Mapping the effects of drugs on the immune system

Kidd, Brian; Wroblewska, Aleksandra; Boland, Mary Regina; Agudo, Judith; Mérad, Miriam; Tatonetti, Nicholas P.; Brown, Brian D.; Dudley, Joel T.

doi:10.1038/nbt.3367

Cited by 67 publications

(62 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As the 85 genes were derived from transplantation datasets and, likely incorporated signatures of ongoing allo-responses, we investigated whether kaempferol and esculetin could have specific effects on immune cells. We applied a recent developed immune-cell specific drug repurposing approach58 to evaluate putative immune modulatory actions of kaempferol and esculetin. Using this methodology we can identify specific immune cell subsets a drug may potentially influence.…”

Section: Resultsmentioning

confidence: 99%

Novel Therapeutics Identification for Fibrosis in Renal Allograft Using Integrative Informatics Approach

Greene

Readhead

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Chronic allograft damage, defined by interstitial fibrosis and tubular atrophy (IF/TA), is a leading cause of allograft failure. Few effective therapeutic options are available to prevent the progression of IF/TA. We applied a meta-analysis approach on IF/TA molecular datasets in Gene Expression Omnibus to identify a robust 85-gene signature, which was used for computational drug repurposing analysis. Among the top ranked compounds predicted to be therapeutic for IF/TA were azathioprine, a drug to prevent acute rejection in renal transplantation, and kaempferol and esculetin, two drugs not previously described to have efficacy for IF/TA. We experimentally validated the anti-fibrosis effects of kaempferol and esculetin using renal tubular cells in vitro and in vivo in a mouse Unilateral Ureteric Obstruction (UUO) model. Kaempferol significantly attenuated TGF-β1-mediated profibrotic pathways in vitro and in vivo, while esculetin significantly inhibited Wnt/β-catenin pathway in vitro and in vivo. Histology confirmed significantly abrogated fibrosis by kaempferol and esculetin in vivo. We developed an integrative computational framework to identify kaempferol and esculetin as putatively novel therapies for IF/TA and provided experimental evidence for their therapeutic activities in vitro and in vivo using preclinical models. The findings suggest that both drugs might serve as therapeutic options for IF/TA.

show abstract

Section: Resultsmentioning

confidence: 99%

Novel Therapeutics Identification for Fibrosis in Renal Allograft Using Integrative Informatics Approach

Greene

Readhead

et al. 2017

Sci Rep

View full text Add to dashboard Cite

show abstract

“…The identification of novel processes, such as TLR4-activated myeloid cells in egg allergy or IFN related pathways in baked egg tolerance, prompts further study using traditional experimental approaches that may change our understanding of the immunology of food allergy. And finally, a transcriptional signature of the aberrant response to egg, and common with other food allergies including peanut, could be used to identify drugs with opposing actions, a computational approach to drug repurposing that has led to discovery of new therapeutics for diseases such as inflammatory bowel disease [31–33]. …”

Section: Discussionmentioning

confidence: 99%

Transcriptional Profiling of Egg Allergy and Relationship to Disease Phenotype

et al. 2016

Self Cite

View full text Add to dashboard Cite

BackgroundEgg allergy is one of the most common food allergies of childhood. There is a lack of information on the immunologic basis of egg allergy beyond the role of IgE.ObjectiveTo use transcriptional profiling as a novel approach to uncover immunologic processes associated with different phenotypes of egg allergy.MethodsPeripheral blood mononuclear cells (PBMCs) were obtained from egg-allergic children who were defined as reactive (BER) or tolerant (BET) to baked egg, and from food allergic controls (AC) who were egg non-allergic. PBMCs were stimulated with egg white protein. Gene transcription was measured by microarray after 24 h, and cytokine secretion by multiplex assay after 5 days.ResultsThe transcriptional response of PBMCs to egg protein differed between BER and BET versus AC subjects. Compared to the AC group, the BER group displayed increased expression of genes associated with allergic inflammation as well as corresponding increased secretion of IL-5, IL-9 and TNF-α. A similar pattern was observed for the BET group. Further similarities in gene expression patterns between BER and BET groups, as well as some important differences, were revealed using a novel Immune Annotation resource developed for this project. This approach identified several novel processes not previously associated with egg allergy, including positive associations with TLR4-stimulated myeloid cells and activated NK cells, and negative associations with an induced Treg signature. Further pathway analysis of differentially expressed genes comparing BER to BET subjects showed significant enrichment of IFN-α and IFN-γ response genes, as well as genes associated with virally-infected DCs.ConclusionsTranscriptional profiling identified several novel pathways and processes that differed when comparing the response to egg allergen in BET, BER, and AC groups. We conclude that this approach is a useful hypothesis-generating mechanism to identify novel immune processes associated with allergy and tolerance to forms of egg.

