Current Pharmaceutical Design, Volume 9, No. 1, 2003
Contents
Cytokines
Executive Editor: Zhou Xing
Intestinal Epithelial Toll-Like Receptors: To Protect. And Serve? Pp. 1-5
Andrew T. Gewirtz
Role of DAP12 in Innate and Adaptive Immune Responses Pp. 7-10
Naoko Aoki, Shoji Kimura and Zhou Xing
Mast Cell Cytokine and Chemokine Responses to Bacterial and Viral
Infection Pp. 11-24
Jean S. Marshall,
Christine King and Jeffrey D. McCurdy
Cytokines in the Pathogenesis of Chronic Obstructive Pulmonary Disease Pp. 25-38
P.T. Reid and J.-M. Sallenave
Re-evaluation of Fibrogenic Cytokines in Lung Fibrosis Pp. 39-49
Margaret Kelly, Martin Kolb, Phillipe Bonniaud and Jack Gauldie
Role of Cytokines in the Development and Maintenance of Memory T Cells
During Respiratory Viral Infection
Pp. 51-59
Ralph A. Tripp
Role of Type I Cytokines in Host Defense Against Mycobacterium avium
Infection Pp. 61-65
Lia Danelishvilli and Luiz E. Bermudez
Role of Cytokines in Chlamydia trachomatis Protective Immunity and
Immunopathology Pp. 67-73
Xi Yang
Cytokine
Therapeutics for the Treatment of Sepsis: Why has Nothing Worked? Pp.75-82
Daniel G. Remick
Immune Modulation
by Plasmid DNA-mediated Cytokine Gene Transfer Pp. 83-94
[Back to top] Intestinal Epithelial Toll-Like Receptors:
To Protect. And Serve?
Andrew T. Gewirtz
The innate immune system uses a series of pattern recognition receptors
to detect the presence of pathogens thus allowing for rapid host defense
responses to invading microbes. A key component of such receptors are the
"toll-like receptors" (TLRs), which recognize a panel of microbial molecules
that tend to be somewhat invariant, at least in select regions, thus permitting
a relatively small number of receptors to recognize a large number of different
microbes. Accordingly, this panel of TLRs bears little ability to distinguish
between commensal and pathogenic microbes as such organisms generally
bear far more structural similarities than differences
between them. For the professional phagocytic cells classically considered to
be the primary mediators of innate immunity such distinction between commensal
and pathogenic microbes is not particularly important since any microbe that
breaches the outer host defensive barriers to reach these phagocytes, whether
doing so by a pathogen-specific or opportunistic mechanism, is likely
potentially hazardous to its host. However, epithelial cells that line mucosal
surfaces, thus being on the front line of host defense, also play an active
role in innate immunity particularly by secreting chemokines and other immune
mediators in response to pathogenic microbes. Epithelial cells have been
reported to express several TLRs suggesting these receptors play a role in
intestinal epithelial innate immune signaling pathways. However, since some
mucosal surfaces such as the intestinal epithelium are normally densely colonized
by a wide variety of microbes, the ability to distinguish the occasional
pathogen from the sea of commensals presents an important challenge. This
minireview considers the current findings regarding TLR expression in the
intestinal epithelium and the role these receptors might serve in host defense.
[Back to top]
Role of DAP12 in Innate and Adaptive
Immune Responses
Naoko Aoki, Shoji Kimura and Zhou Xing
DAP12 is a novel immunoreceptor tyrosine-based activation motifs (ITAM)-bearing
transmembrane adapter molecule. This molecule, together with its partner
receptor complex molecules including the killer cell activating receptors
(KARs), myeloid DAP12 associating lectin-1 (MDL-1), triggering receptor
expressed on myeloid cells 1/2/3 (TREM-1, TREM-2, TREM-3), and signal
regulatory protein b1 (SIRPb1), are expressed on the surface of NK and myeloid
cells including antigen presenting cells. While the function of DAP12 and its
associating molecules has just begun to be unveiled, emerging evidence suggests
that these molecules play an important role in both innate and adaptive immune
responses. In this review, we intend to provide an overview on what have been
known and are still unknown to date about the function of these molecules based
on the observations made by us and others.
[Back to top]
Mast Cell Cytokine and Chemokine
Responses to Bacterial and Viral Infection
Jean S. Marshall, Christine King and Jeffrey D. McCurdy
Mast cells have been most widely studied in the context of allergic
disease but also play a critical role in host defence against bacterial
infection, most elegantly demonstrated in studies using mast cell deficient w/wv mice. There is less data available concerning the role of mast cells in
defence against viral pathogens, however, mast cells have been demonstrated to
be a potential reservoir of infection for several pathogens, such as HIV-1 and
dengue, and capable of producing mediators following challenge with a number of
viral products. Traditional mast cell mediators such as histamine, protease
enzymes and leukotrienes are important for effective host responses. The cytokines
and chemokines produced
by mast cells
in response to pathogens are known to profoundly alter
the nature of the innate immune response and its effectiveness in eliminating
infection. Cytokine and chemokine production by mast cells is closely regulated
and may occur independently of classical mast cell degranulation. Depending
upon the nature of the stimulus or type of infection, a unique profile of
cytokines is induced. In this review, we will examine the role and regulation
of mast cell cytokines and chemokines in the context of a number of bacterial
and viral infections, emphasizing the multiple receptor mechanisms used to
activate mast cells. This area of research is still in its early stages and
much work remains to be done. However, understanding the unique properties of
resident tissue mast cells and how their cytokine responses are regulated by
pathogens or pathogen products, will provide important opportunities for the
therapeutic manipulation of local immune responses.
