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1.
Understanding fungal pathogenesis and host-pathogen immune interaction at various stages of infection is critical to examine
strategies for bolstering antifungal immune defenses. Recombinant myeloid growth factors, especially granulocyte-macrophage
colony-stimulating factor and the protagonist T helper (Th) 1 cytokine, interferon-γ, are most frequently used in patients
with refractory invasive aspergillosis. These cytokines are given alone or in combination and have also been used together
in neutropenic patients receiving donor granulocyte transfusions. Recently, a number of investigators have presented provoking
data regarding auxiliary effect of conventional antifungal drugs on hosts’ immune response and pathogen’s susceptibility for
antifungal immune defenses. Antifungal immunotherapy and its ameliorative role in treatment for Aspergillus disease will need clinical trials that 1) consider well-characterized fungal disease; 2) illustrate underlying immune defect(s)
(such as Th1 vs Th2, vs Th17 and functional status of natural killer and effector scavenger cells); 3) include a more specific
patient population; 4) include standardized antifungal drug therapy; and importantly 5) consider its impact on hosts’ immune
response and changes in pathogen’s susceptibility and virulence. At present, immunotherapy is reserved for patients with life-threatening
invasive fungal disease in whom conventional antifungal drug therapy has failed, or for patients with advanced fungal disease
and with factors associated with high probability of failure of conventional therapy alone. 相似文献
2.
Cannabinoids have been proposed as clinically promising neuroprotective molecules, as they are capable to reduce excitotoxicity,
calcium influx, and oxidative injury. They are also able to decrease inflammation by acting on glial processes that regulate
neuronal survival and to restore blood supply to injured area by reducing the vasoconstriction produced by several endothelium-derived
factors. Through one or more of these processes, cannabinoids may provide neuroprotection in different neurodegenerative disorders
including Parkinson’s disease and Huntington’s chorea, two chronic diseases that are originated as a consequence of the degeneration
of specific nuclei of basal ganglia, resulting in a deterioration of the control of movement. Both diseases have been still
scarcely explored at the clinical level for a possible application of cannabinoids to delay the progressive degeneration of
the basal ganglia. However, the preclinical evidence seems to be solid and promising. There are two key mechanisms involved
in the neuroprotection by cannabinoids in experimental models of these two disorders: first, a cannabinoid receptor-independent
mechanism aimed at producing a decrease in the oxidative injury and second, an induction/upregulation of cannabinoid CB2 receptors,
mainly in reactive microglia, that is capable to regulate the influence of these glial cells on neuronal homeostasis. Considering
the relevance of these preclinical data and the lack of efficient neuroprotective strategies in both disorders, we urge the
development of further studies that allow that the promising expectatives generated for these molecules progress from the
present preclinical evidence till a real clinical application. 相似文献
3.
Viruses have evolved with their hosts, which include all living species. This has been partly responsible for the development
of highly advanced immune systems in the hosts. However, viruses too have evolved ways to regulate and evade the host’s immune
defence. In addition to mutational mechanisms that viruses employ to mimic the host genome and undergo latency to evade the
host’s recognition of the pathogen, they have also developed epigenetic mechanisms by which they can render the host’s immune
responses inactive to their antigens. The epigenetic regulation of gene expression is intrinsically active inside the host
and is involved in regulating gene expression and cellular differentiation. Viral immune evasion strategies are an area of
major concern in modern biomedical research. Immune evasion strategies may involve interference with the host antigen presentation
machinery or host immune gene expression capabilities, and viruses, in these manners, introduce and propagate infection. The
aim of this review is to elucidate the various epigenetic changes that viruses are capable of bringing about in their host
in order to enhance their own survivability and pathogenesis. 相似文献
4.
