Current Drug Targets – Immune, Endocrine & Metabolic Disorders Volume 4, No. 2, 2004
Contents
Common and Uncommon Features of Rheumatoid
Arthritis and Chronic Obstructive Pulmonary Disease: Clues to a Future Therapy Pp.85-92
E.
Andreakos
Hyperferritinaemia Without Iron Overload:
Pathogenic and Therapeutic Implications Pp.93-105
F.
Bertola, D. Veneri, S. Bosio, P. Battaglia, A. Disperati and R. Schiavon
Regulators of G Protein Signaling: Potential
Drug Targets for Controlling Cardiovascular and Immune Function Pp.107-118
H.
Cho, K. Harrison and J.H. Kehrl
The Pathobiology of Osteoarthritis and the
Rationale for Using the Chondroitin Sulfate for its Treatment Pp.119-127
Nicola
Volpi
Therapeutic Implications of Immune-endocrine
Interactions in the Critically Ill Patients Pp.129-139
Reiner
Oberbeck
Treatment of Inflammatory and Paraproteinemic
Neuropathies Pp.141-148
Salvatore
Monaco, Emanuela Turri, Gianluigi Zanusso and Barbara Maistrello
Flt3 Ligand Bioactivity and Pharmacology in
Neoplasia Pp.149-156
A.
J. Reber, A. E. Ashour, S. N. Robinson, J. E. Talmadge and J. C. Solheim
Activins, Myostatin and Related TGF-b Family Members as Novel Therapeutic Targets
for Endocrine, Metabolic and Immune Disorders Pp.157-166
Kunihiro
Tsuchida
Abstracts
[Back to top] Common and Uncommon Features of Rheumatoid
Arthritis and Chronic Obstructive Pulmonary Disease: Clues to a Future Therapy
E.
Andreakos
Over the last decade
it has become apparent that common pathogenic mechanisms are shared between
many human chronic inflammatory diseases of unrelated pathology and
manifestation. These mechanisms include common inflammatory networks that
control tissue destructive and repair processes and their study is of major
therapeutic potential as recently demonstrated for TNFa. Thus, early studies in rheumatoid arthritis
defined TNFa as a major therapeutic target, the blockade of
which was subsequently proved to be of great efficacy in the clinic. This paved
the way for the successful blockade of TNFa in various
other diseases including Crohn’s disease, psoriasis, spondyloarthropathies
and juvenile arthritis,
although no similar networks
with anti-TNFa at their apex had previously been demonstrated.
In this article, we review the current knowledge of the pathogenic mechanisms
involved in rheumatoid arthritis and chronic obstructive pulmonary disease with
particular emphasis on the role of inflammatory cytokines, chemokines, and
tissue degrading enzymes as revealed by studies in the laboratory and the
clinic. Direct comparison of these mechanisms may provide clues for a future
therapy for these painful and incurable diseases.
[Back to top] Hyperferritinaemia Without Iron Overload:
Pathogenic and Therapeutic Implications
F.
Bertola, D. Veneri, S. Bosio, P. Battaglia, A. Disperati and R. Schiavon
It is not unusual to
meet increased levels of ferritinaemia in patients apparently healthy. Among
other causes of hyperferritinaemia, recently was described the Hereditary
Hyperferritinemia Cataract Syndrome, a genetic condition characterized by
increased serum ferritin values without iron overload and bilateral nuclear
cataract, both of early onset. It has been demonstrated that single or double
point mutations or deletions in the stem-loop structure of the iron regulatory
element (I.R.E.) located in the 5 untranslated regions of
the ferritin L-subunit gene (19q13.1)
are responsible for the upregulation
of ferritin. This
overexpression only for the
L-chain gives rise to typical piles in several tissues. When this altered
ferritin accumulates in lens it causes bilateral nuclear cataracts, that is the
peculiar sign of this syndrome. It is essential to differentiate true iron
overload from Hereditary Hyperferritinaemia Cataract Syndrome (H.H.C.S.), because
these patients rapidly develop iron deficient anaemia when venosectioned.
Here we describe a
case report about a 40 years old healthy female blood donor who presented
isolated hyperferritinaemia without iron overload, in the absence of
concomitant pathologies. Anamnestic, biochemical, instrumental and clinical
investigations led us to diagnose H.H.C.S., a pathology first described in
1995. From 1995 to date about 40 cases concerning patients showing the
characteristics of this syndrome from Europe, U.S.A., and Australia were
described. Biochemical, genetical and clinical investigations led finally to
understand every matter of this pathology, providing conclusive and exhaustive
explanations.
[Back to top] Regulators of G Protein Signaling: Potential
Drug Targets for Controlling Cardiovascular and Immune Function
H.
