|
Current Molecular Medicine
ISSN: 1566-5240
Current Molecular Medicine
Volume 6, Number 6, September 2006
Contents
NK Cell Function in HIV-1 Infection
Pp. 621-629
Galit Alter and Marcus Altfeld
[Abstract]
Immunological Tolerance Using Synthetic Peptides
- Basic Mechanisms and Clinical Application Pp. 631-643
Kristin Hochweller, Claire H. Sweenie and Stephen M. Anderton
[Abstract]
Early Genetic Changes Involved in Low-Grade Astrocytic
Tumor Development Pp. 945-650
Dolores Arjona, Juan Antonio Rey and Shirley M. Taylor
[Abstract]
Biomedical Applications and Potential Health Risks
of Nanomaterials: Molecular Mechanisms Pp. 651-663
Sophie Lanone and Jorge Boczkowski
[Abstract]
Molecular Pathogenesis of Chronic Lymphocytic
Leukemia Pp. 665-675
Alexey V. Danilov, Olga V. Danilova, Andreas K. Klein
and Brigitte T. Huber
[Abstract]
Cannabinoid Drugs and Enhancement of Endocannabinoid
Responses: Strategies for a Wide Array of Disease States Pp.
677-684
David A. Karanian and Ben A. Bahr
[Abstract]
Molecular Aspects of Stromal–Parenchymal
Interactions in Malignant Neoplasms Pp. 685-693
Attila Zalatnai
[Abstract]
Network Theory to Understand Microarray Studies
of Complex Diseases Pp. 695-701
Mikael Benson and Rainer Breitling
[Abstract]
Abstracts
[Back to top]
NK Cell Function in HIV-1 Infection
Galit Alter and Marcus Altfeld
NK cells are critical effector cells of the innate immune
response to malignancy and infection. These cells have a wide
array of direct antiviral activities and have been critically
implicated in the regulation and induction of an effective
adaptive immune response. Although the pivotal role of this
cell subset in the context of a number of viral infections
is well established, the role of NK cells in HIV-1 infection
is less well understood. Recent data has demonstrated the
association between an NK cell receptor, KIR3DS1, and it’s
ligand, HLA-Bw4 with an isoleucine at position 80, and slower
disease progression. This data suggests that NK cells may
play an essential role in the control of HIV-1 disease, and
has provided the impetus to begin to better understand the
role of this cell subset in the context of HIV-1 infection,
replication, and pathogenesis. Here we present a review of
the literature pertaining to both the effect of HIV-1 infection
on NK cell activity and the potential role that this subset
of cells may play in controlling HIV-1 disease.
[Back to top]
Immunological Tolerance Using Synthetic Peptides -
Basic Mechanisms and Clinical Application
Kristin Hochweller, Claire H. Sweenie and Stephen M. Anderton
Dysregulation of T lymphocyte function underpins the development
of autoimmune and allergic diseases. These autoantigen-, or
allergen-reactive pathogenic T cells are rare within the entire
immune repertoire and it is therefore desirable to develop
more specific therapies than are currently in use to directly
target these cells and avoid adverse side effects. The obvious
approach is to use the antigens that are recognized to impose
a state of T cell tolerance. T cells recognize antigens as
peptide fragments and we can therefore produce the relevant
antigens as synthetic peptides. It has been known for many
years that the decision of the T cell to mount a productive
response (immunity) or to remain silent (tolerance) is controlled
by the form in which the antigen is administered. Antigen
with adjuvant leads to immunity, whereas soluble antigen without
adjuvant leads to tolerance. This paradigm has been used successfully
to induce tolerance with soluble peptides, preventing several
animal models of autoimmune and allergic disease. These findings
obviously have exciting potential for translation to human
diseases. However, the basic immune mechanisms that lead to
tolerance versus immunity are only beginning to be unravelled.
The “effector” phase of tolerance also remains
controversial with evidence for T cell death, anergy and the
development of immunoregulatory function. This latter possibility
of specifically generating autoantigen- or allergen-reactive
regulatory T cells is particularly attractive. Here we review
recent advances in our understanding of the requirements for
tolerance induction and the potential for establishing dominant
immune-regulation with peptide therapy.
[Back to top]
Early Genetic Changes Involved in Low-Grade Astrocytic
Tumor Development
Dolores Arjona, Juan Antonio Rey and Shirley M. Taylor
Astrocytomas represent the most common form of glial tumors.