show abstract

“…The infiltration of neutrophils from bone marrow to blood requires MIP-2 [29, 30]. Kopydlowski found that MIP-2 mRNA expression of peritoneal macrophages reached peak levels (15-60 folds) at 1-2 h after exposure to LPS in C3H/OuJ mice [31].…”

Section: Discussionmentioning

confidence: 99%

Macrophage Inflammatory Protein-2 in High Mobility Group Box 1 Secretion of Macrophage Cells Exposed to Lipopolysaccharide

Qin

Lou

Yang

et al. 2017

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Macrophage inflammatory protein-2 (MIP-2), a type of leukocyte chemokine, is primarily produced by macrophages, and levels increase significantly in early inflammation. However, the precise biological functions and mechanisms of MIP-2 in the development of inflammation remain unclear. The purposes of the present study were to investigate the role of MIP-2 in inflammation induced by lipopolysaccharide (LPS) in vitro and to determine the possibility of blocking the high mobility group box 1 (HMGB1) signalling pathway via MIP-2 inhibition. Methods: Macrophage cells (RAW264.7, U937 and THP-1 cells) were divided into control and treatments groups. Expression levels of interleukin-6 (IL-6), interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α), HMGB1, chemokine (C-C motif) ligand-2 (Ccl-2), Toll-like receptor-4 (TLR-4), inducible nitric oxide synthase (iNOS), phosphorylated MAPKs (p38, ERKs, JNKs), PI3K/Akts, JAKs/STAT3, IκB, and cytoplasmic and nuclear NF-κB p65 in RAW264.7 cells were detected by qRT-PCR, enzyme-linked immunosorbent assay (ELISA) or western blot assays. Results: mip-2 siRNA and an anti-MIP-2 antibody significantly reduced the expression levels of Ccl-2, TLR-4, iNOS, IL-6, IL-1β, HMGB1, and TNF-α in RAW264.7 cells exposed to LPS (P<0.01). Additionally, mRNA expression levels of HMGB1 and TLR-4 in cells treated with LPS+mip-2 siRNA were significantly lower than those in cells treated with LPS alone (P<0.01 or P<0.05). The MIP-2 antibody significantly suppressed activation of p38-MAPK, p-STAT3, and p-Akts and translocation of NF-κB p65 from the cytoplasm to the nucleus in RAW264.7 exposed to LPS (P<0.01 or P<0.05). Conclusion: mip-2 siRNA and the MIP-2 antibody can reduce the inflammatory effects induced by LPS in macrophage cells. The mechanisms may occur through down-regulation of p38-MAPK, STAT3 and Akts phosphorylation and translocation of NF-κB p65. MIP-2 plays an important role in inflammation induced by LPS.

show abstract

Mapping the effects of drugs on the immune system

Cited by 67 publications

References 67 publications

Novel Therapeutics Identification for Fibrosis in Renal Allograft Using Integrative Informatics Approach

Novel Therapeutics Identification for Fibrosis in Renal Allograft Using Integrative Informatics Approach

Transcriptional Profiling of Egg Allergy and Relationship to Disease Phenotype

Macrophage Inflammatory Protein-2 in High Mobility Group Box 1 Secretion of Macrophage Cells Exposed to Lipopolysaccharide

Contact Info

Product

Resources

About