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Karp C.L.,Cincinnati Childrens Hospital Research Foundation | Murray P.J.,St Jude Childrens Research Hospital
Journal of Experimental Medicine | Year: 2012

Macrophages play pleiotropic, niche-specific roles in all tissues and organs. As immune sentinels, tissue macrophages regulate immune activation and inflammation; in turn, their function is modulated by inflammatory mediators deriving from such activation. Recent papers have established unanticipated roles for interleukin 4 and the alternative activation of tissue macrophages in the organismal response to diverse environmental stressors. © 2012 Karp and Murray. Source

Karp C.L.,Cincinnati Childrens Hospital Research Foundation | Karp C.L.,Bill and Melinda Gates Foundation
Journal of Experimental Medicine | Year: 2012

Mus musculus enjoys pride of place at the center of contemporary biomedical research. Despite being the current model system of choice for in vivo mechanistic analysis, mice have clear limitations. The literature is littered with examples of therapeutic approaches that showed promise in mouse models but failed in clinical trials. More generally, mice often provide poor mimics of the human diseases being modeled. Available data suggest that the cold stress to which laboratory mice are ubiquitously subjected profoundly affects mouse physiology in ways that impair the modeling of human homeostasis and disease. Experimental attention to this key, albeit largely ignored, environmental variable is likely to have a broad transformative effect on biomedical research. © 2012 Karp. Source

Karp C.L.,Cincinnati Childrens Hospital Research Foundation
Journal of Allergy and Clinical Immunology | Year: 2010

Why specific, ubiquitous, otherwise innocuous environmental proteins tend to provoke maladaptive, TH2-polarized immune responses in susceptible hosts is a fundamental mechanistic question for those interested in the pathogenesis, therapy, and prevention of allergic disease. The current renaissance in the study of innate immunity has provided important insights into this question. The theme emerging from recent studies is that direct (dys)functional interactions with pathways of innate immune activation that evolved to signal the presence of microbial infection are central to the molecular basis for allergenicity. This article reviews these data. © 2010 American Academy of Allergy, Asthma & Immunology. Source

Rahrmann E.P.,University of Minnesota | Watson A.L.,University of Minnesota | Keng V.W.,Hong Kong Polytechnic University | Choi K.,Cincinnati Childrens Hospital Research Foundation | And 11 more authors.
Nature Genetics | Year: 2013

Malignant peripheral nerve sheath tumors (MPNSTs) are sarcomas of Schwann cell lineage origin that occur sporadically or in association with the inherited syndrome neurofibromatosis type 1. To identify genetic drivers of MPNST development, we used the Sleeping Beauty (SB) transposon-based somatic mutagenesis system in mice with somatic loss of transformation-related protein p53 (Trp53) function and/or overexpression of human epidermal growth factor receptor (EGFR). Common insertion site (CIS) analysis of 269 neurofibromas and 106 MPNSTs identified 695 and 87 sites with a statistically significant number of recurrent transposon insertions, respectively. Comparison to human data sets identified new and known driver genes for MPNST formation at these sites. Pairwise co-occurrence analysis of CIS-associated genes identified many cooperating mutations that are enriched in Wnt/β-catenin, PI3K-AKT-mTOR and growth factor receptor signaling pathways. Lastly, we identified several new proto-oncogenes, including Foxr2 (encoding forkhead box R2), which we functionally validated as a proto-oncogene involved in MPNST maintenance. © 2013 Nature America, Inc. All rights reserved. Source

Moreno-Fernandez M.E.,Cincinnati Childrens Hospital Research Foundation | Moreno-Fernandez M.E.,University of Cincinnati | Joedicke J.J.,University of Duisburg - Essen | Chougnet C.A.,Cincinnati Childrens Hospital Research Foundation
Frontiers in Immunology | Year: 2014

Formation of immunological synapses (IS) between dendritic cells (DCs) and conventional CD4+ T cells (Tcon) is critical for productive immune responses. However, when DCs are HIV-infected such synapses are critical to establish HIV infection. As regulatory T cells (Treg) control DC-Tcon interactions, we inquired whether Treg might interfere with DC to Tcon HIV infection. We developed a model, using monocyte-derived DC infected with R5-HIV, and cultured with Tcon in the presence or absence of autologous Treg, using the physiological ratio of 1 Treg for 10 Tcon. Cultures containing Treg significantly decreased HIV infection in DC:T cell clusters. Notably, Treg appear to have an effect on the quality of the IS, as Treg decreased actin polymerization and DC maturation. Importantly, Treg decreased the trafficking of HIV punctate to the IS. Further, CD152 and cyclic adenosine monophosphate were critical Treg effector molecules, as their individual or simultaneous blockade abolished Treg activity, however no additive effect was found. Together, these data suggest that Treg can reduce HIV dissemination, which may be beneficial to the host in the early stages of infection. © 2014 Moreno-Fernandez, Joedicke and Chougnet. Source

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