[Back to top] Cytokines in the Pathogenesis of Chronic
Obstructive Pulmonary Disease
P.T. Reid and J.-M. Sallenave
Chronic obstructive pulmonary disease (COPD) is a common cause of morbidity and mortality. The term is
heterogenous and encompasses a number of distinct but often overlapping
phenotypes including chronic bronchitis, small airways obstruction, emphysema
and in some individuals, a systemic component. Although there have been
significant advances in understanding the pathophysiology of COPD,
understanding of the role of the inflammation in the pathogenesis of the
condition remains in its infancy. Indeed, cytokines that are known to
orchestrate the inflammatory response in asthma and other inflammatory diseases
are only beginning to be reported in COPD. In this review, we highlight the
potential role of cytokines in the development of mucus hypersecretion observed
in chronic bronchitis and the morphological changes observed in the small
airways and airspaces contributing to the development of airflow limitation and
respiratory failure respectively. We report evidence that exacerbations are
linked to increased expression of pro-inflammatory cytokines and that the
wasting and skeletal muscle dysfunction observed in some patients is most
probably related to the presence of a systemic inflammatory response. In
addition transgenic and gene therapy technology has been used to explore the
temporal and co-ordinated role of cytokines in the development of COPD animal
models. Enhanced understanding of the events involved in the pathogenesis of
COPD will lead to the development of therapy with potential to modify the
observed progressive decline in lung function and impact on the development of
the illness.
[Back to top] Re-evaluation of Fibrogenic Cytokines in
Lung Fibrosis
Margaret Kelly, Martin
Kolb, Phillipe Bonniaud and Jack
Gauldie
Idiopathic Pulmonary Fibrosis (IPF) is a chronic interstitial lung
disease which results in end-stage fibrosis. The pathogenesis is believed to be
related to a dysregulation in cross-talk between inflammatory and structural
cells, mediated by various cytokines, chemokines and growth factors, which are
responsible for the maintenance of tissue homeostasis and which coordinate the
response to injury. The large number of mediators involved and the complexity
of their interaction makes it difficult to identify the factors responsible for
initiation of fibrogenesis and progression to chronicity. Whether a mediator’s
presence in fibrotic lung is as a result of tissue injury or if it playsan
active role in disease onset and progression has been partly answered by the
use of transient and/or permanent transgenic and gene knock-out approaches to
over-express single factors at a time. Chemokines such as interleukin-8 (IL-8),
RANTES, IP-10, MIG or lymphotactin, do not appear to induce fibrosis when
over-expressed in rodent lung. Amongst many tested, four cytokines and growth
factors have been found to be pro-fibrotic; IL-1b, which demonstrates marked
inflammation, tissue damage and chronic fibrosis, TNF-a, which induces
inflammation and mild fibrosis, and GM-CSF, which induces moderate inflammation
and fibrosis. A common finding with these cytokines are increased lung TGF-b
levels, proportionate to the degree of fibrosis generated, while TGF-b itself
causes minor inflammation but marked progressive chronic fibrosis. A growth
factor ‘downstream’ from the pro-fibrotic effects of TGF-b, CTGF, is a likely
critical mediator. However, over-expression of CTGF produces only mild and
reversible fibrosis.
[Back to top] Role of Cytokines in the Development and
Maintenance of Memory T Cells During Respiratory Viral Infection
Ralph A. Tripp
Much progress has
been made in understanding the relationship between cytokines, T cell
development, and the maintenance of memory T cells by examining the immune
response to respiratory viral infections. Most of these studies have examined
the T cell response to viruses that cause acute infection of limited duration,
and have focused on the interplay between cytokines and individual responses by
T cell subsets. This reductionism approach has been useful to piece together
the puzzle of the host-immune response to respiratory virus infection, and has
added to the holistic view of the networks involved in homeostatic control of T
cell development and maintenance. This review addresses aspects of T cell
biology that constitute the response to respiratory viral infections.
[Back to top] Role of Type I Cytokines in Host Defense
Against Mycobacterium avium Infection
Lia Danelishvilli and Luiz E. Bermudez
Mycobacterium avium is a human pathogen that causes infection in
immunocompetent as well as immunocompromised patients. Infection is acquired
both by the respiratory and gastrointestinal routes, and bacterial invasion of
mucosal epithelial cells is characteristic. M. avium crosses the mucosal
barrier without triggering substantial inflammatory response. Once in the
intestinal submucosa or in the alveolar space M. avium infects macrophages.
