Il6 and Il10 IN Hepatic Arterial infusion then DIC

However, highly regulated expression of several enzymes present in the urea cycle occurs also in many other tissues, where these enzymes are involved in synthesis of nitric oxide, polyamines, proline and glutamate. Glucagon, insulin, and glucocorticoids are major regulators of the expression of urea cycle enzymes in liver. In contrast, the "urea cycle" enzymes in nonhepatic cells are regulated by a wide range of pro- and antiinflammatory cytokines and other agents.

 

Molecular Genetics and Metabolism

September–October, 2003 Volume 80, Issues 1-2, Pages 148–158

Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer

Steven E Raper
Raper ,              

Adam Bagg

 

Guang-ping Gao

James M Wilson

Mark L Batshaw

Narendra Chirmule

Narendra Chirmul

Frank S Lee

 

Frank S Lee

Nelson A Wivel

Nelson A Wive

 

Corresponding author. Fax: 1-202-884-5988

 

Received: May 30, 2003; Received in revised form: August 8, 2003; Accepted: August 11, 2003;

DOI: http://dx.doi.org/10.1016/j.ymgme.2003.08.016

 

Fig. 1

Relevant clinical pathology parameters during hospital course. Note the improvement in laboratory parameters at a time when pulmonary function began to deteriorate. CVVHD, continuous veno-venous hemodialysis; ECMO, extracorporeal membrane oxygenation. The arrows indicate the start and end of vector infusion, and institution of intubation, CVVHD, and ECMO. Normal ranges are represented in shaded bars. Units for clinical and laboratory parameters are as follows: NH₄—μmol/L; bilirubin—mg/dl; alanine aminotransferase (ALT)—U/L; prothrombin time (PT)–s; platelets–×10³/μl; fibrin split products (FSP)—μg/ml; fraction of oxygen in inspired air (FiO₂)—%.

(A) Microscopic appearance of normal lung parenchyma (left) compared to microscopic appearance of lung parenchyma from OTC.019 (right). For detailed description, see text. (B) Microscopic appearance of normal liver (L) compared to the microscopic appearance of liver, with necrosis, from OTC.019 (R). Arrow indicates central vein of hepatic lobule: note centrilobular necrosis. For detailed description, see text. (C) Microscopic appearance of normal spleen (L) compared to the microscopic appearance of spleen, with necrosis, from OTC.019 (R). Arrow indicates scattered lymphocytes in area of widespread necrosis. For detailed description, see text. (D) Immunohistochemical evaluation of normal bone marrow (L) demonstrating presence of erythroid precursors compared to bone marrow from OTC.019 (R), demonstrating absence of hemoglobin A⁺ erythroid precursors. Arrows indicate normal erythroid precursors.

Serum levels of two cytokines in all 18 subjects dosed with recombinant adenoviral vector. (A) Time course of IL-6 elevation in cohorts 5 and 6. (B) Average peak IL-6 level by cohort. (C) Time course of IL-10 elevation in cohorts 5 and 6. (D) Average peak IL-10 level by cohort

Biodistribution of OTC vector in OTC.019. Real-time PCR shows the number of copies of vector DNA detected in each organ at the time of post-mortem examination.

Abstract

We report the death of an 18-year-old male with partial ornithine transcarbmaylase (OTC) deficiency who participated in a pilot (safety) study of gene therapy. The vector used for this trial was based on human adenovirus type 5, deleted in E1 and E4, and contained human OTC cDNA. It was infused into the right hepatic artery at a dose of 6×10¹¹particles/kg. Approximately 18h. following gene transfer the subject was noted to have altered mental status and jaundice—clinical signs not seen in any of the first 17 subjects in this study. Subsequently, his clinical course was marked by systemic inflammatory response syndrome, biochemically detectable disseminated intravascular coagulation, and multiple organ system failure, leading to death 98h following gene transfer. Post-mortem examination was consistent with the clinical course, and vector DNA sequences were readily detectable in most tissues. The subject had high serum levels of IL-6 and IL-10 but normal TNFα immediately after infusion of the vector. This experience points to the limitations of animal studies in predicting human responses, the steep toxicity curve for replication defective adenovirus vectors, substantial subject-to-subject variation in host responses to systemically administered vectors, and the need for further study of the immune response to these vectors.