The most malignant grade of these tumors, glioblastoma multiforme,
may arise as a malignant progression from low-grade astrocytoma
through anaplastic astrocytoma to secondary GBM, or else it
may arise “de novo” as primary GBM. Both
types of glioblastoma are usually histologically indistinguishable.
However, distinct molecular alterations have been described
between them that potentially allow differentiation between
the two mechanisms of origin. Since malignant transformation
is a multistep process, we summarize in this review the earliest
genetic changes that seem to be involved in the appearance
and development of low-grade astrocytic tumors, where early
detection and treatment could be possible.
[Back to top]
Biomedical Applications and Potential Health Risks
of Nanomaterials: Molecular Mechanisms
Sophie Lanone and Jorge Boczkowski
Nanotechnologies, defined as techniques aimed to conceive,
characterize and produce material at the nanometer scale,
represent a fully expanding domain, and one can predict without
risk that production and utilization of nanomaterials will
increase exponentially in the coming years. Applications of
nanotechnologies are numerous, in constant development, and
their potential use in the medical field as diagnosis and
therapeutics tools is very attractive. The size particularity
of these nanomaterials gives them novel properties, allowing
them to adopt new comportments because of the laws of quantum
physics that exist at this scale. However, worries are expressed
regarding the exact properties that make these nanomaterials
attractive, and questions are raised regarding their potential
toxicity, their long-term secondary effects or their biodegradability,
particularly when thinking of their use in the (nano)medical
field. These questions are justified by the knowledge of the
toxic effects of atmospheric pollution micrometric particles
on health, and the fear to get an amplification of these effects
because of the size of the materials blamed.
In this paper, we first expose the sensed medical applications
of nanomaterials, and the physicochemical and molecular determinants
potentially responsible for nanomaterials biological effects.
Finally, we present a synthesis of the actual knowledge regarding
toxicological effects of nanomaterials.
It is clear that, in regard to the almost empty field of what
is known on the subject, there’s an urge to better understand
biological effects of nanomaterials, which will allow their
safe use, in particular in the nanomedicine field.
[Back to top]
Molecular Pathogenesis of Chronic Lymphocytic Leukemia
Alexey V. Danilov, Olga V. Danilova, Andreas K. Klein
and Brigitte T. Huber
Chronic lymphocytic leukemia (CLL) is unique among malignancies
since it represents an accumulation of B-lymphocytes resistant
to apoptosis. Several factors are thought to confer this unusual
feature to a CLL B-cell. Misbalance between cytoplasmic pro-survival
and pro-death molecules, such as Bcl-2, Mcl-1 and alike, appears
to be one of the key factors defining B-cell longevity. Autocrine
pathways, such as vascular endothelial growth factor-receptor
pathway, also contribute to survival. The role of B-cell receptor
(BCR) is less straightforward. In the last decade it became
clear that CLL does not constitute a uniform disease, but,
based on the prevalence of mutations in the BCR heavy chain
(IgVH), can be classified into two distinct subgroups.
Several molecular markers correlate with IgVH mutations.
Some of them, like zeta-chain associated protein kinase, are
also involved in BCR signaling and influence cell cycle. Yet
the primary pathogenic event leading to increased proliferation
and survival in CLL is difficult to ascertain. Molecules involved
in BCR signaling pathways and cytoplasmic pro-survival players
probably act in concert to confer resistance to apoptosis.
In this respect, the role of the B-CLL environment, which
includes nurse-like cells and T-cells, cannot be underestimated.
Nurse-like cells provide stimuli necessary for perpetuation
of life in CLL. On the other hand, abnormal T-cell function,
whether it is excessive immunosuppression delivered by regulatory
T-cells or insufficient anti-tumor immunity rendered by T-helpers,
allows malignant CLL cells to go unnoticed by the cellular
immune system.
[Back to top]
Cannabinoid Drugs and Enhancement of Endocannabinoid
Responses: Strategies for a Wide Array of Disease States
David A. Karanian and Ben A. Bahr
The endogenous cannabinoid system has revealed potential avenues
to treat many disease states. Medicinal indications of cannabinoid
drugs including compounds that result in enhanced endocannabinoid
responses (EER) have expanded markedly in recent years. The
wide range of indications covers chemotherapy complications,
tumor growth, addiction, pain, multiple sclerosis, glaucoma,
inflammation, eating disorders, age-related neurodegenerative
disorders, as well as epileptic seizures, traumatic brain
injury, cerebral ischemia, and other excitotoxic insults.