Intracellular bacteria block the production of cytokines involved in the host
response against the infection, such as TNF-a and IL-12, and suppress antigen
presentation by the macrophage. Innate response against the infection is
effective to certain extent but the ability of the bacterium to remain
"silent" for a period of time prevents neutrophil and NK cells from
effectively controlling the establishing of the infection. CD4+ T cells as well
as CD8+ T cells are activated, although only CD4+ T cells appear to be
effective in inducing anti-M. avium activity in macrophages. M. avium-specific
CD8+ T cells undergo apoptosis early in the infection. Therefore, the immune
mechanisms of the host and bacterial strategies for survival are complex and
fascinating.
[Back to top] Role of Cytokines in Chlamydia trachomatis
Protective Immunity and Immunopathology
Xi Yang
Diseases caused by Chlamydia trachomatis infection and its sequelae
represent major public health concerns worldwide. In order to rationally
develop an effective vaccine to chlamydial infection, we need a better
understanding of the mechanisms underlying the protective and pathological
immune responses to chlamydial antigens. Recent studies in chlamydial
immunobiology have demonstrated a close link between cytokine production
patterns and the type of immune responses to this pathogen. In particular,
IL-10 has been found to be associated with susceptibility to chlamydial
infection and the typical pathological changes caused by the infection such as
granuloma formation and fibrosis. Although Th1 type delayed hypersensitivity (DTH)
is associated with protective immunity, the Th2 type DTH documented in
interferon (IFN)-γ_ gene knockout (KO) mice fails to control chlamydial
infection. The Th2 type DTH is characterized by eosinophil and neutrophil
infiltration and is associated with high levels of IL-4 and IL-5 production.
The capability of dendritic cell (DC) in initiating T cell response to
Chlamydia has been shown in studies using cultured DCs and a DC line. Further
studies should be performed to elucidate the role played by DCs in natural
chlamydial infection and the potential involvement of DC subsets in directing
immune responses to chlamydial infection.
[Back to top] Cytokine Therapeutics for the Treatment of
Sepsis: Why has Nothing Worked?
Daniel G. Remick
Several clinical trials have attempted to treat sepsis by blocking
certain aspects of the inflammatory response. Tumor necrosis factor and
interleukin 1 have been specific targets for inhibition but none of the trials
have been successful. These trials were started on the basis of preclinical
trials that suggested these would be effective. There were three lines of
evidence to support the idea of cytokine inhibition. First, patients with
increased levels of cytokines are more likely to die. Second, experimental
animal models demonstrated that blocking the cytokines would improve outcome.
Third, injection of purified, recombinant cytokines would cause both organ
injury and death in experimental animals. Several additional aspects of the
inflammatory response have been discovered since these trials were initiated.
Included among these potential new targets are interleukin 18 and HMG-1.
However, before new clinical trials are started there must be careful
consideration of why previous interventions were not effective. The concept of
blocking a single elevated cytokine may be too simple to deal with the complex
problem of sepsis. As patients move through different phases of the septic
response, there may be intervals when it is appropriate to inhibit multiple
cytokines while at other times it may be appropriate to augment the immune
response.
[Back to top] Immune Modulation by Plasmid DNA-mediated
Cytokine Gene Transfer
Ciriaco A. Piccirillo and Gérald J. Prud’homme
Autoimmune diseases frequently develop as a result of an abnormal
activation of autoreactive T cells, excessive production of proinflammatory
cytokines, particularly by CD4+ Th1 cells, and subsequent tissue destruction.
Cytokine-dependent immunotherapy can be applied to alter the balance between
Th1 and Th2 cell activity, or proinflammatory versus immunosuppressive cytokine
profiles. Cytotoxic T lymphocyte (CTL) and/or macrophage activity can also be
suppressed. Gene transfer offers numerous advantages for the in vivo delivery
of cytokines or their receptors for immunotherapeutic use. We have relied on
the injection of naked plasmid DNA into skeletal muscle to deliver therapeutic
genes. In particular, we have successfully used this approach to deliver
neutralizing cytokine receptors such as interferon g
(IFNg)-receptor-Ig fusion
proteins or anti-inflammatory cytokines such as transforming growth factor b-1
(TGF-b1) and interleukin 4 (IL-4). Intramuscular gene therapy is effective in
protecting against several experimental autoimmune diseases including
insulin-dependent diabetes mellitus (IDDM), experimental allergic
encephalomyelitis (EAE), and systemic lupus erythematosus (SLE). Another
promising approach involves DNA vaccination by plasmid-based codelivery of
genes encoding an autoantigen and either a cytokine or other immunomodulatory
molecule. Plasmid vectors offer interesting advantages over viral vectors,
since they are simple to produce, nonimmunogenic and non-pathogenic. They can
be repeatedly administered with relatively prolonged periods of expression in
vivo, ranging from weeks to months after each injection. Plasmid-based
intramuscular gene transfer has great therapeutic potential in the areas of
autoimmune and inflammatory disorders.