Current Drug Targets – Immune, Endocrine & Metabolic Disorders Volume 3, No. 3, 2003
Contents
A Discussion of Natural Rubber Latex Allergy
with Special Reference to Children: Clinical Considerations Pp. 171-180
Nettis
Eustachio , Colanardi Maria Cristina, Ferrannini Antonio and Tursi Alfredo
Thalidomide Derived Immunomodulatory Drugs
(IMiDs) as Potential Therapeutic Agents Pp. 181-186
J
Blake Marriott , Keith Dredge and Angus G. Dalgleish
Fc Receptors as Potential Targets for the
Treatment of Allergy, Autoimmune Disease and Cancer Pp. 187-197
Toshiyuki
Takai , Akira Nakamura and Kenichi Akiyama
Do Antidotes for Acute Cyanide Poisoning Act
on Mercaptopyruvate Sulfurtransferase to Facilitate Detoxification? Pp. 198-204
Noriyuki
Nagahara , Qing Li and Nori Sawada
Breast Cancer: Biological Characteristics in
Postmenopausal Type 2 Diabetic Women. Identification of Therapeutic Targets Pp. 205-209
E.
Guastamacchia , F. Resta , A. Mangia , F. Schittulli , A. Ciampolillo , V.
Triggiani , B. Licchelli , A. Paradiso , C. Sabba and E. Tafaro
Evidences for iNOS Expression and Nitric
Oxide Production in the Human Macrophages Pp. 210-221
M.A.
Panaro , O. Brandonisio , A. Acquafredda , M. Sisto and V. Mitolo
Induction of Optimal Immune Responses Against
Human Immunodeficiency Virus at Mucosal Portals of Entry Pp. 222-233
M. Vajdy
Skin Photoprotection by Green Tea:
Antioxidant and Immunomodulatory Effects Pp. 234-242
Santosh K. Katiyar
Abstracts
[Back to top] A Discussion of Natural Rubber Latex Allergy
with Special Reference to Children: Clinical Considerations
Nettis
Eustachio , Colanardi Maria Cristina, Ferrannini Antonio and Tursi Alfredo
Latex allergy is an
increasingly common condition, because the use of latex products is widespread.
Three types of
reactions can occur in persons using natural latex rubber products: 1) Irritant
contact dermatitis, 2) Allergic contact dermatitis, 3) and Type I
hypersensitivity. Children’s subpopulations at particular risk include:
atopics, individuals with spina bifida, or individuals who required frequent
surgical instrumentations. An association between allergy to latex and allergy
to various fruits and vegetables has been reported. Recently, an homology
between latex allergens and mold allergens has been reported leading to postulate
a possible existence of a “latex-mold–syndrome”. Diagnosis of allergy is based
initially on history, skin prick test and search for specific serum IgE.
Provocation tests may confirm the suspicion, although these are seldom
performed on children because they are not easy to bear with.
The most effective
strategy to decrease the incidence of NRL (natural rubber latex) sensitization
is avoidance; however, this is virtually impossible, given the large number of
latex products we encounter since childhood. Studies of secondary prophylaxis
among children demonstrate that notwithstanding recommendations, children could
manifest yet adverse reactions to latex products and have detectable levels of
anti latex IgE..
[Back to top] Thalidomide Derived Immunomodulatory Drugs
(IMiDs) as Potential Therapeutic Agents
J
Blake Marriott , Keith Dredge and Angus G. Dalgleish
Thalidomide is known
to be effective in the treatment of a number of conditions, including leprosy
and various cancers. The exact mechanisms of action remain unclear although
these are known to include antitumour necrosis factor (TNF)-á, T cell
costimulatory, anti-angiogenic and anti-tumour activities. However, thalidomide
is being superceded by novel structural derivatives which have been designed to
have improved immunomodulatory activity and side effect profiles. These are
currently being characterised and some are entering the clinic in phase I/II
studies. One novel group of structural analogues are classified as the
Immunomodulatory Drugs (IMiDs). This review describes the emerging
immunological, anti-angiogenic and direct anti-tumour properties of thalidomide
and the characterisation and clinical application of its ImiD analogues. We
describe the laboratory studies which have led to the characterisation and
development of IMiDs into potentially clinically relevant drugs. Early trial
data suggests that these compounds may themselves become established therapies,
particularly in certain cancers. Furthermore, ongoing studies will determine
how best to apply these compounds to the appropriate clinical settings. We will
describe the various clinical studies of lead compounds that are in progress
and speculate as to the potential and future development of these exciting compounds.
