Efficacy and safety of intratracheal IFN-γ treatment to reverse stroke-induced susceptibility to pulmonary bacterial infections

Jagdmann, Sandra; Berchtold, Daniel; Gutbier, Birgitt; Witzenrath, Martin; Meisel, Andreas; Meisel, Christian; Dames, Claudia

doi:10.1016/j.jneuroim.2021.577568

Cited by 3 publications

(3 citation statements)

References 73 publications

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“…However, experimental data suggest that pulmonary IFN-γ treatment is not an effective preventive measure for SAP. 100 These 2 examples highlight the need to consider both neuroinflammation and peripheral immunodeficiency leading to SAP in immunomodulatory therapies. These predominantly opposing inflammatory processes can lead to beneficial effects in one organ and detrimental effects in the other by the same approach.…”

Section: Immunomodulatory Approaches To Prevent Stroke-associated Inf...mentioning

confidence: 99%

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Immunodepression, Infections, and Functional Outcome in Ischemic Stroke

Westendorp

Dames

Nederkoorn

et al. 2022

Stroke

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Stroke remains one of the main causes of mortality and morbidity worldwide. Immediately after stroke, a neuroinflammatory process starts in the brain, triggering a systemic immunodepression mainly through excessive activation of the autonomous nervous system. Manifestations of immunodepression include lymphopenia but also dysfunctional innate and adaptive immune cells. The resulting impaired antibacterial defenses render patients with stroke susceptible to infections. In addition, other risk factors like stroke severity, dysphagia, impaired consciousness, mechanical ventilation, catheterization, and older age predispose stroke patients for infections. Most common infections are pneumonia and urinary tract infection, both occur in ≈10% of the patients. Especially pneumonia increases unfavorable outcome and mortality in patients with stroke; systemic effects like hypotension, fever, delay in rehabilitation are thought to play a crucial role. Experimental and clinical data suggest that systemic infections enhance autoreactive immune responses against brain antigens and thus negatively affect outcome but convincing evidence is lacking. Prevention of poststroke infections by preventive antibiotic therapy did not improve functional outcome after stroke. Immunomodulatory approaches counteracting immunodepression to prevent stroke-associated pneumonia need to account for neuroinflammation in the ischemic brain and avoid further tissue damage. Experimental studies discovered interesting targets, but these have not yet been investigated in patients with stroke. A better understanding of the pathobiology may help to develop optimized approaches of preventive antibiotic therapy or immunomodulation to effectively prevent stroke-associated pneumonia while improving long-term outcome after stroke. In this review, we aim to characterize epidemiology, risk factors, cause, diagnosis, clinical presentation, and potential treatment of poststroke immunosuppression and associated infections.

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Section: Immunomodulatory Approaches To Prevent Stroke-associated Inf...mentioning

confidence: 99%

“…However, experimental data suggest that pulmonary IFN-γ treatment is not an effective preventive measure for SAP. 100…”

Section: Immunomodulatory Approaches To Prevent Stroke-associated Inf...mentioning

confidence: 99%

Immunodepression, Infections, and Functional Outcome in Ischemic Stroke

Westendorp

Dames

Nederkoorn

et al. 2022

Stroke

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“…39,40 Furthermore, the innate immune response plays a pivotal role in the development of stroke-induced pulmonary infections. 41 Gama-delta (cd) T cells are a subset of innate lymphocytes located mainly in the lamina propria of the small intestinal mucosa that act in a major histocompatibility complex-unrestricted manner. Although cd T cells only account for a small part of the total T-cell pool, they are crucial in maintaining epithelial tissue integrity, repair, and host homeostasis, and in inhibiting pathogen infections.…”

Section: Introductionmentioning

confidence: 99%

Reversal of the detrimental effects of social isolation on ischemic cerebral injury and stroke-associated pneumonia by inhibiting small intestinal γδ T-cell migration into the brain and lung

Xie

Zhang

Han

et al. 2023

J Cereb Blood Flow Metab

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Social isolation (ISO) is associated with an increased risk and poor outcomes of ischemic stroke. However, the roles and mechanisms of ISO in stroke-associated pneumonia (SAP) remain unclear. Adult male mice were single- or pair-housed with an ovariectomized female mouse and then subjected to transient middle cerebral artery occlusion. Isolated mice were treated with the natriuretic peptide receptor A antagonist A71915 or anti-gamma-delta (γδ) TCR monoclonal antibody, whereas pair-housed mice were treated with recombinant human atrial natriuretic peptide (rhANP). Subdiaphragmatic vagotomy (SDV) was performed 14 days before single- or pair-housed conditions. We found that ISO significantly worsened brain and lung injuries relative to pair housing, which was partially mediated by elevated interleukin (IL)-17A levels and the migration of small intestine-derived inflammatory γδ T-cells into the brain and lung. However, rhANP treatment or SDV could ameliorate ISO-exacerbated post-stroke brain and lung damage by reducing IL-17A levels and inhibiting the migration of inflammatory γδ T-cells into the brain and lung. Our results suggest that rhANP mitigated ISO-induced exacerbation of SAP and ischemic cerebral injury by inhibiting small intestine-derived γδ T-cell migration into the lung and brain, which could be mediated by the subdiaphragmatic vagus nerve.

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Spinal Cord Injury Impairs Lung Immunity in Mice

Mifflin

Brennan

Guan

et al. 2022

The Journal of Immunology

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Pulmonary infection is a leading cause of morbidity and mortality after spinal cord injury (SCI). Although SCI causes atrophy and dysfunction in primary and secondary lymphoid tissues with a corresponding decrease in the number and function of circulating leukocytes, it is unknown whether this SCI-dependent systemic immune suppression also affects the unique tissue-specific antimicrobial defense mechanisms that protect the lung. In this study, we tested the hypothesis that SCI directly impairs pulmonary immunity and subsequently increases the risk for developing pneumonia. Using mouse models of severe high-level SCI, we find that recruitment of circulating leukocytes and transcriptional control of immune signaling in the lung is impaired after SCI, creating an environment that is permissive for infection. Specifically, we saw a sustained loss of pulmonary leukocytes, a loss of alveolar macrophages at chronic time points postinjury, and a decrease in immune modulatory genes, especially cytokines, needed to eliminate pulmonary infections. Importantly, this injury-dependent impairment of pulmonary antimicrobial defense is only partially overcome by boosting the recruitment of immune cells to the lung with the drug AMD3100, a Food and Drug Administration–approved drug that mobilizes leukocytes and hematopoietic stem cells from bone marrow. Collectively, these data indicate that the immune-suppressive effects of SCI extend to the lung, a unique site of mucosal immunity. Furthermore, preventing lung infection after SCI will likely require novel strategies, beyond the use of orthodox antibiotics, to reverse or block tissue-specific cellular and molecular determinants of pulmonary immune surveillance.

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Efficacy and safety of intratracheal IFN-γ treatment to reverse stroke-induced susceptibility to pulmonary bacterial infections

Cited by 3 publications

References 73 publications

Immunodepression, Infections, and Functional Outcome in Ischemic Stroke

Immunodepression, Infections, and Functional Outcome in Ischemic Stroke

Reversal of the detrimental effects of social isolation on ischemic cerebral injury and stroke-associated pneumonia by inhibiting small intestinal γδ T-cell migration into the brain and lung

Spinal Cord Injury Impairs Lung Immunity in Mice

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