The practice of hematopoietic stem cell transplantation (HSCT) has undergone many changes that affect the likelihood that
a given patient would develop an invasive fungal infection (IFI). The risks for IFI and the types of IFI that may occur are
not continuous over the time course after transplantation. IFIs vary with the events that occur during the pre-engraftment
neutropenic period, the early post-engraftment period until approximately day 100 post-transplant, and those in the late post-engraftment
period after day 100. A number of well-recognized transplant recipient-, transplant procedure-, and transplant complication-related
factors play a role in the likelihood of IFI. Important recipient-related factors include age, state of the underlying disease
for which the HSCT is being done, and treatment-related history. Transplant procedure-related factors include the type of
transplant (autologous or allogeneic), the use of and timing of anti-fungal prevention strategies including whether or not
the transplant was conducted in a protected environment to minimize environmental exposure to mould conidia, the choice of
conditioning (myeloablative or non-myeloablative), human leucocyte antigen-relatedness [autologous, matched related, mismatched
related (including haploidentical pairings), unrelated (matched or mismatched)], stem cell source (bone marrow, peripheral,
or cord blood), stem cell dosing, and stem cell product processing (red cell, plasma, or T-lymphocyte depletions, or CD34
selections). Transplant-related complications include duration of pre-engraftment period of neutropenia, graft failure or
rejection, the degree of cytotoxic conditioning therapy-related intestinal mucosal damage, acute and chronic graft-versus-host
disease (GvHD), the use of corticosteroids for the prevention or management of GvHD, the presence of cytomegalovirus infection
and disease. The interaction of these factors over a given patient’s journey through HSCT conspires to promote or reduce the
overall IFI risk and set the conditions for the development of any given IFI. The following discussion attempts to look at
this from the perspective of the transplant physician struggling to account for these interactions and their attendant risks
for IFI. 相似文献
5.
Iron is an essential factor for both the growth and virulence of most of microorganisms. As a part of the innate (or nutritional) immune system, mammals have developed different mechanisms to store and transport this element in order to limit free iron bioavailability. To survive in this hostile environment, pathogenic fungi have specific uptake systems for host iron sources, one of the most important of which is based on the synthesis of siderophores-soluble, low-molecular-mass, high-affinity iron chelators. The increase in free iron that results from iron-overload conditions is a well-established risk factor for invasive fungal infection (IFI) such as mucormycosis or aspergillosis. Therefore, iron chelation may be an appealing therapeutic option for these infections. Nevertheless, deferoxamine –the first approved iron chelator– paradoxically increases the incidence of IFI, as it serves as a xeno-siderophore to Mucorales. On the contrary, the new oral iron chelators (deferiprone and deferasirox) have shown to exert a deleterious effect on fungal growth both in vitro and in animal models. The present review focuses on the role of iron metabolism in the pathogenesis of IFI and summarises the preclinical data, as well as the limited clinical experience so far, in the use of new iron chelators as treatment for mucormycosis and invasive aspergillosis. 相似文献
6.
Jerne’s idiotypic network theory stresses the importance of antibody-to-antibody interactions and provides possible explanations
for self-tolerance and increased diversity in the immune repertoire. In this paper, we use an immune network model to build
a user profile for adaptive information filtering. Antibody-to-antibody interactions in the profile’s network model correlations
between words in text. The user profile has to be able to represent a user’s multiple interests and adapt to changes in them
over time. This is a complex and dynamic engineering problem with clear analogies to the immune process of self-assertion.
We present a series of experiments investigating the effect of term correlations on the user’s profile performance. The results
show that term correlations can encode additional information, which has a positive effect on the profile’s ability to assess
the relevance of documents to the user’s interests and to adapt to changes in them. 相似文献
7.
In transmitted prion diseases the immune system supports the replication and the propagation of the pathogenic agent (PrPSc).
DCs, which are mobile cells present in large numbers within lymph organs, are suspected to carry prions through the lymphoid
system and to transfer them towards the peripheral nervous system. In this study, C57Bl/6 mice were orally inoculated with
PrPSc (scrapie strain 139A) and sacrificed at the preclinical stages of the disease. Immunolabelled cryosections of Peyer’s
patches were analysed by confocal microscopy. Membrane prion protein expression was studied by flow cytometry. In Peyer’s
patches (PP), dissected at day one and day 105 after oral exposure to scrapie, we observed an increased population of DCs
localised in the follicular-associated epithelium. On day 105, PrPSc was found in the follicles inside the PP of prion-infected
mice. A subset of Peyer’s patches DCs, which did not express cellular prion protein on their surface in non-infected mice
conditions, was prion-positive in scrapie conditions. Within Peyer’s patches oral scrapie exposure thus induced modifications
of the homeostasis of DCs at the preclinical stages of the disease. These results give new arguments in favour of the implication
of DCs in prion diseases. 相似文献
8.