[Back to top] Fc Receptors as Potential Targets for the
Treatment of Allergy, Autoimmune Disease and Cancer
Toshiyuki
Takai , Akira Nakamura and Kenichi Akiyama
The activation
threshold of various cells in the immune system is tuned by immune inhibitory
receptors. The inhibitory Fc receptor, FcăRIIB, is one of the critical elements
for keeping immune cells silent. Murine models for allergic responses and
autoimmune diseases illustrate the indispensable roles of FcăRIIB in the
suppression of these immune disorders. On the contrary, activating-type Fc
receptors are crucial for the onset and exacerbation of such diseases. In
addition, recent reports have revealed the pivotal roles of Fc receptors in
enhancing antigen presentation by dendritic cells, which leads to efficient
major histocompatibility complex class I- and class II-restricted T cell
activation. In this context, anti-cancer immunopotentiation could be augmented
by targeting the tumor antigens to Fc receptors on dendritic cells. This review
summarizes recent advances in Fc receptor biomedicine in light of exploiting
them as potential therapeutic targets for allergy, autoimmune disease and
cancer.
[Back to top] Do Antidotes for Acute Cyanide Poisoning Act
on Mercaptopyruvate Sulfurtransferase to Facilitate Detoxification?
Noriyuki
Nagahara , Qing Li and Nori Sawada
A well-known combined
therapy for acute cyanide poisoning is intravenous administration of sodium
nitrite, sodium thiosulfate and cobalt EDTA. Sodium nitrite oxidizes
oxy-hemoglobin, resulting in methemoglobin, which has a high affinity for
cyanide. Sodium thiosulfate is a substrate of thiosulfate: cyanide
sulfurtransferase (rhodanese, EC.2.8.1.1), and facilitates catalytic metabolism
of cyanide to less toxic thiocyanate. Cobalt EDTA combines with cyanide to
reduce cyanide in the blood. Here, we focus on cytosolic and mitochondrial
mercaptopyruvate sulfurtransferase (MST, EC. 2.8.1.2), which detoxifies cyanide
more effectively than rhodanese, because rhodanese is localized only in
mitochondria. Thiosulfate also serves as a substrate of MST and cyanide can be
metabolized to thiocyanate. However, the Km value for thiosulfate is so large
that it is not expected to contribute much to the detoxification of cyanide. On
the other hand, nitrite and cobalt EDTA did not affect MST. Thus, combined
therapy only slightly acts on MST to detoxify cyanide. Some investigators have
attempted a new therapy in which mercaptopyruvate, a substrate of MST was
administered intravenously, but this was not effective for detoxification due
to the rapid decomposition of mercaptopyruvate in the blood. There are two
possible strategies to facilitate MST activities: development of modified
mercaptopyruvate with a longer half time and development of a chemical compound
which indirectly increases transcription of MST via regulation of a DNA binding
protein.
[Back to top] Breast Cancer: Biological Characteristics in
Postmenopausal Type 2 Diabetic Women. Identification of Therapeutic Targets
E.
Guastamacchia , F. Resta , A. Mangia , F. Schittulli , A. Ciampolillo , V.
Triggiani , B. Licchelli , A. Paradiso , C. Sabba and E. Tafaro
HYPOTHESIS:
Epidemiological data have suggested a possible relationship between diabetes
mellitus and cancer risk, particularly breast cancer.
We set out to
investigate the effect of diabetes mellitus on the expression of estrogen and
progesterone receptors and on the proliferative activity of primary breast
cancer.
METHODS: We selected
77 diabetic women and 578 control patients all in post-menopause and diagnosed
with primary breast cancer. All patients underwent surgical excision of the
tumor and on the specimens were performed an assessment of estrogen receptor
and progesteron receptor and proliferative activity assay by 3Hthymidine
incorporation.
RESULTS: Diabetic
women showed a decreased proliferative activity, while having the same estrogen
receptor and progesteron receptor status and mean cytoplasmic concentration of
their receptors than control group. Insulin treated women had a lower
proliferative activity than non-insulin treated ones.
CONCLUSION:
Hyperinsulinemia and hyperglicemia influence in negative way the proliferative
activity of diabetic women, likely inducing the expression of transforming
growth factor beta, despite the high serum levels of Insulin-like growth factor
and estrogen.
