<b>Supplementary Table 1.</b> A set of 337 transcripts that demonstrated a significant change in whole blood gene expression in six subjects three months after laparoscopic sleeve gastrectomy compared to the baseline... more
<b>Supplementary Table 1.</b> A set of 337 transcripts that demonstrated a significant change in whole blood gene expression in six subjects three months after laparoscopic sleeve gastrectomy compared to the baseline pre-operative state (false discovery rate (FDR) &lt; 5%) and showed more than one unit of log<sub>2</sub>-fold change (FC).<br>
<b>Supplementary Figure 3.</b> Longitudinal changes in whole blood gene expression after laparoscopic sleeve gastrectomy for six candidate genes of interest (<i>ID1</i>, <i>IFNE</i>,... more
<b>Supplementary Figure 3.</b> Longitudinal changes in whole blood gene expression after laparoscopic sleeve gastrectomy for six candidate genes of interest (<i>ID1</i>, <i>IFNE</i>, <i>IGF2</i>, <i>MMP15</i>, <i>PDPK2P</i>, <i>SLCO2A1</i>) assayed with qPCR in 12 subjects. Dark blue dots indicate values measured at baseline (pre-operatively) and dark red dots indicate values measured during follow-up (post-operatively). Dashed lines between dots indicate missing data for a given subject. Data for each timepoint are summarized as means and 95% confidence intervals. Significant differences adjusted for multiple testing were marked with the following thresholds: <sup>*</sup><i>P</i> &lt; 0.05; <sup>**</sup><i>P</i> &lt; 0.01, <sup>***</sup><i>P</i> &lt; 0.001, <sup>****</sup><i>P</i> &lt; 0.0001. T0, baseline; T3, 3 months post-op; T6, 6 months; T9, 9 months; T12, 12 months.
Supplemental material for "Early changes in immune cell count, metabolism, and function are a hallmark of sleeve gastrectomy: a prospective human study" by Lo <i>et al.</i>
<b>Supplementary Table 2.</b> Forward and reverse quantitative polymerase chain reaction (qPCR) primers for measuring the expression of six candidate genes of interest (<i>ID1</i>, <i>IFNE</i>,... more
<b>Supplementary Table 2.</b> Forward and reverse quantitative polymerase chain reaction (qPCR) primers for measuring the expression of six candidate genes of interest (<i>ID1</i>, <i>IFNE</i>, <i>IGF2</i>, <i>MMP15</i>, <i>PDPK2P</i>, <i>SLCO2A1</i>) related to surgical weight loss. Ubiquitin C was used as a housekeeping gene for comparison.<br>
<b>Supplementary Figure 2. </b>Changes in serum levels of adiponectin (<b>A</b>) and resistin (<b>B</b>) in 23 subjects from baseline to 12 months after undergoing sleeve gastrectomy. Blue bars indicate... more
<b>Supplementary Figure 2. </b>Changes in serum levels of adiponectin (<b>A</b>) and resistin (<b>B</b>) in 23 subjects from baseline to 12 months after undergoing sleeve gastrectomy. Blue bars indicate values at baseline (pre-operatively). Dark blue dots indicate values measured at baseline (pre-operatively) and dark red dots indicate values measured during follow-up (post-operatively). Dashed lines between dots indicate missing data for a given subject. Data for each timepoint are summarized as means and 95% confidence intervals. Significant differences adjusted for multiple testing were marked with the following thresholds: <sup>*</sup><i>P</i> &lt; 0.05; <sup>**</sup><i>P</i> &lt; 0.01, <sup>***</sup><i>P</i> &lt; 0.001, <sup>****</sup><i>P</i> &lt; 0.0001. T0, baseline; T3, 3 months post-op; T6, 6 months; T9, 9 months; T12, 12 months. <br>
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Research Interests: Autoimmunity and Medicine
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ABSTRACT
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Case reports have suggested that bariatric surgery improves pulmonary hypertension. We performed a retrospective, case-control study to evaluate the safety and efficacy of bariatric surgery in obese patients with severe pulmonary... more
Case reports have suggested that bariatric surgery improves pulmonary hypertension. We performed a retrospective, case-control study to evaluate the safety and efficacy of bariatric surgery in obese patients with severe pulmonary hypertension. Morbidly obese patients followed in a specialty pulmonary hypertension clinic who underwent laparoscopic gastric bypass or sleeve gastrectomy between 2008 and 2013 (n = 10) were compared to a BMI-matched cohort managed with maximal medical therapy (n = 10). Patients with advanced malignancy, prior heart/lung transplantation, and pulmonary hypertension from thromboembolism were excluded. Primary outcomes assessed were changes in use of pulmonary vasodilatory and diuretic medications, need for home oxygen therapy, and mean pulmonary arterial pressures. Secondary outcomes measured were excess body weight loss, perioperative