Acute inflammation is a highly regulated defense mechanism of immune system possessing two well-balanced and biologically
opposing arms termed apoptosis (‘Yin’) and wound healing (‘Yang’) processes. Unresolved or chronic inflammation (oxidative
stress) is perhaps the loss of balance between ‘Yin’ and ‘Yang’ that would induce co-expression of exaggerated or ‘mismatched’
apoptotic and wound healing factors in the microenvironment of tissues (‘immune meltdown’). Unresolved inflammation could
initiate the genesis of many age-associated chronic illnesses such as autoimmune and neurodegenerative diseases or tumors/cancers.
In this perspective ‘birds’ eye’ view of major interrelated co-morbidity risk factors that participate in biological shifts
of growth-arresting (‘tumoricidal’) or growth-promoting (‘tumorigenic’) properties of immune cells and the genesis of chronic
inflammatory diseases and cancer will be discussed. Persistent inflammation is perhaps a common denominator in the genesis
of nearly all age-associated health problems or cancer. Future challenging opportunities for diagnosis, prevention, and/or
therapy of chronic illnesses will require an integrated understanding and identification of developmental phases of inflammation-induced
immune dysfunction and age-associated hormonal and physiological readjustments of organ systems. Designing suitable cohort
studies to establish the oxido-redox status of adults may prove to be an effective strategy in assessing individual’s health
toward developing personal medicine for healthy aging. 相似文献
9.
The enormous advances in our understanding of the progression of diseases at the molecular level have been supplemented by
the new field of ‘molecular imaging’, which provides for in vivo visualization of molecular events at the cellular level in living organisms. Molecular imaging is a noninvasive assessment
of gene and protein function, protein–protein interaction and/or signal transduction pathways in animal models of human disease
and in patients to provide insights into molecular pathogenesis. Five major imaging techniques are currently available to
assess the structural and functional alterations in vivo in small animals. These are (i) optical bioluminescence and fluorescence imaging techniques, (ii) radionuclide-based positron
emission tomography (PET) and single photon emitted computed tomography (SPECT), (iii) X-ray-based computed tomography (CT),
(iv) magnetic resonance imaging (MRI) and (v) ultrasound imaging (US). Functional molecular imaging requires an imaging probe
that is specific for a given molecular event. In preclinical imaging, involving small animal models, the imaging probe could
be an element of a direct (‘direct imaging’) or an indirect (‘indirect imaging’) event. Reporter genes are essential for indirect
imaging and provide a general integrated platform for many different applications. Applications of multimodality imaging using
combinations of bioluminescent, fluorescent and PET reporter genes in unified fusion vectors developed by us for recording
events from single live cells to whole animals with high sensitivity and accurate quantification are discussed. Such approaches
have immense potential to track progression of metastasis, immune cell trafficking, stem cell therapy, transgenic animals
and even molecular interactions in living subjects. 相似文献
10.
Purpose of ReviewThis review offers an approach to managing suspected invasive fungal infection (IFI) in a febrile neutropenic patient with hematologic malignancy or hematopoietic cell transplantation (HCT) while on mold-active prophylaxis. We take into consideration host characteristics, new diagnostic tools, and available therapeutics. Recent FindingsDespite use of anti-Aspergillus prophylactic agents, invasive aspergillosis is the most commonly reported IFI breaking through common prophylactic agents including the newest azole, isavuconazole. While more fungal diagnostic modalities are available, how to best incorporate them in the work-up of IFI remains unclear, while sensitivity of any particular fungal biomarker or molecular test is low. SummaryIn a febrile neutropenic patient with hematologic malignancy or HCT and suspected IFI, consider particularly invasive aspergillosis, regardless of the mold-active prophylactic agent. Early diagnosis and intervention are especially important to a favorable outcome; treatment is directed based on the suspected IFI syndrome and suspected organism. Switching azoles, consideration of combination therapy, and reducing immunosuppression are proposed strategies for the management of breakthrough IFI, while surgical debridement remains crucial for Mucormycoses. More study is needed into the optimal antifungal approach in these clinical scenarios. Meanwhile, therapeutic drug monitoring and attention to drug-drug interactions are encouraged. 相似文献
11.
The interaction of bacterial pathogens with their hosts’ innate immune systems can be extremely complex and is often difficult
to disentangle experimentally. Using mouse models of bacterial infections, several laboratories have successfully applied
genetic approaches to identify novel host genes required for innate immune defense. In addition, a variety of creative bacterial
genetic schemes have been developed to identify key bacterial genes involved in triggering or evading host immunity. In cases
where both the host and pathogen are amenable to genetic manipulation, a combination of host and pathogen genetic approaches
can be used. Focusing on bacterial infections of mice, this review summarizes the benefits and limitations of applying genetic
analysis to the study of host–pathogen interactions. In particular, we consider how prokaryotic and eukaryotic genetic strategies
can be combined, or “squared,” to yield new insights in host–pathogen biology. 相似文献
12.