[Back to top] Evidences for iNOS Expression and Nitric
Oxide Production in the Human Macrophages
M.A. Panaro , O. Brandonisio , A. Acquafredda , M. Sisto and V. Mitolo
Nitric oxide (NO) is a
pleiotropic mediator of numerous biological processes, including smooth muscle
relaxation, neurotransmission and defence against pathogens. In addition, NO is
involved in the pathogenesis and control of inflammation, tumors, autoimmunity,
and infectious and chronic degenerative diseases. NO, a highly reactive
radical, is produced from L-arginine and oxygen by the enzyme NO synthase
(NOS). Three NOS isoforms have been identified: two distinct NOS isoforms are
constitutively expressed in cells, whereas a third isoform, inducible NOS
(iNOS), is transcribed in response to specific stimuli. In particular, iNOS is
responsible for the discontinuous synthesis of high amounts of NO and was
originally characterized in murine macrophages after exposure to cytokines
and/or microbial products. A wide range of microorganisms is sensibly inhibited
in its development by NO, like fungi, bacteria, protozoa and viruses. Although
NO production and its antimicrobial effect appear well established in rodent
macrophages, the existence of L-arginine pathway in human mononuclear
phagocytes has long been disputed. Recently, evidences showing the iNOS activity
and NO production in other animal models, including humans, are now emerging,
even if the NO induction has been more difficult to demonstrate.
The present
observations provide evidence for the occurrence of iNOS protein expression and
NO production in human macrophages cultured in vitro.
[Back to top] Induction of Optimal Immune Responses Against
Human Immunodeficiency Virus at Mucosal Portals of Entry
M.
Vajdy
Mucosal surfaces
comprise the largest surface area of the human body and are the first line of
defense against many pathogens. In fact, over 90% of common infectious disease
pathogens in humans gain access to the host through mucosal membranes. A number
of studies have demonstrated that mucosal immunizations induce local as well as
systemic immunity. However, induction of mucosal responses by mucosal
immunization is often hampered by a number of factors including degradation of
vaccines at the site of delivery. Moreover, many pathogens, including the human
immunodeficiency virus, HIV, primarily enter the host through a mucosal
membrane after which they spread systemically. Thus, induction of optimal and
protective immune responses are required at both mucosal and systemic sites.
This review deals with current efforts on the induction of HIVspecific
prophylactic humoral and/or cell mediated immunity in the female genital tract
and rectal mucosa. The importance of the various routes of mucosal or systemic
as well as combinations of mucosal and systemic immunizations through delivery
of gene and protein based experimental vaccines will be reviewed. Furthermore,
a summary of current and future therapeutic treatment targets will be
presented.
[Back to top] Skin Photoprotection by Green Tea: Antioxidant
and Immunomodulatory Effects
Santosh
K. Katiyar
Because of a
characteristic aroma and health benefits, green tea is consumed worldwide as a
popular beverage. The epicatechin derivatives, commonly called polyphenols,
present in green tea possess antioxidant, anti-inflammatory and
anticarcinogenic properties. The major and most highly chemopreventive
constituent in green tea responsible for the biochemical or pharmacological
effects is (-)- epigallocatechin-3-gallate (EGCG). Epidemiological, clinical
and biological studies have implicated that solar ultraviolet (UV) light is a
complete carcinogen and repeated exposure can lead to the development of
various skin disorders including melanoma and nonmelanoma skin cancers. We and
others have shown that topical treatment or oral consumption of green tea
polyphenols (GTP) inhibit chemical carcinogen- or UV radiation-induced skin
carcinogenesis in different laboratory animal models. Topical treatment of GTP
and EGCG or oral consumption of GTP resulted in prevention of UVB-induced
inflammatory responses, immunosuppression and oxidative stress, which are the
biomarkers of several skin disease states. Topical application of GTP and EGCG
prior to exposure of UVB protects against UVB-induced local as well as systemic
immune suppression in laboratory animals, which was associated with the
inhibition of UVB-induced infiltration of inflammatory leukocytes. Prevention
of UVB-induced suppression of immune responses by EGCG was also associated with
the reduction in immunosuppressive cytokine interleukin (IL)-10 production at
UV irradiated skin and draining lymph nodes, whereas IL-12 production was
significantly enhanced in draining lymph nodes. Antioxidant and
anti-inflammatory effects of green tea were also observed in human skin.
Treatment of EGCG to human skin resulted in the inhibition of UVB-induced
erythema, oxidative stress and infiltration of inflammatory leukocytes. We also
showed that treatment of GTP to human skin prevents UVB-induced cyclobutane
pyrimidine dimers formation, which are considered to be mediators of
UVB-induced immune suppression and skin cancer induction. The in vitro and in
vivo animal and human studies suggest that green tea polyphenols are
photoprotective in nature, and can be used as pharmacological agents for the
prevention of solar UVB light-induced skin disorders including photoaging,
melanoma and nonmelanoma skin cancers after more clinical trials in humans.