Publications by authors named "Lisa M Kelly"

16 Publications

  • Page 1 of 1

Cognition and behaviour in children with congenital abdominal wall defects.

Early Hum Dev 2018 01 11;116:47-52. Epub 2017 Nov 11.

Department of Neonatal Medicine, The Royal Children's Hospital, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia; Neonatal Research, Murdoch Childrens Research Institute, Melbourne, Australia.

Aim: To characterise neurodevelopment at age two years and cognition and behaviour at age five years in children born with abdominal wall defects (gastroschisis or exomphalos).

Study Design: Participants were treated as neonates for gastroschisis or exomphalos and invited for routine clinical follow-up at ages two and five years. Thirty-nine two year-olds and 20 five year-olds with gastroschisis and 20 two year-olds and 10 five year-olds with exomphalos returned for age-appropriate assessments of development (two years) and intellectual functioning (IQ), executive function, and behavioural problems. Results were compared with normative data from the tests and published data from local term-born children.

Results: For both gastroschisis and exomphalos two year-olds, neurodevelopment was in line with the test normative data, but below the level of local normative data for all domains (effect sizes from -0.4 to -1.4 standard deviations). At five years, children with gastroschisis performed similarly to the normative mean for IQ but had high rates of various executive functioning problems on parent report (18-41% compared with 7% expected from norms). There was also a tendency for increased frequency of internalising problems (33% compared with normative expectation of 16%). Five year-olds with exomphalos also performed similarly to the normative mean for IQ and had low rates of executive and behavioural problems.

Conclusions: Survivors of gastroschisis and exomphalos may be at risk of poor neurodevelopment in toddlerhood, depending on the reference group, and children with gastroschisis may be particularly at risk for executive functioning difficulties despite an IQ within normal limits.
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http://dx.doi.org/10.1016/j.earlhumdev.2017.11.002DOI Listing
January 2018

Discovery of Highly Selective Inhibitors of the Immunoproteasome Low Molecular Mass Polypeptide 2 (LMP2) Subunit.

ACS Med Chem Lett 2017 Apr 9;8(4):413-417. Epub 2017 Mar 9.

Kezar Life Sciences, 300 Utah Avenue, Suite 105, South San Francisco, California 94080, United States.

Building upon the success of bortezomib (VELCADE) and carfilzomib (KYPROLIS), the design of a next generation of inhibitors targeting specific subunits within the immunoproteasome is of interest for the treatment of autoimmune disease. There are three catalytic subunits within the immunoproteasome (low molecular mass polypeptide-7, -2, and multicatalytic endopeptidase complex subunit-1; LMP7, LMP2, and MECL-1), and a campaign was undertaken to design a potent and selective LMP2 inhibitor with sufficient properties to allow for sustained inhibition . Screening a focused library of epoxyketones revealed a series of potent dipeptides that were optimized to provide the highly selective inhibitor ().
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http://dx.doi.org/10.1021/acsmedchemlett.6b00496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5392757PMC
April 2017

Assessment of Blood Collection from the Lateral Saphenous Vein for Microfilaria Counts in Mongolian Gerbils (Meriones unguiculatus) Infected with Brugia pahangi.

Comp Med 2015 Dec;65(6):492-8

Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, Georgia, USA.

The NIH guidelines for survival bleeding of mice and rats note that using the retroorbital plexus has a greater potential for complications than do other methods of blood collection and that this procedure should be performed on anesthetized animals. Lateral saphenous vein puncture has a low potential for complications and can be performed without anesthesia. Mongolian gerbils (Meriones unguiculatus) are the preferred rodent model for filarial parasite research. To monitor microfilaria counts in the blood, blood sampling from the orbital plexus has been the standard. Our goal was to refine the blood collection technique. To determine whether blood collection from the lateral saphenous vein was a feasible alternative to retroorbital sampling, we compared microfilaria counts in blood samples collected by both methods from 21 gerbils infected with the filarial parasitic worm Brugia pahangi. Lateral saphenous vein counts were equivalent to retroorbital counts at relatively high counts (greater than 50 microfilariae per 20 μL) but were significantly lower than retroorbital counts when microfilarial concentrations were lower. Our results indicate that although retroorbital collection may be preferable when low concentrations of microfilariae need to be enumerated, the lateral saphenous vein is a suitable alternative site for blood sampling to determine microfilaremia and is a feasible refinement that can benefit the wellbeing of gerbils.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4681243PMC
December 2015

Endotracheal intubation and oral gavage in the domestic chicken.

