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1. Inhibition of VEGFR-2 Reverses Type 1 Diabetes in NOD Mice by Abrogating Insulitis and Restoring Islet Function

Author

Villalta, S Armando, Lang, Jiena, Kubeck, Samantha, Kabre, Beniwende, Szot, Gregory L, Calderon, Boris, Wasserfall, Clive, Atkinson, Mark A, Brekken, Rolf A, Pullen, Nick, Arch, Robert H, and Bluestone, Jeffrey A

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Immunology, Pediatric, Autoimmune Disease, Diabetes, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, Aetiology, Development of treatments and therapeutic interventions, Metabolic and endocrine, Animals, Diabetes Mellitus, Type 1, Female, Humans, Hyperglycemia, Indoles, Inflammation, Islets of Langerhans, Mice, Mice, Inbred NOD, Pancreas, Protein Kinase Inhibitors, Pyrroles, Sunitinib, Vascular Endothelial Growth Factor Receptor-2, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences
Abstract

The dysregulation of receptor tyrosine kinases (RTKs) in multiple cell types during chronic inflammation is indicative of their pathogenic role in autoimmune diseases. Among the many RTKs, vascular endothelial growth factor receptor (VEGFR) stands out for its multiple effects on immunity, vascularization, and cell migration. Herein, we examined whether VEGFR participated in the pathogenesis of type 1 diabetes (T1D) in nonobese diabetic (NOD) mice. We found that RTK inhibitors (RTKIs) and VEGF or VEGFR-2 antibodies reversed diabetes when administered at the onset of hyperglycemia. Increased VEGF expression promoted islet vascular remodeling in NOD mice, and inhibition of VEGFR activity with RTKIs abrogated the increase in islet vascularity, impairing T-cell migration into the islet and improving glucose control. Metabolic studies confirmed that RTKIs worked by preserving islet function, as treated mice had improved glucose tolerance without affecting insulin sensitivity. Finally, examination of human pancreata from patients with T1D revealed that VEGFR-2 was confined to the islet vascularity, which was increased in inflamed islets. Collectively, this work reveals a previously unappreciated role for VEGFR-2 signaling in the pathogenesis of T1D by controlling T-cell accessibility to the pancreatic islets and highlights a novel application of VEGFR-2 antagonists for the therapeutic treatment of T1D.

Published
2013

3. Tumor necrosis factor receptor-associated factors (TRAFs)--a family of adapter proteins that regulates life and death

Author

Arch, Robert H., Gedrich, Richard W., and Thompson, Craig B.

Subjects
Tumor necrosis factor -- Observations, Cell death -- Genetic aspects, Cytoplasm -- Observations, Cell physiology -- Observations, Proteins -- Receptors, Cell cycle -- Observations, Genetic regulation -- Observations, Cellular signal transduction -- Observations, Biological sciences
Abstract

Signaling pathways regulating survival of cells are in the early stages of being defined. Components of survival signal transduction are of interest. An important family of cytoplasmic proteins seems to be capable of negatively regulating apoptotic pathways and can induce expression of genes that help cells to survive. The family has been given the name tumor necrosis factor (TNF) receptor-associated factors (TRAFs) because of ability to bind to TNFRII. This family of adapter proteins regulates death as well as life.

Published
1998

4. Antimalarial activity of single-dose DSM265, a novel plasmodium dihydroorotate dehydrogenase inhibitor, in patients with uncomplicated Plasmodium falciparum or Plasmodium vivax malaria infection: a proof-of-concept, open-label, phase 2a study

Author

Llanos-Cuentas, Alejandro, Casapia, Martin, Chuquiyauri, Raúl, Hinojosa, Juan-Carlos, Kerr, Nicola, Rosario, Maria, Toovey, Stephen, Arch, Robert H, Phillips, Margaret A, Rozenberg, Felix D, Bath, Jade, Ng, Caroline L, Cowell, Annie N, Winzeler, Elizabeth A, Fidock, David A, Baker, Mark, Möhrle, Jörg J, Hooft van Huijsduijnen, Rob, Gobeau, Nathalie, Araeipour, Nada, Andenmatten, Nicole, Rückle, Thomas, and Duparc, Stephan

Subjects
Oxidoreductases Acting on CH-CH Group Donors, Plasmodium falciparum, Dihydroorotate Dehydrogenase, DSM265, Triazoles, purl.org/pe-repo/ocde/ford#3.03.08 [https], Article, Antimalarial activity, Antimalarials, novel plasmodium dihydroorotate dehydrogenase inhibitor, Pyrimidines, malaria infection, parasitic diseases, Malaria, Vivax, Humans, Malaria, Falciparum, Plasmodium vivax
Abstract

