Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0392674 (exhaustion)
 13,658 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Preliminary investigations showed high preventive activity of two of three aerosol preparations of Abies sibirica polyprenols with nonionic surface active substances towards influenza infection. At least 2 aerosol administrations are needed to attain a high protective effect, the second dose depending on the first. Relationship between animal reaction to influenza virus infection changed in a nonmonotonous mode, depending on the drug dose injected during the first treatment: as the dose increased, the death rate first decreased and reached the minimum and then increased again. Such a reaction to aerosol treatment can be explained by the hypothesis of hyperstimulation followed by exhaustion of the host defense systems after high doses of the preparation.
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PMID:[Prophylactic efficacy of aerosol preparations based on Abies siberica polyprenols in experimental influenza infection]. 1178 83

The purpose of this presentation is to discuss the possibility that sensitization is a psychobiological mechanism underlying not only multiple chemical sensitivity (MCS), but a much more general cluster of illness, referred to as "subjective health complaints". Sustained arousal, or sustained "stress" responses, may be an important factor for the development of these conditions. Patients with subjective complaints without objective changes are sometimes referred to as having "fashionable diagnoses" or "unexplained symptoms". They may be given diagnoses like MCS, epidemic fatigue, chronic fatigue syndrome, burnout, stress, a variety of intoxications, environmental illness, radiation, multiple chemical hypersensitivity, food intolerance, functional dyspepsia, irritable bowel, myalgic encephalitis, postviral syndrome, yuppie flu, fibromyalgia, or vital exhaustion. One issue is whether this is one general condition or separate entities. Another issue is whether sensitization may be the psychobiological mechanism for most or all of these conditions. Finally, is it likely that sustained arousal may facilitate the development of sensitization in some or many neural circuits? In this review, the main emphasis will be on musculoskeletal pain. This is the most frequent and most expensive condition for sickness compensation and disability. The comorbidity of other complaints, however, will also be taken into account.
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PMID:Sensitization, subjective health complaints, and sustained arousal. 1200 15

Spontaneous tumors frequently express antigens that can be recognized by the immune system but nevertheless manage to evade immune surveillance. To better understand the mechanism of evasion, we followed CD8 and CD4 T cells reacting against a subcutaneously growing tumor, modified to express influenza hemagglutinin (HA) as surrogate tumor antigen. Adoptive transfer of 8,000 antigen-specific CD8 T cells was sufficient to protect against challenge with 1x10(6) tumor cells, while larger numbers of T cells rejected established tumors. HA-specific CD4 T cells could not reject tumors on their own but helped rejection by CD8 T cells. Rejection of the tumor coincided with prolonged survival of expanded antigen-specific CD8 and CD4 T cells, while a failing anti-tumor response was accompanied by transient expansion followed by rapid elimination of antigen-specific T cells. Thus, a highly immunogenic tumor can evade immune surveillance because of an insufficient number of tumor-specific T cells and antigen overload, resulting in exhaustion of the immune response. In this scenario, adoptive immunotherapy rather than vaccination promises successful treatment.
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PMID:Visualizing the course of antigen-specific CD8 and CD4 T cell responses to a growing tumor. 1261 1

Surfactant protein D (SP-D) is a collagenous calcium-dependent lectin constitutively expressed by alveolar type II pneumocytes and non-ciliated bronchiolar epithelial (Clara) cells. It binds to surface glycoconjugates expressed by a wide variety of microorganisms such as Gram-negative bacteria, influenza A virus, and various fungi, leading to pathogen inactivation or enhanced neutrophil and macrophage activity. Since a hallmark of bronchopneumonia is the initiation of inflammation in the bronchi and bronchoalveolar junction, we chose a classic ruminant model of bronchopneumonia caused by Mannheimia haemolytica to study the expression of SP-D within the bronchioles of infected lambs. Healthy weaned lambs were inoculated with either pyrogen-free saline (controls) or M. haemolytica intrabronchially using a fiber-optic bronchoscope. SP-D protein and mRNA expression in lung was detected by immunohistochemistry (IHC) and fluorogenic real-time relative quantitative reverse transcriptase polymerase chain reaction (real-time RT-PCR), respectively, during acute (1 day), subacute (15 days), and chronic (45 days) bronchopneumonia. At 15 and 45 days post-inoculation, areas of lung had peribronchiolar inflammatory cell infiltrate, epithelial cell hyperplasia, tortuosity of the airway lumens, and decreased intensity of SP-D protein staining and number of positive cells. The levels of SP-D mRNA were not increased or significantly altered by M. haemolytica infection when compared to control animals. In conclusion, cell-associated SP-D protein expression significantly decreases within hyperplastic epithelium of lungs from infected animals during chronic bronchopneumonia. Exhaustion of SP-D protein reserves and absence of SP-D gene upregulation during the progression of bacterial pneumonia into chronicity may result in failure to clear the pathogen from the lung and/or cause animals to be more susceptible to re-infection.
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PMID:Surfactant protein D expression in normal and pneumonic ovine lung. 1535 Jul 53

