Publications by authors named "William Hanes"

9 Publications

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Treatment of Aggressive T Cell Lymphoblastic Lymphoma/leukemia Using Anti-CD5 CAR T Cells.

Stem Cell Rev Rep 2021 Apr 6;17(2):652-661. Epub 2021 Jan 6.

Department of Hematology, Peking University Shenzhen Hospital, Shenzhen, People's Republic of China.

While treatment for B-cell malignancies has been revolutionized through the advent of CAR immunotherapy, similar strategies for T-cell malignancies have been limited. Additionally, T-cell leukemias and lymphomas can commonly metastasize to the CNS, where outcomes are poor and treatment options are associated with severe side effects. Consequently, the development of safer and more effective alternatives for targeting malignant T cells that have invaded the CNS remains clinically important. CD5 CAR has previously been shown to effectively target various T-cell cancers in preclinical studies. As IL-15 strengthens the anti-tumor response, we have modified CD5 CAR to secrete an IL-15/IL-15sushi complex. In a Phase I clinical trial, these CD5-IL15/IL15sushi CAR T cells were tested for safety and efficacy in a patient with refractory T-LBL with CNS infiltration. CD5-IL15/IL15sushi CAR T cells were able to rapidly ablate the CNS lymphoblasts within a few weeks, resulting in the remission of the patient's lymphoma. Despite the presence of CD5 on normal T cells, the patient only experienced a brief, transient T-cell aplasia. These results suggest that CD5-IL15/IL15sushi CAR T cells may be a safe and useful treatment of T-cell malignancies and may be particularly beneficial for patients with CNS involvement.Graphical Abstract.
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http://dx.doi.org/10.1007/s12015-020-10092-9DOI Listing
April 2021

Treatment of CML-transformed B Cell Acute Lymphoblastic Leukemia (B-ALL) in Adults with Anti-CD19 Chimeric Antigen Receptor T Cell (CAR T) Therapy.

Stem Cell Rev Rep 2020 12;16(6):1356-1358

Division of Hematology/Oncology MetroHealth System, Case Western Reserve University School Medicine, ‎Cleveland, OH, USA.

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http://dx.doi.org/10.1007/s12015-020-10008-7DOI Listing
December 2020

Adenylyl Cyclase 6 Mediates Inhibition of TNF in the Inflammatory Reflex.

Front Immunol 2018 27;9:2648. Epub 2018 Nov 27.

Department of Medicine, Center for Bioelectronic Medicine, Center for Molecular Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Macrophage cytokine production is regulated by neural signals, for example in the inflammatory reflex. Signals in the vagus and splenic nerves are relayed by choline acetyltransferase T cells that release acetylcholine, the cognate ligand for alpha7 nicotinic acetylcholine subunit-containing receptors (α7nAChR), and suppress TNF release in macrophages. Here, we observed that electrical vagus nerve stimulation with a duration of 0.1-60 s significantly reduced systemic TNF release in experimental endotoxemia. This suppression of TNF was sustained for more than 24 h, but abolished in mice deficient in the α7nAChR subunit. Exposure of primary human macrophages and murine RAW 264.7 macrophage-like cells to selective ligands for α7nAChR for 1 h attenuated TNF production for up to 24 h in response to endotoxin. Pharmacological inhibition of adenylyl cyclase (AC) and knockdown of adenylyl cyclase 6 (AC6) or c-FOS abolished cholinergic suppression of endotoxin-induced TNF release. These findings indicate that action potentials in the inflammatory reflex trigger a change in macrophage behavior that requires AC and phosphorylation of the cAMP response element binding protein (CREB). These observations further our mechanistic understanding of neural regulation of inflammation and may have implications for development of bioelectronic medicine treatment of inflammatory diseases.
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http://dx.doi.org/10.3389/fimmu.2018.02648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277584PMC
September 2019

Blood pressure regulation by CD4 lymphocytes expressing choline acetyltransferase.

Nat Biotechnol 2016 Oct 12;34(10):1066-1071. Epub 2016 Sep 12.

Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, USA.

Blood pressure regulation is known to be maintained by a neuro-endocrine circuit, but whether immune cells contribute to blood pressure homeostasis has not been determined. We previously showed that CD4 T lymphocytes that express choline acetyltransferase (ChAT), which catalyzes the synthesis of the vasorelaxant acetylcholine, relay neural signals. Here we show that these CD4CD44CD62L T helper cells by gene expression are a distinct T-cell population defined by ChAT (CD4 T). Mice lacking ChAT expression in CD4 cells have elevated arterial blood pressure, compared to littermate controls. Jurkat T cells overexpressing ChAT (JT) decreased blood pressure when infused into mice. Co-incubation of JT and endothelial cells increased endothelial cell levels of phosphorylated endothelial nitric oxide synthase, and of nitrates and nitrites in conditioned media, indicating increased release of the potent vasorelaxant nitric oxide. The isolation and characterization of CD4 T cells will enable analysis of the role of these cells in hypotension and hypertension, and may suggest novel therapeutic strategies by targeting cell-mediated vasorelaxation.
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http://dx.doi.org/10.1038/nbt.3663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513182PMC
October 2016

Emetine Di-HCl Attenuates Type 1 Diabetes Mellitus in Mice.