Lab Anim (NY) 2014 Oct;43(10):349-50

University of Georgia, Athens, GA.

The domestic chicken (Gallus gallus) is increasing in popularity as a laboratory animal, as it is useful in multiple fields of biomedical research and has the practical benefits of being relatively inexpensive, easy to handle and able to adapt to various settings. Here, we describe two procedures commonly used with chickens in research: endotracheal intubation and oral gavage.
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http://dx.doi.org/10.1038/laban.628DOI Listing
October 2014

Techniques for collecting blood from the domestic chicken.

Lab Anim (NY) 2013 Oct;42(10):359-61

University of Georgia, Athens, GA.

As the use of chickens in biomedical research is increasing, demand is growing for technical skills involving poultry, particularly techniques such as venipuncture. Phlebotomy (blood collection) is an important diagnostic tool for determining causes of morbidity and mortality and for collection of other research-relevant data. This column describes four standard methods of blood collection from the domestic chicken.
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http://dx.doi.org/10.1038/laban.394DOI Listing
October 2013

Oxysterol gradient generation by lymphoid stromal cells guides activated B cell movement during humoral responses.

Immunity 2012 Sep;37(3):535-48

Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, CA 94143, USA.

7α,25-dihydroxycholesterol (7α,25-OHC) is a ligand for the G protein-coupled receptor EBI2; however, the cellular sources of this oxysterol are undefined. 7α,25-OHC is synthesized from cholesterol by the stepwise actions of two enzymes, CH25H and CYP7B1, and is metabolized to a 3-oxo derivative by HSD3B7. We showed that all three enzymes control EBI2 ligand concentration in lymphoid tissues. Lymphoid stromal cells were the main CH25H- and CYP7B1-expressing cells required for positioning of B cells, and they also mediated 7α,25-OHC inactivation. CH25H and CYP7B1 were abundant at the follicle perimeter, whereas CH25H expression by follicular dendritic cells was repressed. CYP7B1, CH25H, and HSD3B7 deficiencies each resulted in defective T cell-dependent plasma cell responses. These findings establish that CYP7B1 and HSD3B7, as well as CH25H, have essential roles in controlling oxysterol production in lymphoid tissues, and they suggest that differential enzyme expression in stromal cell subsets establishes 7α,25-OHC gradients required for B cell responses.
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http://dx.doi.org/10.1016/j.immuni.2012.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3465460PMC
September 2012

Unassisted blood collection from unanesthetized rats and gerbils.

Lab Anim (NY) 2012 May 21;41(6):155-6. Epub 2012 May 21.

University of Georgia, Athens, GA, USA.

Blood collection is a common procedure in animal research. This column describes humane methods of collecting blood from the rat and the gerbil that can be carried out by a single person on an awake animal.
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http://dx.doi.org/10.1038/laban0612-155DOI Listing
May 2012

Transtracheal aspiration and infusion in the horse.

Lab Anim (NY) 2011 Aug 19;40(9):273-4. Epub 2011 Aug 19.

University Research Animal Resources, University of Georgia, Athens, GA, USA.

Transtracheal access enables researchers to obtain diagnostic samples from or infuse materials into the lower respiratory tract. This column describes transtracheal aspiration and infusion of horses.
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http://dx.doi.org/10.1038/laban0911-273DOI Listing
August 2011

EBI2 guides serial movements of activated B cells and ligand activity is detectable in lymphoid and nonlymphoid tissues.