mortality and morbidity, and hospital length of stay. More patients who underwent bariatric surgery experienced improvements in pulmonary arterial pressures (75 vs. 0 %, p = 0.02), reduction in or discontinuation of pulmonary vasodilatory therapy (67 vs. 0 %, p = 0.01), and decreased diuretic requirements (86 vs. 13 %, p = 0.01) than the control cohort. Seventy-five percent of patients previously on home oxygen discontinued therapy after surgery, while oxygen requirements increased in 50 % of the control cohort. Excess body weight loss was greater in the surgical group (EWL 68 vs. 19 %, p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). Seven significant complications in five patients occurred in the first postoperative year, but there were no mortalities. Mean inpatient length of stay was 5 days. Laparoscopic gastric bypass and sleeve gastrectomy in obese patients improves pulmonary hypertension in the short term.
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Research Interests: Gastroenterology, Reflux, Dysphagia, Medicine, Humans, and 15 moreInternal Medicine, Female, Male, Gerd, Clinical Sciences, Magnets, Adult, Retrospective Studies, Laparoscopy, Gastroesophageal Reflux, Nissen Fundoplication, fundoplication, Hiatal hernia, high resolution manometry, and surgical endoscopy
One of the current challenges in vaccine design is the development of antigen delivery systems or vaccination strategies that induce high protective levels of CD8+ T cells. These cells are crucial for protection against certain tumours... more
One of the current challenges in vaccine design is the development of antigen delivery systems or vaccination strategies that induce high protective levels of CD8+ T cells. These cells are crucial for protection against certain tumours and intracellular pathogens such as the liver-stage parasite of malaria. A liver-stage malaria vaccine should therefore include CD8+ T-cell-inducing components. This review provides an overview of prime-boost immunisation strategies that result in protective CD8+ T-cell responses against malaria with an emphasis on work from our laboratory. Possible mechanisms explaining why heterologous prime-boost strategies, in particular boosting with replication-impaired recombinant poxviruses, are so effective are discussed.
Research Interests: Immunology, Biology, Malaria, Virology, Medicine, and 10 morePrimates, Humans, Mice, Animals, DNA vaccines, Vaccination, CD, Heterologous Expression, Epitopes, and Malaria Vaccines
The expression, or lack thereof, of class I MHC glycoproteins has a marked influence on natural killer cell function. Cells which do not express class I MHC molecules are susceptible to lysis by NK cells, and transfection of these targets... more
The expression, or lack thereof, of class I MHC glycoproteins has a marked influence on natural killer cell function. Cells which do not express class I MHC molecules are susceptible to lysis by NK cells, and transfection of these targets with class I MHC genes can render these cells resistant to NK attack. This inhibition of NK-killing is mediated by a novel family of receptors expressed mainly on NK cells, but also found on some T-cells. The function of these class I MHC binding receptors when expressed on T-cells is discussed also and a novel co-stimulatory activity of NKAR described. Lastly, a novel mechanism by which human cytomegalovirus evades immune surveillance by NK cells is documented.
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Objective To characterize longitudinal changes in blood biomarkers, leukocyte composition, and gene expression following laparoscopic sleeve gastrectomy (LSG). Background LSG is an effective treatment for obesity, leading to sustainable... more
Objective To characterize longitudinal changes in blood biomarkers, leukocyte composition, and gene expression following laparoscopic sleeve gastrectomy (LSG). Background LSG is an effective treatment for obesity, leading to sustainable weight loss and improvements in obesity-related comorbidities and inflammatory profiles. However, the effects of LSG on immune function and metabolism remain uncertain. Methods Prospective data were collected from 23 enrolled human subjects from a single institution. Parameters of weight, comorbidities, and trends in blood biomarkers and leukocyte subsets were observed from preoperative baseline to 1 year postsurgery in 3-month follow-up intervals. RNA sequencing was performed on pairs of whole blood samples from the first 6 subjects of the study (baseline and 3 months postsurgery) to identify genome-wide gene expression changes associated with undergoing LSG. Results LSG led to a significant decrease in mean total body weight loss (18.1%) at 3 month...
