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1.  Dendritic Cells Regulate Natural Killer Cell Activation and Epithelial Injury in Experimental Biliary Atresia 
Science translational medicine  2011;3(102):102ra94.
Biliary atresia is the most common cholangiopathy of childhood. During infancy, an idiopathic activation of the neonatal immune system targets the biliary epithelium, obstructs bile ducts, and disrupts the anatomic continuity between the liver and the intestine. Here, we use a model of virus-induced biliary atresia in newborn mice to trace the initiating pathogenic disease mechanisms to resident plasmacytoid (pDCs) and conventional (cDCs) dendritic cells. We found pDCs to be the most abundant DC population in the livers of newborn mice, and we observed pDCs in the livers of infants at the time of diagnosis. In the livers of newborn mice, cDCs spontaneously overexpressed the costimulatory molecule CD80 soon after birth, and pDCs produced the cytokine interleukin-15 (IL-15) in response to a virus insult. Both subtypes of primed DCs were required for the proliferation of T lymphocytes and the activation of natural killer cells. Disruption of this cellular network by depletion of pDCs or blockade of IL-15 signaling in mice in vivo prevented epithelial injury, maintained anatomic continuity of the bile duct, and promoted long-term survival. These findings identify cellular triggers of biliary injury and have implications for future therapies to block the progression of biliary atresia and liver disease.
doi:10.1126/scitranslmed.3002069
PMCID: PMC4006997  PMID: 21957172
2.  High-Fructose Medium-Chain-Trans-Fat Diet Induces Liver Fibrosis & Elevates Plasma Coenzyme Q9 in a Novel Murine Model of Obesity and NASH 
Hepatology (Baltimore, Md.)  2010;52(3):934-944.
Diets high in saturated fat and fructose have been implicated in the development of obesity and nonalcoholic steatohepatitis (NASH) in humans. We hypothesized that mice exposed to a similar diet would develop NASH with fibrosis associated with increased hepatic oxidative stress that would be further reflected by increased plasma levels of the respiratory-chain component, oxidized coenzyme Q9 (oxCoQ9). Adult male C57Bl/6 mice were randomly assigned to chow, High-Fat (HF), or High-Fat High-Carbohydrate (HFHC) diets for 16 weeks. The chow and HF mice had free access to pure water while the HFHC group received water with 55% fructose & 45% sucrose (w/v). The HFHC and HF groups had increased body weight, body fat mass, fasting glucose, and were insulin resistant compared to the chow mice. HF and HFHC consumed similar calories. Hepatic triglyceride content, plasma ALT, and liver weight were significantly increased in HF and HFHC mice compared to chow mice. Plasma cholesterol (p<0.001), histological hepatic fibrosis, liver hydroxyproline content (p=0.006), collagen1 mRNA (p=0.003), CD11b-F4/80+Gr1+ monocytes (p<0.0001), transforming growth factor β1 mRNA (p=0.04) and alpha-smooth muscle actin mRNA (p=0.001) levels were significantly increased in the HFHC mice. Hepatic oxidative stress, as indicated by liver superoxide expression (p=0.002), 4-hydroxynonenal and plasma oxCoQ9 (p<0.001) levels was highest in HFHC mice.
Conclusions
These findings demonstrate that non-genetically modified mice maintained on a HFHC diet in addition to developing obesity, have increased hepatic ROS and a NASH-like phenotype with significant fibrosis. Plasma oxCoQ9 correlated with fibrosis progression. The mechanism of fibrosis may involve fructose inducing increased ROS associated with CD11b+F4/80+Gr1+ hepatic macrophage aggregation resulting in TGFβ1 signaled collagen deposition and histologically visible hepatic fibrosis.
doi:10.1002/hep.23797
PMCID: PMC2932817  PMID: 20607689
Fibrosis; Obesity; Mitochondria; Inflammation; Steatosis; Murine; Ubiquinone; Coenzyme Q; Oxidative Stress
3.  Postnatal paucity of regulatory T cells and control of NK cell activation in experimental biliary atresia 
Journal of hepatology  2010;52(5):718-726.
Background & Aims
Although recent studies have identified important roles for T and NK cells in the pathogenesis of biliary atresia (BA), the mechanisms by which susceptibility to bile duct injury is restricted to the neonatal period are unknown.