HEPATIC ARTERY INJECTION WOULD YIELD IMMEDIATE PRODUCT ELEVATION AT TOXIC LEVELS POSSIBLY  An oral route with first pass through live would be better. Like a post- ischemic  correction of arterial insufficiency at cardiac level leading to arrhythmias, a pathology may require a more sensitive replacement of deficiencies

Transiently Reduced Activity of Carbamyl Phosphate Synthetase and Ornithine Transcarbamylase in Liver of Children with Reye's Syndrome

Ted Brown, B.A., George Hug, M.D., Lester Lansky, M.D., Kevin Bove, M.D., Annette Scheve, B.A., Mary Ryan, B.A., Henry Brown, M.D., William K. Schubert, M.D., John C. Partin, M.D., and John Lloyd-Still, M.D.

N Engl J Med 1976; 294:861-867April 15, 1976DOI: 10.1056/NEJM19760415294

  

Extra Urea Cycle enzyme activity / Immunity

See comment in PubMed Commons below

AMIE ENTRY .

control at  transcriptional level by inflammatory and non-inflammatory cytokines.

extra Urea cycle

 

These enzymes are involved in synthesis of nitric oxide, polyamines, proline and glutamate. Glucagon, insulin, and glucocorticoids are major regulators of the expression of urea cycle enzymes in liver

subject: Extra urea cycle arginase/arginine metabolism involved in immunity
object_opposite: not exclusively within urea cycle. Extra urea cycle Arginine metabolism and production NO2 involved in other processes relative to immunity.
misc: Regulation of enzymes of the urea cycle and arginine metabolism. Author information The urea cycle is comprised of five enzymes but also requires other enzymes and mitochondrial amino acid transporters to function fully. The complete urea cycle is expressed in liver and to a small degree also in enterocytes. However, highly regulated expression of several enzymes present in the urea cycle occurs also in many other tissues, where these enzymes are involved in synthesis of nitric oxide, polyamines, proline and glutamate. Glucagon, insulin, and glucocorticoids are major regulators of the expression of urea cycle enzymes in liver. In contrast, the "urea cycle" enzymes in nonhepatic cells are regulated by a wide range of pro- and antiinflammatory cytokines and other agents. Regulation of these enzymes is largely transcriptional in virtually all cell types. This review emphasizes recent information regarding roles and regulation of urea cycle and arginine metabolic enzymes in liver and other cell types.
author_year: Morris SM Jr/2002
journal_volume_page: Annu Rev Nutr.22:87-105

 

Annu Rev Nutr. 2002;22:87-105. Epub 2002 Jan 4.

Regulation of enzymes of the urea cycle and arginine metabolism.

Morris SM Jr¹

Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA. smorris@pitt.edu

Abstract

The urea cycle is comprised of five enzymes but also requires other enzymes and mitochondrial amino acid transporters to function fully. The complete urea cycle is expressed in liver and to a small degree also in enterocytes. However, highly regulated expression of several enzymes present in the urea cycle occurs also in many other tissues, where these enzymes are involved in synthesis of nitric oxide, polyamines, proline and glutamate. Glucagon, insulin, and glucocorticoids are major regulators of the expression of urea cycle enzymes in liver. In contrast, the "urea cycle" enzymes in nonhepatic cells are regulated by a wide range of pro- and antiinflammatory cytokines and other agents. Regulation of these enzymes is largely transcriptional in virtually all cell types. This review emphasizes recent information regarding roles and regulation of urea cycle and arginine metabolic enzymes in liver and other cell types.