Summary Background DSM265 is a novel, long-duration inhibitor of plasmodium dihydroorotate dehydrogenase (DHODH) with excellent selectivity over human DHODH and activity against blood and liver stages of Plasmodium falciparum. This study aimed to assess the efficacy of DSM265 in patients with P falciparum or Plasmodium vivax malaria infection. Methods This proof-of-concept, open-label, phase 2a study was conducted at the Asociación Civil Selva Amazónica in Iquitos, Peru. Patients aged 18–70 years, weighing 45–90 kg, who had clinical malaria (P falciparum or P vivax monoinfection) and fever within the previous 24 h were eligible. Exclusion criteria were clinical or laboratory signs of severe malaria, inability to take oral medicine, and use of other antimalarial treatment in the preceding 14 days. Patients were divided into cohorts of those with P falciparum (cohort a) or P vivax (cohort b) infection. Two initial cohorts received single oral doses of 400 mg DSM265. Patients were followed up for efficacy for 28 days and safety for 35 days. Further cohorts received escalated or de-escalated doses of DSM265, after safety and efficacy assessment of the initial dose. The primary endpoints were the proportion of patients achieving PCR-adjusted adequate clinical and parasitological response (ACPR) by day 14 for patients infected with P falciparum and the proportion of patients achieving a crude cure by day 14 for those infected with P vivax. Cohort success, the criteria for dose escalation, was defined as ACPR (P falciparum) or crude cure (P vivax) in at least 80% of patients in the cohort. The primary analysis was done in the intention-to-treat population (ITT) and the per-protocol population, and safety analyses were done in all patients who received the study drug. This study is registered at ClinicalTrials.gov (NCT02123290). Findings Between Jan 12, 2015, and Dec 2, 2015, 45 Peruvian patients (24 with P falciparum [cohort a] and 21 with P vivax [cohort b] infection) were sequentially enrolled. For patients with P falciparum malaria in the per-protocol population, all 11 (100%) in the 400 mg group and eight (80%) of ten in the 250 mg group achieved ACPR on day 14. In the ITT analysis, 11 (85%) of 13 in the 400 mg group and eight (73%) of 11 in the 250 mg group achieved ACPR at day 14. For the patients with P vivax malaria, the primary endpoint was not met. In the per-protocol analysis, none of four patients who had 400 mg, three (50%) of six who had 600 mg, and one (25%) of four who had 800 mg DSM265 achieved crude cure at day 14. In the ITT analysis, none of five in the 400 mg group, three (33%) of nine in the 600 mg group, and one (14%) of seven in the 800 mg group achieved crude cure at day 14. During the 28-day extended observation of P falciparum patients, a resistance-associated mutation in the gene encoding the DSM265 target DHODH was observed in two of four recurring patients. DSM265 was well tolerated. The most common adverse events were pyrexia (20 [44%] of 45) and headache (18 [40%] of 45), which are both common symptoms of malaria, and no patients had any treatment-related serious adverse events or adverse events leading to study discontinuation. Interpretation After a single dose of DSM265, P falciparum parasitaemia was rapidly cleared, whereas against P vivax, DSM265 showed less effective clearance kinetics. Its long duration of action provides the potential to prevent recurrence of P falciparum after treatment with a single dose, which should be further assessed in future combination studies. Funding The Global Health Innovative Technology Fund, the Bill & Melinda Gates Foundation, the National Institutes of Health (R01 AI103058), the Wellcome Trust, and the UK Department of International Development.

Published
2018

6. Extrahepatic Platelet-Derived Growth Factor-β, Delivered by Platelets, Promotes Activation of Hepatic Stellate Cells and Biliary Fibrosis in Mice

Author

Yoshida, Shuhei, primary, Ikenaga, Naoki, additional, Liu, Susan B., additional, Peng, Zhen-Wei, additional, Chung, Jeanhee, additional, Sverdlov, Deanna Y., additional, Miyamoto, Makoto, additional, Kim, Yong Ook, additional, Ogawa, Shinji, additional, Arch, Robert H., additional, Schuppan, Detlef, additional, and Popov, Yury, additional

Published
2014
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7. Multiplex transcriptional analysis of paraffin-embedded liver needle biopsy from patients with liver fibrosis

Author

Staten, Nicholas R, primary, Welsh, Eric A, additional, Sidik, Kurex, additional, McDonald, Sandra A, additional, Dufield, Dawn R, additional, Maqsodi, Botoul, additional, Ma, Yunqing, additional, McMaster, Gary K, additional, Mathews, Rodney W, additional, Arch, Robert H, additional, Masferrer, Jaime L, additional, and Souberbielle, Bernard E, additional

Published
2012
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12. Expression of CD30 and Ox40 on T lymphocyte subsets is controlled by distinct regulatory mechanisms

Author

Toennies, Holly M., Green, Jonathan M., and Arch, Robert H.