Mol Med 2016 Oct 10;22:585-596. Epub 2016 Jun 10.

Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.

Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease characterized by beta cell destruction, insulin deficiency and hyperglycemia. Activated macrophages and autoimmune T cells play a crucial role in the pathogenesis of hyperglycemia in NOD murine diabetes models, but the molecular mechanisms of macrophage activation are unknown. We recently identified pigment epithelium-derived factor (PEDF) as an adipocyte-derived factor that activates macrophages and mediates insulin resistance. Reasoning that PEDF might participate as a proinflammatory mediator in murine diabetes, we measured PEDF levels in NOD mice. PEDF levels are significantly elevated in pancreas, in correlation with pancreatic TNF levels in NOD mice. To identify experimental therapeutics, we screened 2,327 compounds in two chemical libraries (the NIH Clinical Collection and Pharmakon-1600a) for leads that inhibit PEDF mediated TNF release in macrophage cultures. The lead molecule selected, "emetine" is a widely used emetic. It inhibited PEDF-mediated macrophage activation with an EC50 or 146 nM. Administration of emetine to NOD mice and to C57Bl6 mice subjected to streptozotocin significantly attenuated hyperglycemia, reduced TNF levels in pancreas, and attenuated insulitis. Together, these results suggest that targeting PEDF with emetine may attenuate TNF release and hyperglycemia in murine diabetes models. This suggests that further investigation of PEDF and emetine in the pathogenesis of human diabetes is warranted.
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http://dx.doi.org/10.2119/molmed.2016.00082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082289PMC
October 2016

Neuronal Circuits Modulate Antigen Flow Through Lymph Nodes.

Bioelectron Med 2016 20;3:18-28. Epub 2016 Dec 20.

Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.

When pathogens and toxins breech the epithelial barrier, antigens are transported by the lymphatic system to lymph nodes. In previously immunized animals, antigens become trapped in the draining lymph nodes, but the underlying mechanism that controls antigen restriction is poorly understood. Here we describe the role of neurons in sensing and restricting antigen flow in lymph nodes. The antigen keyhole-limpet hemocyanin (KLH) injected into the mouse hind paw flows from the popliteal lymph node to the sciatic lymph node, continuing through the upper lymphatics to reach the systemic circulation. Re-exposure to KLH in previously immunized mice leads to decreased flow from the popliteal to the sciatic lymph node as compared with naïve mice. Administering bupivacaine into the lymph node region restores antigen flow in immunized animals. In contrast, neural activation using magnetic stimulation significantly decreases antigen trafficking in naïve animals as compared with sham controls. Ablating Na1.8 + sensory neurons significantly reduces antigen restriction in immunized mice. Genetic deletion of FcγRI/FcεRI also reverses the antigen restriction. Colocalization of PGP9.5-expressing neurons, FcγRI receptors and labeled antigen occurs at the antigen challenge site. Together, these studies reveal that neuronal circuits modulate antigen trafficking through a pathway that requires Na1.8 and FcγR.
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http://dx.doi.org/10.15424/bioelectronmed.2016.00001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604943PMC
December 2016

Galantamine Attenuates Type 1 Diabetes and Inhibits Anti-Insulin Antibodies in Nonobese Diabetic Mice.

Mol Med 2015 Nov 17;21(1):702-708. Epub 2015 Aug 17.

Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.

Type 1 diabetes in mice is characterized by autoimmune destruction of insulin-producing pancreatic β-cells. Disease pathogenesis involves invasion of pancreatic islets by immune cells, including macrophages and T cells, and production of antibodies to self-antigens, including insulin. Activation of the inflammatory reflex, the neural circuit that inhibits inflammation, culminates on cholinergic receptor signals on immune cells to attenuate cytokine release and inhibit B-cell antibody production. Here, we show that galantamine, a centrally acting acetylcholinesterase inhibitor and an activator of the inflammatory reflex, attenuates murine experimental type 1 diabetes. Administration of galantamine to animals immunized with keyhole limpet hemocyanin (KLH) significantly suppressed splenocyte release of immunoglobulin G (IgG) and interleukin (IL)-4 and IL-6 during KLH challenge . Administration of galantamine beginning at 1 month of age in nonobese diabetic (NOD) mice significantly delayed the onset of hyperglycemia, attenuated immune cell infiltration in pancreatic islets and decreased anti-insulin antibodies in serum. These observations indicate that galantamine attenuates experimental type 1 diabetes in mice and suggest that activation of the inflammatory reflex should be further studied as a potential therapeutic approach.
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http://dx.doi.org/10.2119/molmed.2015.00142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4749496PMC
November 2015

D-lactate increases pulmonary apoptosis by restricting phosphorylation of bad and eNOS in a rat model of hemorrhagic shock.