Delicate balance of Th1 vs TH2 is regualted by their respective cytokines as opposed to cell to cell interaction

J Immunol. 1998 Jun 1;160(11):5347-54.

Alternative metabolic states in murine macrophages reflected by the nitric oxide synthase/arginase balance: competitive regulation by CD4+ T cells correlates with Th1/Th2 phenotype.

Munder M¹, Eichmann K, Modolell M.

 

 

Abstract

Activated murine macrophages metabolize L-arginine via two main pathways that are catalyzed by the inducible enzymes nitric oxide synthase (iNOS) and arginase. We have previously shown that CD4+ T cell-derived cytokines regulate a competitive balance in the expression of both enzymes in macrophages; Thl-type cytokines induce iNOS while they inhibit arginase, whereas the reverse is the case for Th2-type cytokines. Here we addressed the regulation of both metabolic pathways by CD4+ T cells directly. Macrophages were used as APCs for established Th1 and Th2 T cell clones as well as for in vitro polarized Th1 or Th2 T cells of transgenic mice bearing an MHC class II-restricted TCR. Both systems revealed a similar dichotomy in the macrophages; Th1 T cells led to an exclusive induction of iNOS, whereas Th2 T cells up-regulated arginase without inducing iNOS. Arginase levels induced by Th2 T cells far exceeded those inducible by individual Th2 cytokines. Similarly, high arginase levels could be induced by supernatants of Th2 cells stimulated in various ways. Ab blocking experiments revealed the critical importance of IL-4 and IL-10 for arginase up-regulation. Finally, strong synergistic effects between IL-4/IL-13 and IL-10 were observed, sufficient to account for the extraordinarily high arginase activity induced by Th2 cells. Our results suggest that the iNOS/arginase balance in macrophages is competitively regulated in the context of Th1- vs Th2-driven immune reactions, most likely by cytokines without the requirement for direct cell interaction.

Intact Urea Cycle in face of Arginine is required for antiinflammatory balance in TH2 expression. Antiflammatory index could be Th1/Th2 ratio .

This dichotomy also characterizes two alternative states that are often correlated with the course of a disease. The Th1 cytokines are considered proinflammatory cytokines, and they are often correlated with a gaseous messenger known to modulate specific functions of cell populations involved in the immune response. This messenger is nitric oxide (NO), a gaseous metabolite produced by the degradation of amino acid l-arginine by nitric oxide synthase (NOS). NO has been shown to be a crucial host-protective and antimicrobial effector molecule as well as a potential host-destructive mediator in diverse scenarios of immunopathology. Nevertheless, l-arginine may be metabolized by an alternative metabolic pathway. It can also be catalyzed by arginase, which converts l-arginine to l-ornithine and urea. Th2, in contrast to Th1 cytokines, often exhibits anti-inflammatory properties, and their expression has been related to the induction of arginase.

Note that as  arginase is stimulated which promotes Th2, anti-inflammatory activity, ornithine is produced, which of course can be eliminated by the Urea Cycle. If Urea cycle is dysfunctional ornithine backs up and obviously pushes back on arginase performance. This pushes arginine toward inflammatory lines with inducible nitric Acid synthase. This of course could be the explanation of the pathology in the Hepato-renal syndrome

AMIE implementation report: Breast Cancer : In survival analysis, absolute numbers of TILs do not represent major prognostic indicators a ratio > 1 of total FOXP3+/CD4+ TILs