J Immunol 2011 Sep 15;187(6):3026-32. Epub 2011 Aug 15.

Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143, USA.

EBV-induced gene 2 (EBI2) was recently shown to direct the delayed movement of activated B cells to interfollicular and outer follicular regions of secondary lymphoid organs and to be required for mounting a normal T-dependent Ab response. In this study, we show that EBI2 promotes an early wave of Ag-activated B cell migration to the outer follicle in mice. Later, when B cells have moved to the T zone in a CCR7-dependent manner, EBI2 helps distribute the cells along the B zone-T zone boundary. Subsequent EBI2-dependent movement to the outer follicle coincides with CCR7 downregulation and is promoted by CD40 engagement. Using a bioassay, we identify a proteinase K-resistant, hydrophobic EBI2 ligand activity in lymphoid and nonlymphoid tissues. Production of EBI2 ligand activity by a cell line is sensitive to statins, suggesting production in a 3-hydroxy-3-methyl-glutaryl-CoA reductase-dependent manner. CD40-activated B cells show sustained EBI2-dependent responsiveness to the bioactivity. These findings establish a role for EBI2 in helping control B cell position at multiple stages during the Ab response and they suggest that EBI2 responds to a broadly distributed lipid ligand.
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http://dx.doi.org/10.4049/jimmunol.1101262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3169736PMC
September 2011

Oxysterols direct immune cell migration via EBI2.

Nature 2011 Jul 27;475(7357):524-7. Epub 2011 Jul 27.

Euroscreen S.A., 6041 Gosselies, Belgium.

Epstein-Barr virus-induced gene 2 (EBI2, also known as GPR183) is a G-protein-coupled receptor that is required for humoral immune responses; polymorphisms in the receptor have been associated with inflammatory autoimmune diseases. The natural ligand for EBI2 has been unknown. Here we describe the identification of 7α,25-dihydroxycholesterol (also called 7α,25-OHC or 5-cholesten-3β,7α,25-triol) as a potent and selective agonist of EBI2. Functional activation of human EBI2 by 7α,25-OHC and closely related oxysterols was verified by monitoring second messenger readouts and saturable, high-affinity radioligand binding. Furthermore, we find that 7α,25-OHC and closely related oxysterols act as chemoattractants for immune cells expressing EBI2 by directing cell migration in vitro and in vivo. A critical enzyme required for the generation of 7α,25-OHC is cholesterol 25-hydroxylase (CH25H). Similar to EBI2 receptor knockout mice, mice deficient in CH25H fail to position activated B cells within the spleen to the outer follicle and mount a reduced plasma cell response after an immune challenge. This demonstrates that CH25H generates EBI2 biological activity in vivo and indicates that the EBI2-oxysterol signalling pathway has an important role in the adaptive immune response.
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http://dx.doi.org/10.1038/nature10280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297623PMC
July 2011

Finding the right niche: B-cell migration in the early phases of T-dependent antibody responses.

Int Immunol 2010 Jun;22(6):413-9

Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, 94143, USA.

Humoral immune responses depend on B cells encountering antigen, interacting with helper T cells, proliferating and differentiating into low-affinity plasma cells or, after organizing into a germinal center (GC), high-affinity plasma cells and memory B cells. Remarkably, each of these events occurs in association with distinct stromal cells in separate subcompartments of the lymphoid tissue. B cells must migrate from niche to niche in a rapid and highly regulated manner to successfully mount a response. The chemokine, CXCL13, plays a central role in guiding B cells to follicles whereas T-zone chemokines guide activated B cells to the T zone. Sphingosine-1-phosphate (S1P) promotes cell egress from the tissue, as well as marginal-zone B-cell positioning in the spleen. Recent studies have identified a role for the orphan receptor, EBV-induced molecule 2 (EBI2; GPR183), in guiding activated B cells to inter and outer follicular niche(s) and down-regulation of this receptor is essential for organizing cells into GCs. In this review, we discuss current understanding of the roles played by chemokines, S1P and EBI2 in the migration events that underlie humoral immune responses.
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http://dx.doi.org/10.1093/intimm/dxq047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2877811PMC
June 2010

EBI2 mediates B cell segregation between the outer and centre follicle.

