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Costa WK, do Nascimento MF, Soares Barbosa ÉL, Dos Santos Souza TG, Chagas CA, Napoleão TH, Dos Santos Correia MT, Brayner FA, de Oliveira AM, Vanusa da Silva M. Cytotoxicity, oral toxicity, genotoxicity, and mutagenicity evaluation of essential oil from Psidium glaziovianum Kiaersk leaves. JOURNAL OF ETHNOPHARMACOLOGY 2023; 303:115955. [PMID: 36436714 DOI: 10.1016/j.jep.2022.115955] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 11/07/2022] [Accepted: 11/17/2022] [Indexed: 06/16/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Members of the Psidium genus have been suggested in ethnobotanical research for the treatment of various human diseases, and some studies have already proven their popular uses through research, such as Psidium glaziovianum, which is found in Brazil's northeast and southeast regions and has antinociceptive and anti-inflammatory properties; however, the safety of use has not yet been evaluated. AIM OF THE STUDY This study investigated the safety of using essential oil obtained from P. glaziovianum leaves (PgEO) in vitro and in vivo models. MATERIALS AND METHODS Cytotoxicity was evaluated in murine erythrocytes, while acute toxicity, genotoxicity (comet assay) and mutagenicity (micronucleus test) studies were performed using Swiss albino mice. RESULTS In the cytotoxicity assay, the hemolysis rate indicated a low capacity of PgEO to cause cell lysis (0.33-1.78%). In the acute oral toxicity study, animals treated with up to up to 5000 mg/kg body weight did not observe mortality or physiological changes. Neither dosage caused behavioral problems or death in mice over 14 days. The control and 2,000 mg/kg groups had higher feed intake and body weight than the 5,000 mg/kg PgEO group. Erythrocyte count, hemoglobin level, mean corpuscular volume, and MCV decreased, but serum alanine and aspartate aminotransferases increased. In the genotoxic evaluation, 5000 mg/kg PgEO enhanced nucleated blood cell DI and DF. CONCLUSIONS The present study describes that PgEO can be considered well tolerated in acute exposure at doses up to 2000 mg/kg, however the dose of 5000 mg/kg of PgEO should be used with caution.
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Affiliation(s)
- Wêndeo Kennedy Costa
- Departamento de Bioquímica, Universidade Federal de Pernambuco, Recife, PE, 50670-901, Brazil.
| | | | | | | | - Cristiano Aparecido Chagas
- Centro Acadêmico de Vitória, Universidade Federal de Pernambuco, Vitória de Santo Antão, PE, 55608-680, Brazil
| | | | | | - Fábio André Brayner
- Instituto Aggeu Magalhães, Fundação Oswaldo Cruz, Recife, PE, 50670-420, Brazil
| | | | - Márcia Vanusa da Silva
- Departamento de Bioquímica, Universidade Federal de Pernambuco, Recife, PE, 50670-901, Brazil
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Kanikarla Marie P, Fowlkes NW, Afshar-Kharghan V, Martch SL, Sorokin A, Shen JP, Morris VK, Dasari A, You N, Sood AK, Overman MJ, Kopetz S, Menter DG. The Provocative Roles of Platelets in Liver Disease and Cancer. Front Oncol 2021; 11:643815. [PMID: 34367949 PMCID: PMC8335590 DOI: 10.3389/fonc.2021.643815] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 06/30/2021] [Indexed: 12/12/2022] Open
Abstract
Both platelets and the liver play important roles in the processes of coagulation and innate immunity. Platelet responses at the site of an injury are rapid; their immediate activation and structural changes minimize the loss of blood. The majority of coagulation proteins are produced by the liver—a multifunctional organ that also plays a critical role in many processes: removal of toxins and metabolism of fats, proteins, carbohydrates, and drugs. Chronic inflammation, trauma, or other causes of irreversible damage to the liver can dysregulate these pathways leading to organ and systemic abnormalities. In some cases, platelet-to-lymphocyte ratios can also be a predictor of disease outcome. An example is cirrhosis, which increases the risk of bleeding and prothrombotic events followed by activation of platelets. Along with a triggered coagulation cascade, the platelets increase the risk of pro-thrombotic events and contribute to cancer progression and metastasis. This progression and the resulting tissue destruction is physiologically comparable to a persistent, chronic wound. Various cancers, including colorectal cancer, have been associated with increased thrombocytosis, platelet activation, platelet-storage granule release, and thrombosis; anti-platelet agents can reduce cancer risk and progression. However, in cancer patients with pre-existing liver disease who are undergoing chemotherapy, the risk of thrombotic events becomes challenging to manage due to their inherent risk for bleeding. Chemotherapy, also known to induce damage to the liver, further increases the frequency of thrombotic events. Depending on individual patient risks, these factors acting together can disrupt the fragile balance between pro- and anti-coagulant processes, heightening liver thrombogenesis, and possibly providing a niche for circulating tumor cells to adhere to—thus promoting both liver metastasis and cancer-cell survival following treatment (that is, with minimal residual disease in the liver).