Serological laboratory diagnosis is inflicted with at least two kinds of basic problems. One type relates to the fact that
the serological diagnosis of infectious diseases is double indirect: First, to diagnose an infectious disease, the identification
of the microbial agent is sought that caused the disease. Second, to identify this infectious agent, the patient’s immune
response to potential agents is measured. So, the serological test is neither measuring directly disease nor the cause of
the disease, but the patient’s immune system. Another type of problem is based on the fact that each person’s immune system
is very individual. The exact physicochemical properties of antibodies are unique for each clone of antibodies. The way an
individual’s immune system sees an infectious agent depends not only on the genetic makeup of the person but also on the personal
experience from former encounters with infectious agents. Both types of problems lead to complexities in selecting the appropriate
test, in interpreting the results, and in standardizing serological tests. Therefore, a close collaboration of the laboratory
with the clinic is mandatory to avoid erroneous conclusions from serological test results, which might lead to wrong decisions
in patient care. 相似文献
13.
In organic farming animal welfare is one important aspect included in the internationally agreed organic principles of health,
ecology, fairness and care (IFOAM 2006), reflecting expectation of consumers and farmers. The definition of organic animal welfare includes—besides traditional
terms of animal welfare—‘regeneration’ and ‘naturalness’. Organic animal welfare assessment needs to reflect this and use
complex parameters, include natural behaviour and a systemic view. Furthermore, various parties with seemingly conflicting
interests are involved, causing ethical dilemmas, such as the use of nose rings for outdoor sows (impaired animal welfare
vs. destruction of humus). Solutions can only be found when foundational concepts are translated and applied to practical
situations. On-farm animal welfare assessment and implementation of improvement strategies are increasingly relevant scientific
areas. They combine on-farm welfare assessment, identification of key problem areas and connected risk factors. Constant communication
between all parties is crucial for success. Animal health and welfare planning is one application of this approach, which
was carried out on Austrian organic pig farms as well as organic dairy farms in seven European countries. The projects included
welfare assessment, feedback and benchmarking as a tool for communication between farmers, advisors and scientists. Finally
goals were set by the farmer and improvement strategies applicable to organic farming were implemented. This included prevention
of disease by management strategies instead of routine treatment with pharmaceutical products. It appeared that next to problem
structuring, multidisciplinary problem solving demands good communications skills to relate animal welfare science to value
reflections. 相似文献
15.
A large number of observational and theoretical studies have investigated animal movement strategies for finding randomly
located food items. Many of these studies have claimed that a particular strategy is advantageous over other strategies or
that the spatial distribution of the food items affects the search efficiency. Here, we study a deliberately idealised problem,
in which a blind forager searches for re-visitable food items. We show analytically that the forager’s efficiency is completely
independent of both its movement strategy and the spatial pattern of the food items and depends only on the density of food
in the environment. However, in some cases, apparent optima in search strategies can arise as artefacts of inappropriate and
inaccurate numerical simulations. We discuss modifications to the idealised foraging problem that can confer an advantage
on certain strategies, including when the forager has some memory or knowledge of the environment; when the food items are
non-revisitable; and when the problem is viewed in an evolutionary context. 相似文献
16.
Many interventions try to address farmers’ seed insecurity, though few assess the causes of farmers’ vulnerability or understand
their coping strategies. This paper analyzes farmers’ practices for maintaining sorghum seed security in a specific season
(1998–99) in Ethiopia, which provides a richer picture of coping strategies than accounts of “general” practices, as it shows
how responses reflect events unfolding over time and household-specific situations. High seeding rates ensure against environmental
uncertainty, but not everyone has sufficient seed for repeated sowing should stands fail to establish. Off-farm seed fills
this gap, though payment is usually required for substantial quantities; only 20% of seed from other farmers came for free
in 1998. Differences between seed suppliers and recipients suggest indicators for chronic seed insecurity. The discussion
explores implications for supporting farmers’ coping strategies. Helping the poorest farmers access off-farm seed, from other
farmers or from merchants, can reduce their vulnerability. 相似文献
17.
