29
Giulia De Vivo, Antonio Martin, Tiziana Trotta and Vittorio
Gentile
[Abstract]
Emerging Mucus Regulating Drugs in Inflammatory and
Allergic Lung Disease Pp. 30-34
Hans-Peter Hauber and Peter Zabel
[Abstract]
Selective Inhibitors of Nuclear Factor of Activated
T Cells: Potential Therapeutic Drugs for the Treatment of
Immunological and Inflammatory Diseases Pp. 35-40
Osamu Kaminuma
[Abstract]
Transferrin and the Transferrin Receptor: Of Magic
Bullets and Other Concerns Pp. 41-52
Maria F. Macedo and Maria de Sousa
[Abstract]
Molecular Targets of Rheumatoid Arthritis
Pp. 53-66
Hiroshi Okamoto, Daisuke Hoshi, Akiko Kiire, Hisashi Yamanaka
and Naoyuki Kamatani
[Abstract]
Abstracts
[Back to top]
Mesalamine for Inflammatory Bowel Disease: Recent Reappraisals
Giovanni C. Actis, Paola Pazienza and Floriano Rosina
Derived from the historical molecule sulfasalazine, mesalamine
has remained one of the mainstays for treatment of inflammatory
bowel disease in the last 50 years. Recent advancement in
both clinical and basic research has led to reappraise the
drug under two crucial aspects.
Firstly, there has been a re-evaluation of the chemo-protective
effect of mesalamine against sporadic colorectal cancer. Evidence
that inflammation plays a strong role in tumor induction from
one side, and demonstration that mesalamine can touch on specific
molecular steps enhancing apoptosis on the other side have
re-shaped the indications of mesalamine for ulcerative colitis.
Secondly, the role of thiopurines (azathioprine and 6-MP)
in the maintenance of remission of ulcerative colitis has
been reiterated by the results of several clinical trials.
During attempts at clarifying the reasons why certain patients
appear to be resistant to thiopurines, it was interestingly
found that mesalamine can interfere thiopurine metabolism,
causing an increased blood concentration of the specific immunosuppressive
metabolites and a sequential enhancement of drug effectiveness.
Mesalamine is therefore being studied as a means to overcome
the genetically determined resistance to thiopurines. Such
sharpened indications have reiterated attention to correct
dosing: the results of controlled trials have shown mesalamine
to be fully effective at twice the traditional daily dosage
(4.8 grams instead of 2.4). The attendant problems of compliance
seem to find solution in the availability of multi-matrix
system formulations. This mesalamine story reminds us that
in the absence of an etiological target capable to guide research
to trace one abrogating molecule, (as it has happened for
viral hepatitides for example), treatment of inflammatory
bowel disease remains anti-inflammatory in nature and thus
multifaceted. Besides justified use of cutting-edge technology
to find novel molecules, smart re-evaluation of what is already
in our hands can sometimes bring about unexpected breakthroughs.
[Back to top]
Liver Tolerance and the Manipulation of Immune Outcomes
Lauren E. Holz, Geoffrey W. McCaughan, Volker Benseler,
Patrick Bertolino and David G. Bowen
In recent years it has become apparent that the liver holds
a distinct immunological position. Previously described as
a “graveyard” for T cells activated in the periphery,
emerging evidence indicates that this organ may have a more
active role in mediating tolerance. Attenuated immune responses
in the liver can be beneficial in the transplantation setting,
as liver transplants are more readily accepted than other
organ allografts even in the absence of immunosuppressive
drugs. However, the ability of the liver to induce immunological
unresponsiveness could be exploited by some pathogens, such
as the hepatitis C virus (HCV), to establish chronic infections
with potentially fatal outcomes. Understanding the mechanisms
controlling the balance between intrahepatic tolerance and
immunity is critical in order to design new strategies to
enhance acceptance of solid organ allografts and to promote
efficient immune responses against HCV. In this article, we
will review current knowledge of the mechanisms regulating
intrahepatic immunity and discuss how these mechanisms might
potentially be targeted to achieve advantageous clinical outcomes
in transplantation and persistent hepatotropic infections.
[Back to top]
Inflammatory Aspects of Depression
Ubiratan C. Adler, Andrea H. Marques and Helena M. Calil
A bidirectional relation between depression and natural immunity
has been identified: depressive episodes are associated to
a relative immunodeficiency, conversely inflammatory activity
has been implicated in the development of depressive symptoms
and in the pathophysiology of depression. Depression has been
associated with a decrease in the number and activity of NK
lymphocytes and hence patients with depression may show immunodeficiency
towards intracellular microorganisms and tumors. Paradoxically,
depression is sometimes accompanied by an inflammatory state,
developed from the peripheral stimuli (atopy) or central stimuli
(chronic stress) and mediated by proinflammatory cytokines
(IL-6, TNF and IL-1). These cytokines can play a role in the
pathophysiology of depression and of various diseases, supporting
the hypothesis that many chronic diseases are individual manifestations
of a common proinflammatory denominator.