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Affiliation(s)
- Preeti Kanikarla Marie
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Natalie W Fowlkes
- Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Vahid Afshar-Kharghan
- Division of Internal Medicine, Benign Hematology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Stephanie L Martch
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Alexey Sorokin
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - John Paul Shen
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Van K Morris
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Arvind Dasari
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Nancy You
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Anil K Sood
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Michael J Overman
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - David George Menter
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
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Sanz-García C, Fernández-Iglesias A, Gracia-Sancho J, Arráez-Aybar LA, Nevzorova YA, Cubero FJ. The Space of Disse: The Liver Hub in Health and Disease. LIVERS 2021; 1:3-26. [DOI: 10.3390/livers1010002] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Since it was first described by the German anatomist and histologist, Joseph Hugo Vincenz Disse, the structure and functions of the space of Disse, a thin perisinusoidal area between the endothelial cells and hepatocytes filled with blood plasma, have acquired great importance in liver disease. The space of Disse is home for the hepatic stellate cells (HSCs), the major fibrogenic players in the liver. Quiescent HSCs (qHSCs) store vitamin A, and upon activation they lose their retinol reservoir and become activated. Activated HSCs (aHSCs) are responsible for secretion of extracellular matrix (ECM) into the space of Disse. This early event in hepatic injury is accompanied by loss of the pores—known as fenestrations—of the endothelial cells, triggering loss of balance between the blood flow and the hepatocyte, and underlies the link between fibrosis and organ dysfunction. If the imbalance persists, the expansion of the fibrotic scar followed by the vascularized septae leads to cirrhosis and/or end-stage hepatocellular carcinoma (HCC). Thus, researchers have been focused on finding therapeutic targets that reduce fibrosis. The space of Disse provides the perfect microenvironment for the stem cells niche in the liver and the interchange of nutrients between cells. In the present review article, we focused on the space of Disse, its components and its leading role in liver disease development.
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Affiliation(s)
- Carlos Sanz-García
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain
| | - Anabel Fernández-Iglesias
- Liver Vascular Biology Research Group, IDIBAPS, 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain
| | - Jordi Gracia-Sancho
- Liver Vascular Biology Research Group, IDIBAPS, 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain
- Hepatology, Department of Biomedical Research, University of Bern, 3012 Bern, Switzerland
| | - Luis Alfonso Arráez-Aybar
- Department of Anatomy and Embriology, Complutense University School of Medicine, 28040 Madrid, Spain
| | - Yulia A. Nevzorova
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain
- Department of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany
- 12 de Octubre Health Research Institute (imas12), 28040 Madrid, Spain
| | - Francisco Javier Cubero
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain
- 12 de Octubre Health Research Institute (imas12), 28040 Madrid, Spain
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Sorski L, Shaashua L, Melamed R, Matzner P, Ben-Eliyahu S. Selective Harvesting of Marginating-hepatic Leukocytes. J Vis Exp 2016. [PMID: 27500423 DOI: 10.3791/53918] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Marginating-hepatic (MH) leukocytes (leukocytes adhering to the sinusoids of the liver), were shown to exhibit unique composition and characteristics compared to leukocytes of other immune compartments. Specifically, evidence suggests a distinct pro- and anti-inflammatory profile of the MH-leukocyte population and higher cytotoxicity of liver-specific NK cells (namely, pit cells) compared to circulating or splenic immunocytes in both mice and rats. The method presented herein enables selective harvesting of MH leukocytes by forced perfusion of the liver in mice and rats. In contrast to other methods used to extract liver-leukocytes, including tissue grinding and biological degradation, this method exclusively yields leukocytes from the liver sinusoids, uncontaminated by cells from other liver compartments. In addition, the perfusion technique better preserves the integrity and the physiological milieu of MH leukocytes, sparing known physiological responses to tissue processing. As many circulating malignant cells and infected cells are detained while passing through the liver sinusoids, physically interacting with endothelial cells and resident leukocytes, the unique MH leukocyte population is strategically located to interact, identify, and react towards aberrant circulating cells. Thus, selective harvesting of MH-leukocytes and their study under various conditions may advance our understanding of the biological and clinical significance of MH leukocytes, specifically with respect to circulating aberrant cells and liver-related diseases and cancer metastases.