Methods
We characterised hepatic regulatory T cells (Tregs) by flow cytometry in two groups of neonatal mice challenged with rhesus rotavirus (RRV) at day 7 (no ductal injury) or day 1 of life (resulting in BA), determined the functional interaction with effector cells in co-culture assays, and examined the effect of adoptive transfer of CD4+ cells on the BA phenotype.
Results
While day 7 RRV infection increased hepatic Tregs (Foxp3+ CD4+ CD25+) by 10-fold within 3 days, no increase in Tregs occurred at this time point following infection on day 1. In vitro, Tregs effectively suppressed NK cell activation by hepatic dendritic cells and decreased the production of pro-inflammatory cytokines, including TNFα and IL-15, following RRV infection. In vivo, adoptive transfer of CD4+ cells prior to RRV inoculation led to increased survival, improved weight gain, decreased population of hepatic NK cells, and persistence of donor Tregs in the liver.
Conclusions
1) The liver is devoid of Tregs early after perinatal RRV infection; 2) Tregs suppress DC-dependent activation of naive NK cells in vitro, and Treg-containing CD4+ cells inhibit hepatic NK cell expansion in vivo. Thus, the postnatal absence of Tregs may be a key factor that allows hepatic DCs to act unopposed in NK cell activation during the initiation of neonatal bile duct injury.
doi:10.1016/j.jhep.2009.12.027
PMCID: PMC2864543  PMID: 20347178
Regulatory T cells; Experimental biliary atresia; NK cell activation; Neonatal biliary injury
4.  Dual Roles of Immunoregulatory Cytokine TGF-β in the Pathogenesis of Autoimmunity-Mediated Organ Damage1 
Ample evidence suggests a role of TGF-β in preventing autoimmunity. Multiorgan inflammatory disease, spontaneous activation of self-reactive T cells, and autoantibody production are hallmarks of autoimmune diseases, such as lupus. These features are reminiscent of the immunopathology manifest in TGF-β1-deficient mice. In this study, we show that lupus-prone (New Zealand Black and White)F1 mice have reduced expression of TGF-β1 in lymphoid tissues, and TGF-β1 or TGF-β1-producing T cells suppress autoantibody production. In contrast, the expression of TGF-β1 protein and mRNA and TGF-β signaling proteins (TGF-β receptor type II and phosphorylated SMAD3) increases in the target organs, i.e., kidneys, of these mice as they age and develop progressive organ damage. In fact, the levels of TGF-β1 in kidney tissue and urine correlate with the extent of chronic lesions that represent local tissue fibrosis. In vivo TGF-β blockade by treatment of these mice with an anti-TGF-β Ab selectively inhibits chronic fibrotic lesions without affecting autoantibody production and the inflammatory component of tissue injury. Thus, TGF-β plays a dual, seemingly paradoxical, role in the development of organ damage in multiorgan autoimmune diseases. According to our working model, reduced TGF-β in immune cells predisposes to immune dysregulation and autoantibody production, which causes tissue inflammation that triggers the production of anti-inflammatory cytokines such as TGF-β in target organs to counter inflammation. Enhanced TGF-β in target organs, in turn, can lead to dysregulated tissue repair, progressive fibrogenesis, and eventual end-organ damage.
PMCID: PMC2291535  PMID: 18209088
5.  Differential Contribution of IL-4 and STAT6 vs STAT4 to the Development of Lupus Nephritis1 
Mechanisms that initiate lupus nephritis and cause progression to end-stage renal disease remain poorly understood. In this study, we show that lupus-prone New Zealand Mixed 2410 mice that develop a severe glomerulosclerosis and rapidly progressive renal disease overexpress IL-4 in vivo. In these mice, STAT6 deficiency or anti-IL-4 Ab treatment decreases type 2 cytokine responses and ameliorates kidney disease, particularly glomerulosclerosis, despite the presence of high levels of IgG anti-dsDNA Abs. STAT4 deficiency, however, decreases type 1 and increases type 2 cytokine responses, and accelerates nephritis, in the absence of high levels of IgG anti-dsDNA Abs. Thus, STAT6 and IL-4 may selectively contribute to the development of glomerulosclerosis, whereas STAT4 may play a role in autoantibody production.
PMCID: PMC2291553  PMID: 12707364
6.  An ACE inhibitor reduces Th2 cytokines and TGF-β1 and TGF-β2 isoforms in murine lupus nephritis 
Kidney international  2004;65(3):846-859.