J Trauma 2004 Aug;57(2):262-69; discussion 269-70

Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA.

Unlabelled: Resuscitation with racemic lactated Ringer's solution (containing equal amounts of D and L isomers of lactate) has been shown to induce pulmonary apoptosis. Substitution of DL-isomer lactate with ketone bodies (beta-hydroxybutyrate, BHB), sodium pyruvate, or L-isomer of lactate decrease this injury without changing the energy status of the tissues or the expression of apoptotic genes. These modified solutions however alter the function of apoptotic proteins through an unknown mechanism. We postulated that DL-LR induces apoptosis by restricting the phosphorylation of key apoptotic proteins.

Methods: Male Sprague Dawley rats (n = 30, 5/group) were subjected to a three stage, volume-controlled hemorrhage and randomized to the following groups. 1) No hemorrhage (Sham); 2) Hemorrhage and no resuscitation (NR); 3) Resuscitation with 3x shed blood volume of racemic LR (DL-LR); 4) Resuscitation with 3x shed blood volume of LR containing only the L-isomer of lactate (L-LR); 5) Resuscitation with 3s shed blood volume of pyruvate Ringer's (PR); 6) Resuscitation with 3s shed blood volume of ketone Ringer's (KR). The modified Ringer's solutions were identical to racemic LR except for equimolar substitution of DL-lactate for L-lactate, pyruvate and BHB respectively. Lung tissue was obtained 2 hours later and subjected to Western Blotting. The levels of Akt, Bad, and eNOS (total and phosphorylated) proteins were measured. Finally, the expression of gene coding for protein 14-3-3 was measured using RT-PCR.

Results: Resuscitation with DL-LR caused a significant (p < 0.05) increase in the total Bad and a decrease in phosphorylated Bad protein expression in the lung. It also caused an increase in the phosphorylated Akt levels and a decrease in gene coding for protein 14-3-3. These changes were consistent with signaling imbalances that favor apoptosis. Modified LR solutions, on the other hand, did not cause these alterations. Phosphorylation pattern of eNOS supported the involvement of PI3K/Akt pathway in this process.

Conclusion: Racemic lactate plays a role in the induction of pulmonary apoptosis by restricting phosphorylation of Bad and eNOS proteins.
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http://dx.doi.org/10.1097/01.ta.0000133841.95455.73DOI Listing
August 2004

Ketone and pyruvate Ringer's solutions decrease pulmonary apoptosis in a rat model of severe hemorrhagic shock and resuscitation.

Surgery 2003 Aug;134(2):267-74

Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.

Background: Resuscitation fluids containing beta-hydroxybutyrate (BHB) have been shown to decrease cellular injury after hemorrhagic shock and resuscitation through an unknown mechanism. We tested whether this effect was related to BHB-induced metabolic modulations.

Methods: Male Sprague Dawley rats (n=30) were subjected to volume-controlled hemorrhage (27 mL/kg during 10 minutes followed by 75 minutes of shock during which another 8 mL/kg of blood was withdrawn). Experimental groups included the following: (1) sham, (2) no resuscitation (NR), (3) racemic lactated Ringer's (DL-LR) solution, (4) LR containing L-isomer only (L-LR), (5) ketone Ringer's solution with lactate substituted by BHB (KR), and (6) pyruvate Ringer's solution with lactate substituted by pyruvate (PR). The resuscitation fluids were infused during 45 minutes simultaneously with additional hemorrhage of 8 mL/kg. Hemodynamic and physiologic parameters and the plasma levels of BHB were serially measured. The animals were killed 2 hours after resuscitation, and tissues were frozen instantaneously for cellular adenylate extraction and adenosine triphosphate (ATP) and adenosine diphosphate analysis. Pulmonary apoptosis was studied using Western blotting, immunohistochemistry, and reverse transcriptase-polymerase chain reaction. Expression of enzymes involved in ketogenesis and ketolysis was analyzed by reverse transcriptase-polymerase chain reaction.

Results: NR and resuscitation with DL-LR increased the expression of apoptotic markers, whereas resuscitation with KR and PR significantly decreased the expression of apoptotic markers in rat lungs. Resuscitation with KR was followed by a profound increase in plasma BHB levels; however, the expression levels of ketolytic enzymes were essentially unaffected. KR infusion did not induce significant improvements in tissue ATP levels.

Conclusions: Resuscitation with KR and PR protects against pulmonary apoptosis without improving tissue ATP content. Therefore, metabolic modulation is unlikely to be the major mechanism by which BHB exerts its protective effects during reperfusion.
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http://dx.doi.org/10.1067/msy.2003.245DOI Listing
August 2003