We studied CD8 T cell responses against HIV-1, cytomegalovirus, Epstein-Barr virus, and influenza in 128 subjects and demonstrate that polyfunctional CD8 T cell responses, also including IL-2 production and Ag-specific proliferation, are predominantly driven by virus epitopes restricted by HLA-B alleles. Interestingly, these protective CD8 T cells are equipped with low-avidity T cell receptors (TCRs) for the cognate virus epitope. Conversely, HLA-A-restricted epitopes are mostly associated with "only effector" IFN-gamma-secreting, with cytotoxicity, and with the lack of IL-2 production and Ag-specific proliferation. These CD8 T cells are equipped with high-avidity TCR and express higher levels of the T cell exhaustion marker PD-1. Thus, the functional profile of the CD8 T cell response is strongly influenced by the extent to which there is stimulation of polyfunctional (predominantly restricted by HLA-B) versus only effector (restricted by HLA-A) T cell responses. These results provide the rationale for the observed protective role of HLA-B in HIV-1-infection and new insights into the relationship between TCR avidity, PD-1 expression, and the functional profile of CD8 T cells.
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PMID:Skewed association of polyfunctional antigen-specific CD8 T cell populations with HLA-B genotype. 1791 Dec 49

Anti-viral CD8(+) T cell responses involve an initial expansion and effector phase, followed by contraction phase and formation of CD8(+) memory T cells. During this contraction phase, increased surface expression of the negative regulator PD-1 is associated with functional exhaustion of CD8(+) T cells. Although its role in T cell suppression has been established, the importance of PD-1 in the differentiation of CD8(+) T cells remains unclear. In this study, we examine PD-1 expression in relation to viral specificity of CD8(+) T cells against persistent or non-persistent viruses, and further define differentiation phenotypes of CD8(+) T cells by CD27 and CD28 expression. Surprisingly, the inhibitory receptor PD-1 was expressed by Flu-specific CD8(+) T cells in a level comparable to HCMV-and EBV-specific cells. Moreover, in virus-specific CD8(+) T cells, CD127(+)/CD127(-) and CD62L(+)/CD62L(-) cells expressed similar levels of PD-1 molecules. These results suggest that the PD-1/PD-L1 pathway may play a regulatory role in memory T cell subsets in addition to its association with T-cell exhaustion.
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PMID:CD8(+) T cells specific for both persistent and non-persistent viruses display distinct differentiation phenotypes but have similar level of PD-1 expression in healthy Chinese individuals. 1794 71

Human immunodeficiency virus (HIV) disease leads to impaired B cell and antibody responses through mechanisms that remain poorly defined. A unique memory B cell subpopulation (CD20(hi)/CD27(lo)/CD21(lo)) in human tonsillar tissues was recently defined by the expression of the inhibitory receptor Fc-receptor-like-4 (FCRL4). In this study, we describe a similar B cell subpopulation in the blood of HIV-viremic individuals. FCRL4 expression was increased on B cells of HIV-viremic compared with HIV-aviremic and HIV-negative individuals. It was enriched on B cells with a tissuelike memory phenotype (CD20(hi)/CD27(-)/CD21(lo)) when compared with B cells with a classical memory (CD27(+)) or naive (CD27(-)/CD21(hi)) B cell phenotype. Tissuelike memory B cells expressed patterns of homing and inhibitory receptors similar to those described for antigen-specific T cell exhaustion. The tissuelike memory B cells proliferated poorly in response to B cell stimuli, which is consistent with high-level expression of multiple inhibitory receptors. Immunoglobulin diversities and replication histories were lower in tissuelike, compared with classical, memory B cells, which is consistent with premature exhaustion. Strikingly, HIV-specific responses were enriched in these exhausted tissuelike memory B cells, whereas total immunoglobulin and influenza-specific responses were enriched in classical memory B cells. These data suggest that HIV-associated premature exhaustion of B cells may contribute to poor antibody responses against HIV in infected individuals.
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PMID:Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compartment in HIV-infected viremic individuals. 1862 47