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Affiliation(s)
- Liat Sorski
- Sagol School of Neuroscience & School of Psychological Sciences, Tel-Aviv University
| | - Lee Shaashua
- Sagol School of Neuroscience & School of Psychological Sciences, Tel-Aviv University
| | - Rivka Melamed
- Sagol School of Neuroscience & School of Psychological Sciences, Tel-Aviv University
| | - Pini Matzner
- Sagol School of Neuroscience & School of Psychological Sciences, Tel-Aviv University
| | - Shamgar Ben-Eliyahu
- Sagol School of Neuroscience & School of Psychological Sciences, Tel-Aviv University;
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The marginating-pulmonary immune compartment in mice exhibits increased NK cytotoxicity and unique cellular characteristics. Immunol Res 2014; 58:28-39. [PMID: 24132552 DOI: 10.1007/s12026-013-8435-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
To test whether marginating-pulmonary (MP) leukocytes in mice have a unique potential to identify and destroy aberrant circulating cells, we compared MP to circulating leukocytes with respect to natural killer (NK) cytotoxicity, proinflammatory characteristics, molecular determinants of activation, and response to IL-12 immunostimulation. Cytotoxicity was assessed employing the YAC-1, B16F10, and 3LL target lines. C57BL/6 mice were injected with either saline or murine IL-12 (0.1 or 0.5 µg/mouse), either once or three times 48-h apart. Twenty-four hours after last injection, cardiac blood was withdrawn and MP leukocytes were collected by forced lung perfusion. NK cytotoxicity, cellular composition, and surface molecular markers were studied. MP leukocytes exhibited greater NK cytotoxicity than circulating leukocytes against the syngeneic B16F10 and 3LL tumor lines, but not against the allogeneic YAC-1 line. NKG2D and IL-12 receptor expression predicted NK cytotoxicity in circulating leukocytes, but not in MP leukocytes. IFNγ-receptor, IL-12-receptor, CD69, CD11a, and CD11b showed different patterns of expression in the two leukocyte populations, suggesting pro-inflammatory characteristics of the MP compartment. IL-12 stimulation caused differential effects on these markers and also elevated cytotoxicity in both compartments, but in different effector: target ratio-dependent patterns. MP leukocytes may play a critical role in eliminating aberrant circulating cells due to their enhanced NK cytotoxicity and given their strategic location in the lungs vasculature, which forces physical interactions with all circulating aberrant cells. MP-NK cells are unique in their cytotoxic mechanisms against syngeneic targets and in their activation profile and response to immunostimulatory agents.
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Hosoya S, Ikejima K, Takeda K, Arai K, Ishikawa S, Yamagata H, Aoyama T, Kon K, Yamashina S, Watanabe S. Innate immune responses involving natural killer and natural killer T cells promote liver regeneration after partial hepatectomy in mice. Am J Physiol Gastrointest Liver Physiol 2013; 304:G293-G299. [PMID: 23086918 DOI: 10.1152/ajpgi.00083.2012] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
To clarify the roles of innate immune cells in liver regeneration, here, we investigated the alteration in regenerative responses after partial hepatectomy (PH) under selective depletion of natural killer (NK) and/or NKT cells. Male, wild-type (WT; C57Bl/6), and CD1d-knockout (KO) mice were injected with anti-NK1.1 or anti-asialo ganglio-N-tetraosylceramide (GM1) antibody and then underwent the 70% PH. Regenerative responses after PH were evaluated, and hepatic expression levels of cytokines and growth factors were measured by real-time RT-PCR and ELISA. Phosphorylation of STAT3 was detected by Western blotting. Depletion of both NK and NKT cells with an anti-NK1.1 antibody in WT mice caused drastic decreases in bromodeoxyuridine uptake, expression of proliferating cell nuclear antigen, and cyclin D1, 48 h after PH. In mice given NK1.1 antibody, increases in hepatic TNF-α, IL-6/phospho-STAT3, and hepatocyte growth factor (HGF) levels following PH were also blunted significantly, whereas IFN-γ mRNA levels were not different. CD1d-KO mice per se showed normal liver regeneration; however, pretreatment with an antiasialo GM1 antibody to CD1d-KO mice, resulting in depletion of both NK and NKT cells, also blunted regenerative responses. Collectively, these observations clearly indicated that depletion of both NK and NKT cells by two different ways results in impaired liver regeneration. NK and NKT cells most likely upregulate TNF-α, IL-6/STAT3, and HGF in a coordinate fashion, thus promoting normal regenerative responses in the liver.
