Frontiers in Nephrology

Beilke, Joshua; Gill, Ronald G.

doi:10.1681/asn.2007040423

Cited by 29 publications

(25 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The subtle inflammatory infiltrates in IF/TA are important to the scarring process and for ultimate graft outcome81. Importantly, our transcriptomic data supports the growing theory that immune cell types such as T, B cells82, NK cells8384, dendritic cells858687 are involved in IF/TA and may be driving the immunological processes after transplantation, and possible therapeutic interventions such as kaempferol and esculetin could be applied to target these cell types. However, these predicted immune cell-specific inhibitory effects of kaempferol and esculetin cannot be confirmed or ruled out from our murine UUO model, a commonly used model for examining tubulointerstitial fibrosis8889.…”

Section: Discussionsupporting

confidence: 77%

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: Discussionsupporting

confidence: 77%

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

“…In literature, the precise role of human NK cells in organ transplantation is unclear. NK cells were shown to integrate complex stimulatory (NKp46, NKp30, NKG2D) and inhibitory (KIRs, CD94/NKG2A) signals combined with the release of diverse cytokines (49, 50). In general, NK cells are considered rapid initiators of a pro-inflammatory milieu that promotes the licensing of DC and T cells into Type-1-polarized effectors, able to mediate acute or/and chronic allograft injury (50).…”

Section: Discussionmentioning

confidence: 99%

Rapamycin Augments Human DC IL-12p70 and IL-27 Secretion to Promote Allogeneic Type1 Polarization Modulated by NK Cells

Macedo¹,

Turnquist

Castillo-Rama³

et al. 2013

American Journal of Transplantation

View full text Add to dashboard Cite

Mammalian target of rapamycin kinase inhibitor (mTORi) rapamycin (RAPA) use in transplantation can lead to inflammatory complications in some patients. Our goal was to better understand how mTORi-exposed human monocyte-derived dendritic cells (DC) stimulated with pro-inflammatory cytokines shape T cell allo-immunity. RAPA-conditioned-DC (RAPA-DC) displayed a more immature phenotype than untreated, control (CTRL)-DC. However, subsequent exposure of RAPA-DC to an inflammatory cytokine cocktail (ICC) plus IFN-γ induced a mature Type-1 promoting phenotype, consisting of elevated HLA-DR and co-stimulatory molecules, augmented IL-12p70 and IL-27 production, but decreased IL-10 secretion compared to CTRL-DC. Co-culture of mature (m) RAPA-DC with allogeneic peripheral blood mononuclear cells resulted in significantly increased Type-1 (IFN-γ) responses by T cells. Moreover, NK cells acted as innate modulators that conveyed activating cell-to-cell contact signals in addition to helper (IFN-γ) and/or regulatory (IL-10) soluble cytokines. We conclude that production of IL12-p70, IL-27, and low IL-10 by RAPA-DC allowed us to elucidate how these cytokines as well as NK-DC interaction shapes T cell allo-immunity. Thus, lack of inhibitory NK cell function during allo-specific T cell activation by human ICC+IFN-γ-stimulated RAPA-DC may represent an unwanted effector mechanism that may underlie RAPA-induced inflammatory events in transplant patients undergoing microbial infection or allograft rejection.

show abstract

“…The usefulness and benefits for patient care have to be evaluated in further independent studies. These questions were not addressed in this study but we know for instance that activated monocytes (CD14 pos /CD16 pos ) are modulated during atopic eczema, malaria infection, and sepsis, whereas the monitoring of NK cells could give relevant information following a kidney allograft (27)(28)(29)(30)(31). Recently, efforts have been made to improve the differential count in several ways, such as by integrating directly fluorescent antibodies in a cell counter (32).…”

Section: Original Articlementioning

confidence: 97%

Refining the white blood cell differential: The first flow cytometry routine application

et al. 2010

View full text Add to dashboard Cite

A Complete Blood Count performed by an automated hematology analyzer frequently needs a microscopic slide review. This step is time consuming and requires experienced personnel. Recently, several teams have proposed and validated convenient combinations of monoclonal antibodies for an extended white blood cell (WBC) differential by flow cytometry. The aim of this study was to evaluate the usefulness of this approach in the routine workflow of a hematology laboratory. We compared a workflow chain comprised of a robotic blood preparation system (for antibody labeling), a flow cytometer, and data management software to the standard manual review of a blood film and evaluated the diagnostic quality, the turnaround time, and the labor needed for the two different approaches. The study on 1,973 samples was organized, firstly, to determine analytic thresholds and these settings were then validated. The flow cytometric data management software automatically validated 52% of the samples without significant numbers of false negatives. Of the remaining specimens, an operator validated a further 33% of the samples and 15% needed a manual microscopic review. These results were obtained in a mean timeline similar to the traditional microscopic manual review. Our study demonstrates, for the first time, the efficiency of a flow cytometer integrated into a WBC differential workflow in a routine hematology laboratory. ' 2010 International Society for Advancement of Cytometry

show abstract

Frontiers in Nephrology

Cited by 29 publications

References 52 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

Rapamycin Augments Human DC IL-12p70 and IL-27 Secretion to Promote Allogeneic Type1 Polarization Modulated by NK Cells

Refining the white blood cell differential: The first flow cytometry routine application

Contact Info

Product

Resources

About