Background
Angiotensin-converting enzyme (ACE) inhibitors, such as captopril, are used to control hypertension. In patients and animals with primary nephropathies, these agents improve renal function more than that would be expected from their control of hypertension. Here, we examine the effects of treatment with captopril on lupus nephritis and discuss the potential mechanism(s) by which this agent exerts its renoprotective effects.
Methods
Lupus-prone, NZB/NZW F1 and MRL-lpr/lpr, mice were treated with captopril or with a control antihypertensive agent, verapamil. Mice were monitored for nephritis, and their sera and tissues analyzed for cytokine and transforming growth factor-β (TGF-β) expression.
Results
Captopril treatment delayed the onset of proteinuria when administered to prenephritic mice, whereas verapamil did not. Captopril treatment also retarded disease progression when given to lupus mice that had early disease, and even reversed severe proteinuria in at least some older animals with advanced disease. It reduced chronic renal lesions, but had no effect on autoantibody production. The improvement in renal disease correlated with reduced TGF-β expression, particularly of the TGF-β1 and TGF-β2 isoforms, in the kidneys. Interestingly, in vivo or in vitro exposure to captopril reduced splenic levels of type 2 cytokines, interleukin (IL)-4 and IL-10, suggesting a possible role of the immune system in captopril-mediated disease modulation.
Conclusion
Since type 2 cytokines are known to promote lupus glomerulosclerosis, decreased IL-4 and IL-10 production in captopril-treated mice may be related to this agent’s renoprotective effects. We argue here that ACE inhibitors not only act as selective TGF-β inhibitors, but also as selective immunomodulators, to improve lupus nephritis.
doi:10.1111/j.1523-1755.2004.00462.x
PMCID: PMC2291513  PMID: 14871404
animal models; autoantibodies; cytokines; lupus nephritis; systemic lupus erythematosus; transforming growth factor β
7.  Characterization of mixed lymphocyte reaction blocking antibodies (MLR-Bf) in human pregnancy 
Background
It is known that during normal pregnancy and after immunotherapy blocking antibodies are developed, these antibodies inhibit mixed lymphocyte reaction and are also anti-mitogenic in nature. Mixed lymphocyte reaction blocking antibodies are specific to the husband's lymphocytes. In the present study an attempt has been made to characterize the mixed lymphocyte reaction blocking antibodies in normal pregnancy and in women with recurrent spontaneous abortion after immunotherapy.
Methods
Serum was obtained from women of different gestational windows of pregnancy (Ist, IInd, IIIrd trimesters and post delivery period of normal pregnancy), recurrent spontaneous aborters from pre and post immunization. Healthy (male and females) controls were screened for the presence of mixed lymphocyte reaction blocking antibodies. The standard mixed lymphocyte reaction technique was used to evaluate the inhibitory effect of serum in the mixed lymphocyte reaction. Each serum was tested for cytotoxic antibodies. Immunoglobulin G and its isotypes were isolated according to the standard protocol.
Results
In the present study we have observed that there was significant inhibition of proliferation response when immunoglobulin G from different trimesters of pregnancy were added to one way mixed lymphocyte reaction or to phytohemagglutinin activated lymphocyte proliferation assay. Similar pattern was seen when immunoglobulin G isolated from adequately immunized women with recurrent spontaneous abortion was used. It was further confirmed that amongst all the isotypes of immunoglobulin G, only immunoglobulin G-3 was found to be positive for the inhibitory effect.
Conclusions
Present study indicates that mixed lymphocyte reaction blocking antibodies are immunoglobulin G-3 in nature. It is developed during pregnancy and also after immunotherapy in women with recurrent spontaneous abortion who subsequently have the successful pregnancy.
doi:10.1186/1471-2393-3-2
PMCID: PMC150574  PMID: 12593676
8.  A Minicomputer Based Scheme for Turbulence Measurements with Pulsed Doppler Ultrasound 
The present paper describes the design and performance of a digital-based Doppler signal processing system that is currently being used in hemodynamics research on arteriosclerosis. The major emphasis is on the development of the digital signal processing technique and its implementation in a small but powerful minicomputer. The work reported on here is part of a larger ongoing effort that the authors are undertaking to study the structure of turbulence in blood flow and its relation to arteriosclerosis. Some of the techniques and instruments developed are felt to have a broad applicability to fluid mechanics and especially to pipe flow fluid mechanics.
PMCID: PMC2231874

Results 1-8 (8)