subject: Ductal and lobular breast cancers appear to be infiltrated by different lymphocyte subpopulations. In ductal cancers increased CD4+ and FOXP3+ TIL numbers are associated with more aggressive tumor features. In survival analysis, absolute numbers of TILs do not represent major prognostic indicators in ductal and lobular breast cancer. Remarkably however, a ratio > 1 of total FOXP3+/CD4+ TILs in ductal carcinoma appears to represent an independent favorable prognostic factor.
object_opposite: Ratio < 1 of total FOXP3+/CD4+ TILs in ductal carcinoma appears to represent an independent unfavorable prognostic factor.
misc: Tumor-infiltrating lymphocytes (TILs) are frequently considered to reflect host immune response against malignant tumors [1]. TILs have been shown to infiltrate a variety of tumors of diverse histological origin [2,3]. Their exquisite tumor specificity has been demonstrated in a number of cases and it has led to the characterization of tumor associated antigens. Although resident TILs have frequently been reported to be in a functionally "anergic" state [4,5], importantly, following "ex vivo" culture, TILs have been used to treat different types of cancers [6]. In line with these data, tumor infiltration by T lymphocytes has been shown to be associated with favorable prognosis, particularly in melanoma and colorectal cancers [2,7]. On the other hand, tumor infiltration by T-lymphocytes subsets endowed with immuno-regulatory or suppressive potential, e.g. CD4+ T-cells expressing FOXP3 transcription factor, has been suggested to be associated with tumor progression and unfavorable prognosis [8]. More recently, a CD4+ T-cell subset producing IL-17 has been implicated in the pathogenesis of several autoimmune diseases [9]. However, the role of the so-called Th17 in antitumor immunity is still debated [10-13]
author_year: Raoul Droeser/Inti Zlobec/ Ergin Kilic / Uwe Güth/ Michael Heberer/, Giulio Spagnoli/ Daniel Oertli1 / Coya Tapia/2012
journal_volume_page: http://1.usa.gov/1DWHklJ BMC Cancer / 12/134

AMIE /TH17 /regulatory examples

subject: chagas + extent of myocardiopathy Deficient regulatory T cell activity and low frequency of IL-17-producing T cells
object_opposite: 1L17/Deficient regulatory T cell activity and low frequency of IL-17-producing T cells
misc: Deficient regulatory T cell activity and low frequency of IL-17-producing T cells correlate with the extent of cardiomyopathy in human Chagas' disease/Myocardium damage during Chagas' disease results from the immunological imbalance between pro- and production of anti-inflammatory cytokines and has been explained based on the Th1-Th2 dichotomy and regulatory T cell activity. Recently, we demonstrated that IL-17 produced during experimental T. cruzi infection regulates Th1 cells differentiation and parasite induced myocarditis. Here, we investigated the role of IL-17 and regulatory T cell during human Chagas' disease.
author_year: Authors: Guedes PM, /Gutierrez FR, /Silva GK, Dellalibera-Joviliano R, /Rodrigues GJ,/ Bendhack LM, Rassi A,/ Rassi A, /Schmidt A, /Maciel BC, /Marin Neto JA/
journal_volume_page: pubmed 6(4): e1630

AMIE implementation

subject: We show that Teff and Treg require distinct metabolic programs to support these functions. Th1, Th2, and Th17 cells expressed high surface levels of the glucose transporter Glut1 and were highly glycolytic
object_opposite: Treg, in contrast, expressed low levels of Glut1 and had high lipid oxidation rates. Consistent with glycolysis and lipid oxidation promoting Teff and Treg, respectively, Teff were selectively increased in Glut1 transgenic mice and reliant on glucose metabolism, whereas Treg had activated AMP-activated protein kinase and were dependent on lipid oxidation. Importantly, AMP-activated protein kinase stimulation was sufficient to decrease Glut1 and increase Treg generation in an asthma model
misc: Cutting Edge: Distinct Glycolytic and Lipid Oxidative Metabolic Programs Are Essential for Effector and Regulatory CD4+ T Cell Subsets
author_year: Ryan D. Michalek/ Valerie A. Gerriets/ Sarah R. Jacobs/ Andrew N. Macintyre/ Nancie J. MacIver/ Emily F. Mason/ Sarah A. Sullivan/ Amanda G. Nichols/ Jeffrey C. Rathmell/2011
journal_volume_page: Journal of Immunology/10/4049