Chronic infection results in continuous formation and exhaustion of effector CD8 T cells and in failure of memory CD8 T cell development. Expression of CD70 and other molecules that provide costimulation to T cells is maintained during chronic infection. To analyze the impact of constitutive CD70-driven costimulation, we generated transgenic mice expressing CD70 specifically on T cells. We show that CD70 promoted accumulation of CD8 T cells with characteristics strikingly similar to exhausted effector CD8 T cells found during chronic infection. CD70 on T cells provided costimulation that enhanced primary CD8 T cell responses against influenza. In contrast, memory CD8 T cell maintenance and protection against secondary challenge with influenza was impaired. Interestingly, we found no effect on the formation of either effector or memory CD4 T cells. We conclude that constitutive expression of CD70 is sufficient to deregulate the CD8 T cell differentiation pathway of acute infection reminiscent of events in chronic infection.
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PMID:Protective CD8 T cell memory is impaired during chronic CD70-driven costimulation. 1938 Jul 82

The failure of CD8(+) T cells to respond to chronic infection has been termed "exhaustion" and describes the condition in which CD8(+) T cells exhibit reduced differentiation, proliferation, and effector function. CD8(+) T cell exhaustion has been extensively studied in the murine model of chronic infection, lymphocytic choriomeningitis virus (LCMV). Although LCMV-based studies have yielded many interesting findings, they have not allowed for discrimination between the roles of cytokine- and Ag-driven exhaustion. We have created a system of chronic Ag stimulation using murine influenza A virus that leads to exhaustion and functional disability of virus-specific CD8(+) T cells, in the absence of high viral titers, sustained proinflammatory cytokine production and lymphocyte infection. Our findings show that Ag alone is sufficient to drive CD8(+) T cell impairment, that Ag-driven loss of virus-specific CD8(+) T cells is TRAIL mediated, and that removal of Ag reverses exhaustion. Although programmed death 1 was up-regulated on chronic Ag-stimulated CD8(+) T cells, it played no role in the exhaustion. These findings provide a novel insight into the mechanisms that control functional exhaustion of CD8(+) T cells in chronic infection.
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PMID:Chronic antigen stimulation alone is sufficient to drive CD8+ T cell exhaustion. 1945 64

In an epidemic situation or large-scale disaster, medical and human resources may be stretched to the point of exhaustion. Appropriate planning must incorporate plans of action that minimize public health morbidity and mortality while maximizing the appropriate use of medical and human healthcare resources. While the current novel H1N1 influenza has spread throughout the world, the severity of this strain of influenza appears to be relatively less virulent and lethal compared to the 1918 influenza pandemic. However, the presence of this new influenza strain has reignited interest in pandemic planning. Amongst other necessary resources needed to combat pandemic influenza, a major medical resource concern is the limited number of mechanical ventilators that would be available to be used to treat ill patients. Recent reported cases of avian influenza suggest that mechanical ventilation will be required for the successful recovery of many individuals ill with this strain of virus. However, should the need for ventilators exceed the number of available machines, how will care providers make the difficult ethical decisions as to who should be placed or who should remain on these machines as more influenza patients arrive in need of care? This paper presents a decision-making model for clinicians that is based upon the bioethical principles of beneficence and justice. The model begins with the basic assumptions of triage and progresses into a useful algorithm based upon utilitarian principles. The model is intended to be used as a guide for clinicians in making decisions about the allocation of scarce resources in a just manner and to serve as an impetus for institutions to create or adapt plans to address resource allocation issues should the need arise.
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PMID:Rationing of resources: ethical issues in disasters and epidemic situations. 1961 58


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