The pathogenesis of Alzheimer’s disease (AD) has been strongly associated with the accumulation of amyloid beta (Aβ) peptides
in brain, and immunotherapy targeting Aβ provides potential for AD prevention. A clinical trial in which AD patients were
immunized with Aβ42 peptide was stopped when 6% of participants showed meningoencephalitis, apparently due to an inflammatory
Th1 immune response. Previously, we and other have shown that Aβ42 DNA vaccination via gene gun generates a Th2 cellular immune
response, which was shown by analyses of the respective antibody isotype profiles. We also determined that in vitro T cell
proliferation in response to Aβ42 peptide re-stimulation was absent in DNA Aβ42 trimer-immunized mice when compared to Aβ42
peptide-immunized mice. To further characterize this observation prospectively and longitudinally, we analyzed the immune
response in wild-type mice after vaccination with Aβ42 trimer DNA and Aβ42 peptide with Quil A adjuvant. Wild-type mice were
immunized with short-term (1–3× vaccinations) or long-term (6× vacinations) immunization strategies. Antibody titers and isotype
profiles of the Aβ42 specific antibodies, as well as cytokine profiles and cell proliferation studies from this longitudinal
study were determined. Sufficient antibody titers to effectively reduce Aβ42, but an absent T cell proliferative response
and no IFNγ or IL-17 secretion after Aβ42 DNA trimer immunization minimizes the risk of inflammatory activities of the immune
system towards the self antigen Aβ42 in brain. Therefore, Aβ42 DNA trimer immunization has a high probability to be effective
and safe to treat patients with early AD. 相似文献
18.
Complement proteins of the classical pathway can be immunohistochemically identified in cerebral amyloid plaques in Alzheimer’s
disease. Microglial cells in and around amyloid plaques express class II major histocompatibility (MHC) antigens and complement
receptors CR3 and CR4. Negative immunostaining for immunoglobulins and for T-cell subsets in the brain parenchyma demonstrates
a lack of evidence for the involvement of specific immune responses (such as an immune complex-mediated complement activation
or a cell-mediated immune response) in cerebral amyloid deposits in Alzheimer’s disease. Cerebral amyloid plaques in scrapie-affected
mice (slow-virus induced encephalopathy) do not contain complement factors C1q and C3c and are not clustered with microglial
cells expressing MHC class II molecules or complement receptor CR3. The data presented suggest the induction of a reactive
inflammatory process by β/A4 amyloid in the human brain, but not by scrapie-induced PrP amyloid in mice. Our findings do not
support the hypothesis that the immune system is involved in the generation of amyloid plaques in Alzheimer’s disease.
This study was partly supported by a grant from the Praeventiefonds, project 28–1945 相似文献
19.
Recombinant adenovirus serotype 5 (Ad5) vectors have been studied extensively in preclinical gene therapy models and in a range of clinical trials. However, innate immune responses to adenovirus vectors limit effectiveness of Ad5 based therapies. Moreover, extensive pre‐existing Ad5 immunity in human populations will likely limit the clinical utility of adenovirus vectors, unless methods to circumvent neutralizing antibodies that bind virus and block target cell transduction can be developed. Furthermore, memory T cell and humoral responses to Ad5 are associated with increased toxicity, raising safety concerns for therapeutic adenovirus vectors in immunized hosts. Most preclinical studies have been performed in naïve animals; although pre‐existing immunity is among the greatest hurdles for adenovirus therapies, it is also one of the most neglected experimentally. Here we summarize findings using adenovirus vectors in naïve animals, in Ad‐immunized animals and in clinical trials, and review strategies proposed to overcome innate immune responses and pre‐existing immunity. J. Cell. Biochem. 108: 778–790, 2009. © 2009 Wiley‐Liss, Inc. 相似文献
20.
Two major difficulties facing widespread clinical implementation of existing Tissue Engineering (TE) strategies for the treatment
of musculoskeletal disorders are (1) the cost, space and time required for ex vivo culture of a patient’s autologous cells
prior to re-implantation as part of a TE construct, and (2) the potential risks and availability constraints associated with
transplanting exogenous (foreign) cells. These hurdles have led to recent interest in endogenous TE strategies, in which the
regenerative potential of a patient’s own cells is harnessed to promote tissue regrowth without ex vivo cell culture. This
article provides a focused perspective on key issues in the development of endogenous TE strategies, progress to date, and
suggested future research directions toward endogenous repair and regeneration of musculoskeletal tissues and organs. 相似文献
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