Abstract

Members of the TNF receptor (TNFR) superfamily are cell‐surface proteins that can be found on most cell types including lymphocytes. Although some TNFR‐related molecules are constitutively expressed, others, such as CD30 and Ox40, are induced upon activation of lymphocytes. CD30 and Ox40 are predominantly expressed on activated T helper (Th)2 cells. Both receptors can activate c‐Jun N‐terminal kinase (JNK) and nuclear factor‐κB (NF‐κB) and have been suggested to play costimulatory roles in lymphocyte activation. To gain further insight into events triggered by both TNFR‐related molecules, a detailed analysis of their expression patterns has been prformed. We found that CD30 and Ox40 were coexpressed on Th2 cells. However, in contrast to CD30, Ox40 was also expressed on Th1 cells. Although expression of both receptors is augmented by interleukin‐4, only CD30 expression is dependent on signal transducer and activator of transcription (STAT)‐6‐mediated signaling. Differences in the regulatory pathways controlling expression of CD30 and Ox40 suggest distinct, functional effects triggered by the two TNFR‐related molecules during lymphocyte activation.

Published
2004
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13. 4-1BB and Ox40 Are Members of a Tumor Necrosis Factor (TNF)-Nerve Growth Factor Receptor Subfamily That Bind TNF Receptor-Associated Factors and Activate Nuclear Factor ?B

Author

Arch, Robert H. and Thompson, Craig B.

Abstract

ABSTRACTMembers of the tumor necrosis factor (TNF)-nerve growth factor (NGF) receptor family have been shown to be important costimulatory molecules for cellular activation. 4-1BB and Ox40 are two recently described members of this protein family which are expressed primarily on activated T cells. To gain insight into the signaling pathways employed by these factors, yeast two-hybrid library screens were performed with the cytoplasmic domains of 4-1BB and Ox40 as baits. TNF receptor-associated factor 2 (TRAF2) was identified as an interacting protein in both screens. The ability of both 4-1BB and Ox40 to interact with TRAF2 was confirmed in mammalian cells by coimmunoprecipitation studies. When the binding of the receptors to other TRAF proteins was investigated, 4-1BB and Ox40 displayed distinct binding patterns. While 4-1BB bound TRAF2 and TRAF1, Ox40 interacted with TRAF3 and TRAF2. Using deletion and alanine scanning analysis, we defined the elements in the cytoplasmic domains of both receptors that mediate these interactions. The 4-1BB receptor was found to have two independent stretches of acidic residues that can mediate association of the TRAF molecules. In contrast, a single TRAF binding domain was identified in the cytoplasmic tail of Ox40. The cytoplasmic domains of both receptors were shown to activate nuclear factor ?B in a TRAF-dependent manner. Taken together, our results indicate that 4-1BB and Ox40 bind TRAF proteins to initiate a signaling cascade leading to activation of nuclear factor ?B.

Published
1998
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14. Assessment of liver fibrosis progression and regression by a serological collagen turnover profile.

Author

Karsdal MA, Hjuler ST, Luo Y, Rasmussen DGK, Nielsen MJ, Holm Nielsen S, Leeming DJ, Goodman Z, Arch RH, Patel K, and Schuppan D

Subjects
Adult, Biomarkers metabolism, Biopsy, Disease Progression, Female, Humans, Male, Middle Aged, Phenotype, Collagen metabolism, Fibrosis metabolism, Liver Cirrhosis metabolism
Abstract

There is a need for noninvasive biomarkers that can identify patients with progressive liver fibrosis and monitor response to antifibrotic therapy. An equally important need is identification of patients with spontaneous fibrosis regression, since they may not need treatment nor be included in clinical studies with fibrosis as end point. Circulating biomarkers, originating from defined fragments of the scar tissue itself, may serve as valuable tools for this aspect of precision medicine. We investigated a panel of serological collagen formation and degradation markers to identify patients likely to regress or progress in absence of a therapeutic intervention. Plasma samples from patients with moderate-stage hepatitis C receiving placebo treatment in a phase II trial of the peroxisome proliferator-activated receptor agonist farglitazar were included. The patients had matched liver biopsies at baseline and 52 wk of follow-up. Serological biomarkers of collagen formation (PRO-C3, PRO-C4, PRO-C5) and collagen degradation (C3M, C4M, and C6M) were analyzed. Logistic regression analysis including PRO-C3 and C6M identified subjects with progressive liver fibrosis with an AUROC of 0.91 ( P < 0.0001) and positive and negative predictive values (PPV/NPV) of 75.0%/88.6%. Low levels of PRO-C5 predicted a spontaneous regression phenotype, with an odds ratio of 33.8 times higher compared with patients with high levels ( P < 0.0025) with an AUROC of 0.78 ( P < 0.0001) and PPV/NPV of 60.0%/95.7%. Two collagen fragments (PRO-C3 and C6M) identified liver fibrosis progressors, and one collagen fragment (PRO-C5) identified liver fibrosis regressors. These biomarkers may improve patient stratification and monitor treatment efficacy in studies with fibrosis as clinical end point. NEW & NOTEWORTHY In this study we report two biomarkers of collagen fragments (PRO-C3 and C6M) that are able to identify liver fibrosis progressors while one biomarker (PRO-C5) identified liver fibrosis regressors. In particular, we present three noninvasive biomarkers that can be used to identify patients with progressive liver fibrosis, monitor response to antifibrotic therapy, and also identify the spontaneous liver fibrosis regression phenotype.

Published
2019
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