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Obesity is widespread and linked to various co-morbidities. Bariatric surgery has been identified as the only effective treatment, promoting sustained weight loss and the remission of co-morbidities.We performed sleeve-gastrectomies (SGx)... more
Obesity is widespread and linked to various co-morbidities. Bariatric surgery has been identified as the only effective treatment, promoting sustained weight loss and the remission of co-morbidities.We performed sleeve-gastrectomies (SGx) in a pre-clinical mouse model of diet-induced obesity (DIO), delineating the effects on long-term remission from obesity. SGx resulted in sustained weight loss and improved glucose tolerance. Mass-spectrometric metabolomic profiling revealed significantly reduced systemic levels of taurodeoxycholic acid (TDCA) and L-valine in DIO mice. Notably, TDCA and L-Valine levels were restored after SGx in both human and mice to levels comparable with lean controls.Strikingly, combined systemic treatment with TDCA and valine induced a profound weight loss in DIO mice analogous to effects observed after SGx. Utilizing indirect calorimetry, we confirmed reduced food intake as causal for TDCA/valine-mediated weight loss via a central inhibition of the melanin-co...
Research Interests: Endocrinology, Obesity, Biology, Medicine, Appetite, and 4 moreInternal Medicine, Weight Loss, Elife, and Valine
Bariatric surgery, the most effective treatment for obesity and type 2 diabetes, is consistently associated with increased levels of the incretin hormone GLP-1 and changes in overall levels of circulating bile acids. The levels of... more
Bariatric surgery, the most effective treatment for obesity and type 2 diabetes, is consistently associated with increased levels of the incretin hormone GLP-1 and changes in overall levels of circulating bile acids. The levels of individual bile acids in the GI tract following surgery, however, have remained largely unstudied. Using UPLC-MS-based quantification, we observed an increase in an endogenous bile acid, cholic acid-7-sulfate (CA7S), in the GI tract of both mice and humans after sleeve gastrectomy. We show that CA7S is a TGR5 agonist that induces GLP-1 secretion in vitro and in vivo and that CA7S administration increases glucose tolerance in insulin-resistant mice in a GLP-1 receptor-dependent manner. CA7S remains gut-restricted, minimizing off-target effects previously observed for TGR5 agonists absorbed into circulation. By studying changes in individual metabolites following surgery, this study has revealed a naturally occurring TGR5 agonist that exerts systemic glucore...
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Ischemia-reperfusion injury (I/R) is an inflammatory response to hypoxia that is dependent on antibodies. We have previously shown that the N2 peptide blocks binding of autoreactive antibody to ischemic tissue and reduces I/R injury in... more
Ischemia-reperfusion injury (I/R) is an inflammatory response to hypoxia that is dependent on antibodies. We have previously shown that the N2 peptide blocks binding of autoreactive antibody to ischemic tissue and reduces I/R injury in rodents. Whether these same antibodies exist and target the same antigen in humans is unknown. In this study, we create a novel "humanized" mice model of intestinal I/R and test the efficacy of N2. Humanized mice were generated by transplanting human lymphocytes into immunodeficient mice. Human T- and B-cell engraftment in the spleen and peritoneum was confirmed using flow cytometry, and circulating human antibody in mouse serum was measured with ELISA. Injury in the small intestine and lung after intestinal I/R was measured in the presence or absence of N2. Immunohistochemistry was used to assess for human antibody deposition in the small intestine. Humanized mice engrafted with functional CD20+ B cells generated high circulating serum leve...