Cho, K. Harrison and J.H. Kehrl
Heterotrimeric
G-protein-coupled receptors (GPCRs) mediate a wide variety of organismal functions
ranging from vision, olfaction, and gustation to the development and physiology
of the cardiovascular, neuronal, and immune system. Naturally they are targets
of a large number of therapeutic drugs. The regulators of G protein signaling
(RGS) are a family of diverse proteins that regulate the GPCR-mediated
signaling pathways principally by acting as GTPase activating proteins (GAPs)
for the a subunit of the heterotrimeric G-proteins. Certain members of the RGS
family contain multiple domains and motifs that mediate interactions with other
signaling molecules, thus linking
GPCR-dependent and GPCR-independent signaling pathways. Because
of their ability to fine-tune
vital GPCR-mediated processes and recent findings linking them to brain disorders,
retinitis pigmentosa, and cancer RGS proteins have become excellent candidates
for new drug discovery. The focus of this review is to discuss the roles of the
RGS proteins in the development and normal physiology of cardiovascular and
immune system, and to explore their potential as drug targets useful for the
treatment of pathological conditions of the cardiovascular and immune systems.
[Back to top] The Pathobiology of Osteoarthritis and the
Rationale for Using the Chondroitin Sulfate for its Treatment
Nicola
Volpi
Structure-modifying
osteoarthritis (OA) drugs are agents that reverse, retard, or stabilize the
pathology of OA, thereby providing symptomatic relief in the long-term
treatment. The objective of this review is to evaluate the literature on
chondroitin sulfate (CS) with respect to the pathobiology of OA to ascertain
whether this agent should be classified as a symptomatic slow-acting drug
(SYSADOA), a compound that has a slow onset of action and improve OA symptoms
after a couple of weeks.
CS exhibits a wide
range of biological activities and from a pharmacological point of view it
produces a slow but gradual decrease of the clinical symptoms of OA and these
benefits last for a long period after the end of treatment. Many literature
data show that CS could have an anti-inflammatory activity and a
chondroprotective action by modifying the structure of cartilage. These
properties are also related to the oral adsorption of this molecule as
high-molecular mass compounds having clusters of sulfate groups and high charge
density capable of exert their chondroprotective activity in vivo.
[Back to top] Therapeutic Implications of Immune-endocrine
Interactions in the Critically Ill Patients
Reiner
Oberbeck
The existence of an
immune-endocrine interaction has been demonstrated decades ago. An
immunomodulatory effect was reported for a wide range of hormones. The best
known example for this interaction is the glucocorticoids released by the
adrenal cortex. Apart of the glucocorticoids several hormones and
neurotransmitters released by these systems are capable of altering immune
functions. This includes the catecholamines epinephrine, norepinephrine and
dopamine, the pituitary hormone prolac-tin, and the adrenal hormone
dehydroepiandrosterone (DHEA).
Several pathological
states are paralleled by an activation of the endocrine system leading to an
increased hormone release. In line with this an elevated release of
catecholamines, of prolactin, and of DHEA has been demonstrated after major
surgery, during systemic inflammation and following trauma hemorrhage.
Furthermore, due to their pharmacologic properties several neurotransmitters
are used as pharmaceutical agents to stabilize cardiovascular function or to
prevent organ failure (e.g. epinephrine, norepinephrine, dopamine). Several
pharmacological substances interact with the release of immunomodulatory
hormones (e.g. metoclopramid and prolactin, dopamine and prolactin) and some
hormones are available as over-the counter self medications like DHEA.
Therefore, alterations
of the serum concentrations of these hormones may affect the immunocompetence
of the organism and may thereby affect the clinical course of critically ill
patients.
The clinical and
pharmacological implications of this complex relationship between the endocrine
and the immune system will be provided on the background of a review of the
recent literature and of our research work.
[Back to top] Treatment of Inflammatory and Paraproteinemic
Neuropathies
Salvatore Monaco, Emanuela Turri, Gianluigi Zanusso and Barbara Maistrello
Acquired demyelinating
and inflammatory neuropathies encompass a number of acute and chronic
autoimmune conditions characterized by variable degrees of clinical
involvement. These disorders, including Guillain-BarrZ syndrome (GBS), chronic
inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor
neuropathy (MMN), and paraprotein-associated neuropathy, have an overall annual
incidence of 2-4/100,000 worldwide and are potentially treatable. Over the last
few years, several investigations have helped clarify the pathogenesis of
immune neuropathies and the definition of molecular targets involved in these diseases, thus providing firmer grounds for treatment with classical
immunosuppressive drugs and new biological agents.
In GBS and related
variants, which are characterized by cellular inflammation and alterations of
the blood-nerve barrier, randomized clinical trials show that plasma exchange
(PE) and intravenous immunoglobulin (IVIg) are equally effective as
disease-modifying treatments, although IVIg has been adopted as the favourite
treatment in most centres.