Indeed, a great effort has led to the discovery of agents
that selectively activate the cannabinoid system or that enhance
the endogenous pathways of cannabinergic signaling. The endocannabinoid
system is comprised of three primary components: (i) cannabinoid
receptors, (ii) endocannabinoid transport system, and (iii)
hydrolysis enzymes that break down the endogenous ligands.
Two known endocannabinoids, anandamide (AEA) and 2-arachidonoyl
glycerol (2-AG), are lipid molecules that are greatly elevated
in response to a variety of pathological events. This increase
in endocannabinoid levels is suggested to be part of an on-demand
compensatory response. Furthermore, activation of signaling
pathways mediated by the endogenous cannabinoid system promotes
repair and cell survival. Similar cell maintenance effects
are elicited by EER through inhibitors of the endocannabinoid
deactivation processes (i.e., internalization and hydrolysis).
The therapeutic potential of the endocannabinoid system has
yet to be fully determined, and the number of medical maladies
that may be treated will likely continue to grow. This review
will underline studies that demonstrate medicinal applications
for agents that influence the endocannabinoid system.
[Back to top]
Molecular Aspects of Stromal–Parenchymal Interactions
in Malignant Neoplasms
Attila Zalatnai
Carcinomas are composed of parenchymal and stromal elements,
and the malignant behavior is principally dictated by the
cancer cells. However, the malignant tumors not merely grow
into a preexisting interstitial tissue, but they actively
form a new stroma and modify their composition. Thus, the
tumor stroma is significantly different from that of the neighboring
tissues. Cancer cells may alter their stroma by cell-to-cell
contact, soluble factors or by modification of the extracellular
matrix (ECM), they induce myofibroblast differentiation and
govern the desmoplastic stroma reaction. On the other hand,
the stromal cells (especially the myofibroblasts) are able
to modify the phenotype, invasiveness, metastatic capacity
of carcinomas, typically promoting the progression. Regarding
pancreatic cancer, the pancreatic stellate cells (PSCs) seem
to be the key elements in the cross-talk between the parenchymal
cells and the desmoplastic stroma. The tumor stroma is also
rich in tumor-associated macrophages (TAM), but their role
in the malignant process is contradictory and may be different
in various tumor types, but most studies suggest a negative
impact on the tumor growth. The relationship between the parenchymal
and stromal elements is highly complex, they mutually alter
their characteristics. Because the neostroma of the carcinomas
largely seems to promote the invasiveness of the malignant
tumors, novel therapeutic strategies are being evaluated targeting
the stromal elements, with some encouraging, but still fragmentary
results.
[Back to top]
Network Theory to Understand Microarray Studies of
Complex Diseases
Mikael Benson and Rainer Breitling
Complex diseases, such as allergy, diabetes and obesity
depend on altered interactions between multiple genes, rather
than changes in a single causal gene. DNA microarray studies
of a complex disease often implicate hundreds of genes in
the pathogenesis. This indicates that many different mechanisms
and pathways are involved. How can we understand such complexity?
How can hypotheses be formulated and tested?
One approach is to organize the data in network models and
to analyze these in a top-down manner. Globally, networks
in nature are often characterized by a small number of highly
connected nodes, while the majority of nodes have few connections.
The highly connected nodes serve as hubs that affect many
other nodes. Such hubs have key roles in the network. In yeast
cells, for example, deletion of highly connected proteins
is associated with increased lethality, compared to deletion
of less connected proteins.
This suggests the biological relevance of networks. Moving
down in the network structure, there may be sub-networks or
modules with specific functions. These modules may be further
dissected to analyze individual nodes. In the context of DNA
microarray studies of complex diseases, gene-interaction networks
may contain modules of co-regulated or interacting genes that
have distinct biological functions. Such modules may be linked
to specific gene polymorphisms, transcription factors, cellular
functions and disease mechanisms. Genes that are reliably
active only in the context of their modules can be considered
markers for the activity of the modules and may thus be promising
candidates for biomarkers or therapeutic targets.
This review aims to give an introduction to network theory
and how it can be applied to microarray studies of complex
diseases.
|