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An important feature of the human immune system is the ability of T cells to respond to small quantities of antigen. Class II major histocompatibility complex (MHC)-restricted T cells that expressed a costimulatory natural killer (NK)... more
An important feature of the human immune system is the ability of T cells to respond to small quantities of antigen. Class II major histocompatibility complex (MHC)-restricted T cells that expressed a costimulatory natural killer (NK) cell receptor for class I MHC proteins were cloned. In the presence of low doses of superantigen, the proliferative response of these T cell clones was three- to ninefold greater when the T cells were costimulated by way of the NK receptor. Thus, the action of costimulatory NK receptors on T cells may play a significant role in initiating and sustaining immune responses.
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To generate broadly protective T cell responses more similar to those acquired after vaccination with radiation-attenuated Plasmodium falciparum sporozoites, we have constructed candidate subunit malaria vaccines expressing six... more
To generate broadly protective T cell responses more similar to those acquired after vaccination with radiation-attenuated Plasmodium falciparum sporozoites, we have constructed candidate subunit malaria vaccines expressing six preerythrocytic antigens linked together to produce a 3,240-aa-long polyprotein (L3SEPTL). This polyprotein was expressed by a plasmid DNA vaccine vector (DNA) and by two attenuated poxvirus vectors, modified vaccinia virus Ankara (MVA) and fowlpox virus of the FP9 strain. MVAL3SEPTL boosted anti-thrombospondin-related adhesive protein (anti-TRAP) and anti-liver stage antigen 1 (anti-LSA1) CD8 + T cell responses when primed by single antigen TRAP- or LSA1-expressing DNAs, respectively, but not by DNA-L3SEPTL. However, prime boost regimes involving two heterologous viral vectors expressing L3SEPTL induced a strong cellular response directed against an LSA1 peptide located in the C-terminal region of the polyprotein. Peptide-specific T cells secreted IFN-γ and ...
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Copolymer 1 [Cop1, glatiramer acetate, Copaxone, poly(Y,E,A,K)n] is widely used in the treatment of relapsing/remitting multiple sclerosis in which it reduces the frequency of relapses by ≈30%. In the present study, copolymers with... more
Copolymer 1 [Cop1, glatiramer acetate, Copaxone, poly(Y,E,A,K)n] is widely used in the treatment of relapsing/remitting multiple sclerosis in which it reduces the frequency of relapses by ≈30%. In the present study, copolymers with modified amino acid compositions (based on the binding motif of myelin basic protein 85–99 to HLA-DR2) have been developed with the aim of suppressing multiple sclerosis more effectively. The enhanced efficacy of these copolymers in experimental autoimmune encephalomyelitis (EAE) induced in SJL/J mice with proteolipid protein 139–151 was demonstrated by using three protocols: ( i ) simultaneous administration of autoantigen and copolymer (termed prevention), ( ii ) pretreatment with copolymers (vaccination), or ( iii ) administration of copolymers after disease onset (treatment). Strikingly, in the treatment protocol administration of soluble VWAK and FYAK after onset of disease led to stasis of its progression and suppression of histopathological evidenc...
Research Interests: Multiple sclerosis, Biology, Cytokines, Autoimmunity, Medicine, and 15 moreMultidisciplinary, Medical Immunology, Mice, Animals, Peptides, Medical Biochemistry, Amino Acid Profile, Amino Acid Sequence, Experimental Autoimmune Encephalomyelitis, Protein Binding, Glatiramer acetate, Adoptive Transfer, Amino acid composition, myelin basic protein, and Myelin proteolipid protein
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Understanding the protective mechanism in the liver induced by recombinant vaccines against the pre-erythrocytic stages of malaria is important for vaccine development. Most studies in mice have focused on splenic and peripheral blood T... more
Understanding the protective mechanism in the liver induced by recombinant vaccines against the pre-erythrocytic stages of malaria is important for vaccine development. Most studies in mice have focused on splenic and peripheral blood T cells and identified gamma interferon (IFN-γ)-producing CD8 + T cells as correlates of protection, which can be induced by prime-boost vaccination with recombinant poxviruses. Invariant natural killer T (Vα14 i NKT) cells can also protect against liver stage malaria, when activated, and are abundant in the liver. Since poxviruses have nonspecific immunomodulating effects, which are incompletely understood, we investigated whether recombinant poxviruses affect the protective properties of hepatic Vα14 i NKT cells and thus vaccine efficacy. We show that intradermal vaccination with recombinant poxviruses activated Vα14 i NKT cells and NK cells in the livers of BALB/c mice while inducing IFN-γ- and tumor necrosis factor alpha (TNF-α)-producing pre-eryth...