[Back to top]
Role of Transglutaminase-Catalyzed Reactions in the
Post- Translational Modifications of Proteins Responsible
for Immunological Disorders
Giulia De Vivo, Antonio Martin, Tiziana Trotta and Vittorio
Gentile
Transglutaminases (TG, E.C. 2.3.2.13) are a family of related
and ubiquitous enzymes which catalyze the cross linking of
a glutaminyl residue of a protein/peptide substrate to a lysyl
residue of a protein/peptide co-substrate. These enzymes are
also capable of catalyzing other reactions which are important
for cell life. The distribution and the physiological roles
of human TGs have been widely studied in numerous cell types
and tissues and recently their roles in several diseases have
begun to be identified. It has been hypothesized that transglutaminase
activity is directly involved in the pathogenetic mechanisms
responsible for several human diseases. In particular, “tissue”
TG (tTG, type 2), a member of the TG enzyme family, has been
recently shown to be involved in the molecular mechanisms
responsible for a very widespread human pathology, Celiac
Disease (CD), which is characterized, in part, by aberrant
transglutaminase activity and by the presence of transglutaminase-modified
proteins. In this review we describe the biochemistry of TGs,
with particular reference to the molecular mechanisms involved
in the physiopathology of this human disease, as a model for
the study of other immunological disorders.
[Back to top]
Emerging Mucus Regulating Drugs in Inflammatory and
Allergic Lung Disease
Hans-Peter Hauber and Peter Zabel
Mucus hypersecretion is common in inflammatory and allergic
lung disease. Excessive mucus production leads to obstruction
of airways and favours bacterial colonization. Advances in
understanding the signalling and transduction pathways of
mucin gene expression as well as mechanisms of mucin protein
production and secretion have defined new therapeutic targets.
Conventional therapies include anticholinergics, β2-adrenoceptor
agonists, glucocorticosteroids, mucolytics and macrolide antibiotics.
Novel therapeutic approaches are inhibitors of cholinergic
nerve activity, tachykinin receptor antagonists, epoxygenase
inducers, inhibitors of mucin exocytosis, inhibitors of mucin
synthesis and goblet cell hyperplasia, inducers of goblet
cell apoptosis and P2Y2 purinoceptor antagonists to inhibit
mucin secretion. After providing a short overview on conventional
therapies this review will focus on new therapeutic targets.
[Back to top]
Selective Inhibitors of Nuclear Factor of Activated
T Cells: Potential Therapeutic Drugs for the Treatment of
Immunological and Inflammatory Diseases
Osamu Kaminuma
Structurally-unrelated immunosuppressive drugs, cyclosporin
A and FK506 (tacrolimus), that share a common intracellular
target protein, calcineurin, display strong and similar efficacy
in the cases of organ transplantation and other immunological
diseases. However, prolonged use of these drugs in many chronic
diseases is restricted due, at least in part, to their side
effects. The pharmacological effects of cyclosporin A and
FK506, represented by the suppression of T cell activation
and proliferation, are exhibited via inhibiting the
activity of a transcription factor, nuclear factors of activated
T cells (NFAT). The NFAT family members are involved in inducible
expression of numerous genes concerned with immune responses
as well as other biological events. Studies using gene-targeted
mice have suggested that each NFAT family member plays a differential
role in the synthesis of multiple cytokines. The diversity
of the NFAT family is one of the reasons for the potent and
wide-variety of side effects induced by cyclosporin A and
FK506. However, molecular mechanisms underlying the functional
differences among the NFAT family have not been fully elucidated.
We have been investigating the comparative roles of NFAT members
in regulating T cell cytokine synthesis. In addition, in order
to identify the essential region in NFAT responsible for the
specificity of individual NFAT members, we have applied a
novel assay technique to accurate assessment of interacting
properties between NFAT and its binding partners. This article
summarizes the potential and possibility of selective NFAT
inhibitors in the treatment of immunological and inflammatory
diseases with introducing our recently elucidated findings.
[Back to top]
Transferrin and the Transferrin Receptor: Of Magic
Bullets and Other Concerns
Maria F. Macedo and Maria de Sousa
Transferrin (Trf) is a highly conserved serum glycoprotein
mostly known for its iron transport capacity. As iron is an
indispensable nutrient for cell division, Trf and its receptor
have long been used as targets of pharmacological intervention
mostly for cancer therapy and for diagnosis in inflammation.
In recent years several independent pieces of work including
data from our group, indicated that Trf can also have an iron
independent role in the immune system. In this article new
emerging roles of Trf and its receptor on iron independent
processes and in drug delivery are reviewed.
[Back to top]
Molecular Targets of Rheumatoid Arthritis
Hiroshi Okamoto, Daisuke Hoshi, Akiko Kiire, Hisashi Yamanaka
and Naoyuki Kamatani
Rheumatoid arthritis (RA) is a multifactorial disease characterized
by chronic inflammation of the joints. Both genetic and environmental
factors are involved in the pathogenesis of joint destruction
and disability. In the inflamed RA joint, the synovium is
highly infiltrated by CD4+ T cells, B cells, and macrophages.
Furthermore, the intimal lining becomes hyperplastic due to
the increased numbers of macrophage-like and fibroblast-like
synoviocytes. This hyperplastic intimal synovial lining forms
an aggressive front, called pannus, which invades cartilage
and bone structures, leading to compromised function and/or
destruction of affected joints. RA pathology is mediated by
a number of cytokines (TNF-α,
IL-1, IL-6, IL-17, IFNγ,
etc.), chemokines (MCP-1, MCP-4, CCL18, etc.),
cell adhesion molecules (ICAM-1, VCAM-1, etc.) and
matrix metalloproteinases. Currently, treatment strategies
targeted against TNF-α,
IL-1 and IL-6 are available. In this review, we will summarize
the use of biologics, the pros and cons of the use of biologics,
and discuss on the potential molecular targets of RA.
|