In CIDP, controlled clinical
trials have established the efficacy of oral prednisone, PE and IVIg, with
intermittent IVIg treatment or corticosteroids being usually preferred. Adding
azathioprine can help keep lower the required dose of prednisone, while other
immunosuppressive agents, such as cyclophosphamide and cyclosporin A may have
side effects, limiting their use to selected cases. Currently, the efficacy of
interferon beta and alfa is under evaluation.
Controlled trials
support the view that IVIg is the treatment of choice in MMN. Patients
resistant to IVIg administration may benefit of treatments which deplete B
cells, such as cyclophosphamide and rituximab.
Demyelinating
neuropathies associated with circulating paraproteins are clinically
heterogeneous, depending on the reactivity and type of the monoclonal (M)
protein. In many cases, neuropathies associated with IgM M proteins are not
treated because of their slow progression. In patients with a disabling or
rapid progression, small trials have shown short-term benefits from IVIg or PE.
Recently, fludarabine and rituximab have been reported as beneficial in
selected cases.
[Back to top] Flt3 Ligand Bioactivity and Pharmacology in
Neoplasia
A.
J. Reber, A. E. Ashour, S. N. Robinson, J. E. Talmadge and J. C. Solheim
Fms-like tyrosine
kinase 3 ligand (Flt3L) has multiple effects on the hematopoietic and immune
systems. Further, preclinical studies have suggested potential therapeutic
activity against cancer. Flt3L is a potent hematopoietic cytokine, capable of
stimulating the expansion and differentiation of hematopoietic progenitor and
stem cells. Administration of
Flt3L mobilizes
hematopoietic cells from
the bone marrow (BM) into the blood, lymphoid organs, and parenchymal
tissues. This mobilization activity, especially effective in combination with
granulocyte colony stimulating factor
(G-CSF), has stimulated studies of
Flt3L in hematopoietic stem cell (HSC) transplantation. In addition to its
effects on hematopoietic stem and progenitor cells, Flt3L has been shown to
increase the frequency and number of dendritic cells (DCs) within the
circulatory system and solid organs. DC expansion by Flt3L has been the focus
of preclinical and clinical studies on antigen (Ag) specific T-cell mediated
immunity. The mechanism for the augmentation of T-cell mediated immunity has
yet to be completely identified, although Flt3L’s ability to expand DCs in
lymphoid and non-lymphoid tissues is involved. This expansion occurs primarily
with DCs, which secrete interleukin (IL) 12. Consistent with the expansion of
this DC population, treatment with Flt3L enhances T-cell mitogenesis and
preferentially induces type 1 T-cell responses. However, the DCs resulting from
Flt3L administration are immature, leading in some studies to the induction of
tolerance. This review focuses on the effects of Flt3L on DCs and other
effector populations, and on its potential activity as a therapeutic agent for
cancer, alone and in combination with vaccines.
[Back to top] Activins, Myostatin and Related TGF-b Family Members as Novel Therapeutic Targets
for Endocrine, Metabolic and Immune Disorders
Kunihiro
Tsuchida
Activins and inhibins
were first identified by virtue of their ability to regulate
follicle-stimulating hormone (FSH) secretion from the anterior pituitary.
Activins are also powerful regulators of gonadal functions. However, the
physiological functions of activins are not restricted to reproductive tissues.
Activins are involved in apoptosis of hepatocytes and B cells, fibrosis,
inflammation and neurogenesis. Activins are regarded as novel drug targets
since blocking activins would provide benefits by preventing apoptosis,
fibrosis, inflammation and growth of several cancers. Activins are members of
the transforming growth factor-b (TGF-b) family, which has numerous peptide growth
and differentiation factors
including activins, bone
morphogenetic proteins (BMPs), growth and differentiation factors
(GDFs) and TGF-bs. Among them, GDF8 is also known as myostatin
and is structurally related to activins. Myostatin is specifically expressed in
the skeletal muscle lineage and is a candidate for muscle chalone negatively
regulating the growth of myoblasts. Myostatin is regarded as a good drug target
since therapeutics that modulate skeletal muscle growth would be useful for
disease conditions such as muscular dystrophy, sarcopenia, cachexia and even
diabetes. Recent studies have revealed that activins and myostatin signal
through activin type II receptors (ActRIIA and ActRIIB) and their activities
are regulated by extracellular binding proteins, follistatins and
follistatin-related gene (FLRG). Furthermore, signaling of activins, myostatin
and related ligands is also controlled by intracellular receptor-interacting
proteins by novel mechanisms. In this review, I would like to show the current
progress in the field emphasizing the importance of activins and myostatin as
novel drug targets for immune, endocrine and metabolic disorders.