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Introduction There are past indications that the adaptive immune response of B cells plays a role in tumor development. We examined this issue in vivo by examining the growth of Lewis Lung Carcinoma (LLC) and murine melanoma in B cell... more
Introduction There are past indications that the adaptive immune response of B cells plays a role in tumor development. We examined this issue in vivo by examining the growth of Lewis Lung Carcinoma (LLC) and murine melanoma in B cell knockout (Bcell ko) mice. Methods Cultured LLC or melanoma cells were implanted into hindlimbs of C57BL/6 (B6) and Bcell ko mice. Tumors were measured every 3-4 days, and tissue was harvested for histological examination 2-3 weeks after tumor implantation. Tissues were stained with labeled anti-IgG, -CD4, -CD8, and -CD31 antibody. Results Melanomas in B6 and B cell ko mice enlarged at the same rate. However, tumor growth of LLC was significantly slower in B cell KO mice compared to B6 (p=0.02). Though both tumor-infiltrating CD4+ T cells and CD8+ T cells were identified in B6 mice, tumor-infiltrating CD4+ T cells but no tumor-infiltrating CD8+ T cells were seen in B cell KO mice in LLC. Angiogenesis was significantly inhibited in LLC in B cell KO mice. Conclusions The absence of B cells selectively inhibited tumor growth for LLC, and was associated with less tumor angiogenesis and an absence of CD8+ T cells. Blocking this aspect of the B cell response might be useful therapy for selected tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3532. doi:1538-7445.AM2012-3532
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Research Interests: Incidence Geometry, Calcium, Medicine, Prospective studies, Humans, and 15 moreFemale, Male, Parathyroid Hormone, Clinical Sciences, Aged, Middle Aged, Adult, Primary hyperparathyroidism, Adenoma, Hypercalcemia, Cohort Studies, Postoperative Complications, Parathyroidectomy, Prospective Cohort Study, and minimally invasive surgical procedures
Murine reperfusion injury follows binding of specific IgM natural antibodies to neo-antigens exposed in ischemic tissue. Peptides that mimic the site of antibody binding in the injury prevent IgM binding when administered intravenously... more
Murine reperfusion injury follows binding of specific IgM natural antibodies to neo-antigens exposed in ischemic tissue. Peptides that mimic the site of antibody binding in the injury prevent IgM binding when administered intravenously before reperfusion. To determine whether this pathogenic sequence is restricted to mice, we have tested the ability of the peptide to prevent reperfusion injury in a dissimilar species, the rat. Sprague-Dawley rats were subjected to 40 min of mesenteric ischemia followed by 180 min of reperfusion. The peptide mimic was administered intravenously prior to reperfusion. Gut injury was quantified using a scoring system based on the hematoxylin-and-eosin section. 125I-labeled albumin was used to assess local (gut) and remote (lung) injury. The macroscopic appearance of bowel from peptide-treated animals was less edematous and hemorrhagic. Microscopic analysis showed a significantly reduced injury score in peptide-treated animals. Permeability data indicate...
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Sleeve gastrectomy (SG) has profound, immediate weight-loss independent effects on obesity related diabetes (T2D). Our prior studies have shown that immunologic remodeling may play a part in this metabolic improvement. However, to date,... more
Sleeve gastrectomy (SG) has profound, immediate weight-loss independent effects on obesity related diabetes (T2D). Our prior studies have shown that immunologic remodeling may play a part in this metabolic improvement. However, to date, little is known about how the major immune cell populations change following SG. Using mass cytometry with time of flight analysis (CyTOF) we aimed to broadly explore the organ-specific immune cell repertoire induced by SG. Surgery was performed on obese, insulin resistant and lean mice in order to understand surgery-specific phenotypes. We identified a shift within the splenic B cell compartment with a reduction in follicular and an increase in innate-like B cell subsets in SG animals. There was a concomitant increase in multiple circulating immunoglobulin classes. Further, SG animals had a conserved increase in splenic neutrophils and a tendency toward M2 macrophage polarization. Others have shown that these, weight-loss independent, surgery-specif...