Inhaled <i>vs</i> subcutaneous effects of a dual IL‐4/IL‐13 antagonist in a monkey model of asthma

Tomkinson, Adrian; Tepper, Jeffrey S.; Morton, Matthew T.; Bowden, Alexandra; Stevens, Lauren; Harris, Peter; Lindell, Dennis M.; Fitch, Neil; Gundel, Robert H.; Getz, E. B.

doi:10.1111/j.1398-9995.2009.02156.x

Cited by 45 publications

(26 citation statements)

References 44 publications

(67 reference statements)

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“…When STAT-6 was reconstituted only in the lung epithelia of IL-13-overexpressing mice AHR and mucus hypersecretion, but not BAL eosinophilia or fibrosis, phenotypes returned implicating the epithelium as a key IL-13 target cell type in the asthmatic phenotype [88]. Cynomolgus monkey testing of the IL-4 mutant pitrakinra demonstrated that local (inhaled) dosing delivered similar effects, of reduced AHR and a trend toward decreased lung eosinophils, as systemic (subcutaneous) dosing [89]. This important study confirmed the notion that neutralization of IL-4 and IL-13 in the lung, rather than the periphery, is important for efficacy against AHR and eosinophilia in models mimicking key aspects of human asthma.…”

Section: Animal Model Datamentioning

confidence: 84%

Strategies targeting the IL-4/IL-13 axes in disease

May¹,

Fung²

2015

Cytokine

146

108

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Section: Animal Model Datamentioning

confidence: 84%

Strategies targeting the IL-4/IL-13 axes in disease

May¹,

Fung²

2015

Cytokine

146

108

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“…Furthermore, our study revealed that evaluation of circulating IL-13Rα2 concentration and saturation may be useful to understand the kinetics of IL-13 elaboration in injury models and to appropriately time anti-IL-13 interventions. Indeed, several investigators have previously studied the anti-fibrotic efficacy of targeting IL-13-induced signaling, either through targeted delivery of immunotoxins8, disruption of ligand-receptor interactions262728, or by direct IL-13 neutralization, a strategy that is currently yielding promising results in humanized models29, and has advanced to clinical trials in human subjects with severe asthmatic airway disease and other disease driven by IL-1330313233. In our experiments, we used an IL-13 neutralizing IgG during the period of IL-13Rα2 nadir and saturation significantly disrupted the progression of radiation-induced pulmonary fibrosis.…”

Section: Discussionmentioning

confidence: 99%

IL-13 is a therapeutic target in radiation lung injury

Chung

Horton

Ramalingam³

et al. 2016

Sci Rep

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Pulmonary fibrosis is a potentially lethal late adverse event of thoracic irradiation. Prior research indicates that unrestrained TGF-β1 and/or type 2 cytokine-driven immune responses promote fibrosis following radiation injury, but the full spectrum of factors governing this pathology remains unclear. Interleukin 13 (IL-13) is a key factor in fibrotic disease associated with helminth infection, but it is unclear whether it plays a similar role in radiation-induced lung fibrosis. Using a mouse model, we tested the hypothesis that IL-13 drives the progression of radiation-induced pulmonary fibrosis. Irradiated lungs from wild-type c57BL/6NcR mice accumulated alternatively-activated macrophages, displayed elevated levels of IL-13, and extensive fibrosis, whereas IL-13 deficient mice were resistant to these changes. Furthermore, plasma from irradiated wild-type mice showed a transient increase in the IL-13 saturated fraction of the circulating decoy receptor IL-13Rα2. Finally, we determined that therapeutic neutralization of IL-13, during the period of IL-13Rα2 saturation was sufficient to protect mice from lung fibrosis. Taken together, our results demonstrate that IL-13 is a major regulator of radiation-induced lung injury and demonstrates that strategies focusing on IL-13 may be useful in screening for timely delivery of anti-IL-13 therapeutics.

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“…Although it has yet to be firmly established in a model of CMV infection, it has been suggested that apoptotic pathways may be directly induced as a result of TLR2 activation. For example, there exists evidence for extrinsic apoptosis, demonstrated by the in vitro exposure of HCMV to syncytiotrophoblasts, which produce TNF-a as a result of TLR2 activation, inducing apoptosis in neighboring cells (Tomkinson et al, 2010).…”

Section: Integration Of Innate Immunity and Cell Deathmentioning

confidence: 99%

Dying to Replicate: The Orchestration of the Viral Life Cycle, Cell Death Pathways, and Immunity

Yatim

Albert

2011

Immunity

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Manipulation of cell death pathways has been identified as a common feature of host-microbe interactions. We examine two examples: influenza A as a representative acute infection and cytomegalovirus as an example of chronic infection. From the perspective of viral entry, replication, and transmission, we identify points of interconnection with the host response to infection, namely the induction of host cell death, inflammation, and immunity. Following from this analysis, we argue that the evolution and fine-tuned regulation of death-associated genes may result from constant microbial pressure--past and present--that helped to support and coordinate cell death programs within the host. Interestingly, the delay in host cell death allows time for the virus to replicate while perturbations in cell death allow the host cell to initiate an immune response. This may represent a genetically encoded trade-off ensuring survival of both host and virus, or it may be a part of the complex agenda of infectious microbes.

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Inhaled vs subcutaneous effects of a dual IL‐4/IL‐13 antagonist in a monkey model of asthma

Abstract: Local administration of pitrakinra to the lung is sufficient to inhibit AHR, one of the cardinal features of asthma, indicating the therapeutic potential of inhaled pitrakinra in the treatment of atopic asthma.

Cited by 45 publications

References 44 publications

Strategies targeting the IL-4/IL-13 axes in disease

Strategies targeting the IL-4/IL-13 axes in disease

IL-13 is a therapeutic target in radiation lung injury

Dying to Replicate: The Orchestration of the Viral Life Cycle, Cell Death Pathways, and Immunity

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