Nature 2009 Aug 13;460(7259):1122-6. Epub 2009 Jul 13.

Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California San Francisco, California 94143, USA.

B cell follicles are specialized microenvironments that support events necessary for humoral immunity. After antigen encounter, activated B cells initially seek T-cell help at the follicle-T-zone boundary and then move to interfollicular and T-zone distal (outer) regions of the follicle. Subsequently, some cells move to the follicle centre, become germinal centre B cells and undergo antibody affinity maturation. Although germinal centres within follicles were described in 1885 (ref. 12), the molecular cues mediating segregation of B cells between the outer and centre follicle have remained undefined. Here we present a role for the orphan G-protein-coupled receptor, Epstein-Barr virus induced molecule-2 (EBI2, also known as GPR183), in this process. EBI2 is expressed in mature B cells and increases in expression early after activation, before being downregulated in germinal centre B cells. EBI2 deficiency in mice led to a reduction in the early antibody response to a T-dependent antigen. EBI2-deficient B cells failed to move to the outer follicle at day 2 of activation, and instead were found in the follicle centre, whereas EBI2 overexpression was sufficient to promote B cell localization to the outer follicle. In mixed bone marrow chimaeras, EBI2-deficient B cells phenocopied germinal centre B cells in preferentially localizing to the follicle centre. When downregulation of EBI2 in wild-type B cells was antagonized, participation in the germinal centre reaction was impaired. These studies identify an important role for EBI2 in promoting B cell localization in the outer follicle, and show that differential expression of this receptor helps position B cells appropriately for mounting T-dependent antibody responses.
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http://dx.doi.org/10.1038/nature08226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2809436PMC
August 2009

Visualizing B cell capture of cognate antigen from follicular dendritic cells.

J Exp Med 2009 Jul 8;206(7):1485-93. Epub 2009 Jun 8.

Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.

The prominent display of opsonized antigen by follicular dendritic cells (FDCs) has long favored the view that they serve as antigen-presenting cells for B cells. Surprisingly, however, although B cell capture of antigen from macrophages and dendritic cells has been visualized, acquisition from FDCs has not been directly observed. Using two-photon microscopy, we visualized B cell capture of cognate antigen from FDCs. B cell CXCR5 expression was required, and encounter with FDC-associated antigen could be detected for >1 wk after immunization. B cell-FDC contact times were often brief but occasionally persisted for >30 min, and B cells sometimes acquired antigen together with FDC surface proteins. These observations establish that FDCs can serve as sites of B cell antigen capture, with their prolonged display time ensuring that even rare B cells have the chance of antigen encounter, and they suggest possible information transfer from antigen-presenting cell to B cell.
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http://dx.doi.org/10.1084/jem.20090209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715076PMC
July 2009

Recanalization of chronic total peripheral arterial occlusions using optical coherent reflectometry with guided radiofrequency energy: a single center experience.

Catheter Cardiovasc Interv 2007 Mar;69(4):532-40

Phoenix Heart Center, St. Joseph's Hospital and Medical Center, 500 W. Thomas Road, Phoenix, AZ 85013, USA.

Background: A forward-looking, fiberoptic guided device (Safe-Cross System, Intraluminal Therapeutics, Carlsbad, CA) has been used with guided radiofrequency energy to open chronic total occlusions (CTOs). This report describes the use of optical coherent reflectometry (OCR) system to assess safety and efficacy of opening CTOs in native peripheral arteries in the lower extremities: iliac, femoral, and popliteal.

Methods: 18 CTOs in native peripheral arteries in 17 patients were treated with OCR after failed attempts with conventional wires (minimum 10 min of fluoroscopic time). When the CTO was crossed, routine angioplasty with or without stent was performed. Efficacy was defined as achievement of distal lumen position. Safety was defined as device success without perforation, dissection (> or =Grade C), or distal embolization. The mean patient age was 72 years with 8 females and 10 males. Lesion characteristics included a mean vessel diameter of 5.8 mm and a mean lesion length of 22.4 cm. Ankle-brachial indices was < or =0.8 in all patients.

Results: The OCR system was successful in crossing 100% of the CTOs in patients that failed conventional wire crossing, whereas clinical success occurred in 94% of these patients. Complications consisted of a single dissection > or =Grade C. No perforations or distal embolization occurred.

Conclusions: The Safe-Cross OCR System is both efficacious and safe in the treatment of CTOs that failed crossing with conventional wires and indirect visualization of the intraluminal position by using OCR technology appears to minimize vessel trauma, dissection, perforation, and distal embolization.
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http://dx.doi.org/10.1002/ccd.20716DOI Listing
March 2007

Naive CD4 T cells constitutively express CD40L and augment autoreactive B cell survival.

Proc Natl Acad Sci U S A 2006 Jul 30;103(28):10717-22. Epub 2006 Jun 30.

Howard Hughes Medical Institute and Department of Microbiology and Immunology, and Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143-7242, USA.

Chronic engagement of the B cell receptor by soluble autoantigen leads to reduced B cell survival. Using the Ig and hen egg lysozyme double transgenic mouse model, we demonstrate that the survival of soluble autoantigen-engaged B cells is further reduced in mice lacking CD4 T cells or deficient in CD40. Mixed bone marrow chimera experiments reveal that, under homeostatic conditions, the CD40L-CD40 pathway can augment autoreactive B cell survival in a non-cell-autonomous manner. Naive CD4 T cells are shown to constitutively express CD40L mRNA and protein, although cell surface CD40L abundance is low because of engagement with CD40 on other cells. These observations indicate that the CD40L-CD40 pathway can augment the survival of autoantigen-engaged B cells in the absence of T cell activation. We propose that constitutive CD40L expression by naive CD4 T cells influences the composition of the B cell repertoire and may also affect the homeostasis of other cell types such as regulatory T cells in lymphoid organs.
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http://dx.doi.org/10.1073/pnas.0601539103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1484418PMC
July 2006

Elevated interferon gamma expression in the central nervous system of tumour necrosis factor receptor 1-deficient mice with experimental autoimmune encephalomyelitis.

Immunology 2006 Aug 16;118(4):527-38. Epub 2006 Jun 16.

Neuroimmunology Unit, Montreal Neurological Institute, Montreal, Quebec, Canada.

Inflammation in the central nervous system (CNS) can be studied in experimental autoimmune encephalomyelitis (EAE). The proinflammatory cytokines interferon-gamma (IFN-gamma) and tumour necrosis factor (TNF) are implicated in EAE pathogenesis. Signals through the type 1 TNF receptor (TNFR1) are required for severe EAE to develop, whereas deficiency in IFN-gamma or its receptor result in more severe EAE. We investigated IFN-gamma expression in TNFR1-deficient (TNFR1-/-) mice. We describe here that there were more IFN-gamma-secreting T cells present in the CNS of TNFR1-/- mice during EAE compared to wild-type (WT) mice, despite that clinical symptoms were mild, with delayed onset. There was greater expression of IL-12/23p40 by antigen-presenting cells in these mice, and in vitro, TNFR1-/- antigen-presenting cells induced greater secretion of IFN-gamma but not interleukin (IL)-17 when cultured with primed T cells than did WT antigen presenting cells. TNFR1-/- mice with EAE had significantly higher expression of CXCL10 mRNA (but not CCL5 mRNA) in the CNS compared to WT mice with EAE. These data demonstrate that IFN-gamma expression is enhanced in the CNS of TNFR1-/- mice with EAE and suggest that IFN-gamma levels do not necessarily correlate with EAE severity.
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http://dx.doi.org/10.1111/j.1365-2567.2006.02395.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1782311PMC
August 2006