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MESH Headings
- Animals
- Antibodies, Blocking/pharmacology
- Antigens, CD1d/genetics
- Antigens, CD1d/immunology
- Antigens, Ly/immunology
- Blotting, Western
- Cells, Cultured
- Enzyme-Linked Immunosorbent Assay
- G(M1) Ganglioside/immunology
- Hepatectomy
- Immunity, Innate/drug effects
- Immunity, Innate/physiology
- Immunohistochemistry
- Killer Cells, Natural/drug effects
- Killer Cells, Natural/immunology
- Killer Cells, Natural/physiology
- Liver Regeneration/physiology
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- NK Cell Lectin-Like Receptor Subfamily B/immunology
- Natural Killer T-Cells/drug effects
- Natural Killer T-Cells/immunology
- Natural Killer T-Cells/physiology
- Rats
- Real-Time Polymerase Chain Reaction
- STAT3 Transcription Factor/metabolism
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Affiliation(s)
- Satoko Hosoya
- Dept. of Gastroenterology, Juntendo University Graduate School of Medicine, Tokyo, Japan
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7
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Mazzolini G, Ochoa MC, Morales-Kastresana A, Sanmamed MF, Melero I. The liver, liver metastasis and liver cancer: a special case for immunotherapy with cytokines and immunostimulatory monoclonal antibodies. Immunotherapy 2012. [DOI: 10.2217/imt.12.99] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Affiliation(s)
- Guillermo Mazzolini
- Gene Therapy Laboratory, Universidad Austral, Avda. Presidente Perón, 1500, B1629ODT Buenos Aires, Argentina
| | - María C Ochoa
- Center for Applied Medical Research, University of Navarra, Avda. Pio XII, 55, 31008 Pamplona, Spain
| | - Aizea Morales-Kastresana
- Center for Applied Medical Research, University of Navarra, Avda. Pio XII, 55, 31008 Pamplona, Spain
| | - Miguel F Sanmamed
- Department of Oncology, Clínica Universidad de Navarra, 31008 Pamplona, Spain
| | - Ignacio Melero
- Center for Applied Medical Research, University of Navarra, Avda. Pio XII, 55, 31008 Pamplona, Spain and Department of Oncology, Clínica Universidad de Navarra, 31008 Pamplona, Spain
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8
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Lv LH, Yu JD, Li GL, Long TZ, Zhang W, Chen YJ, Min J, Wan YL. Functional distinction of rat liver natural killer cells from spleen natural killer cells under normal and acidic conditions in vitro. Hepatobiliary Pancreat Dis Int 2012; 11:285-93. [PMID: 22672823 DOI: 10.1016/s1499-3872(12)60162-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND The microenvironment within solid tumors has often been shown to exhibit an acidic extracellular pH. Although the morphologic and functional differences in natural killer (NK) cells of the liver and spleen have been reported previously under physiological conditions, the difference under acidic conditions is still unclear. This study was to investigate the differences in the morphological and functional characteristics between rat liver and spleen NK cells under normal and acidic conditions in vitro. METHODS Liver and spleen NK cells were isolated and purified from Sprague-Dawley rats by density gradient centrifugation and the Dynabeads(®) FlowComp(TM) Flexi system, and stimulated for 4 days with or without IL-2 or treated with low pH or control for different times. Morphology was examined by scanning electron microscopy (SEM) and transmission electron microscopy (TEM), cell death and proliferation assays were performed by flow cytometry, IFN-gamma production was tested by ELISA, and cytotoxic activity was evaluated by lactate dehydrogenase (LDH) release assay. RESULTS Liver NK cells had significantly higher levels of cytotoxic activity than spleen NK cells under normal and acidic conditions, and the maximum difference was observed at pH 5.6. Further analysis revealed that the cytotoxic activity of NK cells was correlated with morphology, cell death, proliferative activity and IFN-gamma production. By TEM, liver NK cells contained a greater number of electron-dense granules per cell at pH 5.6. Moreover, a modest elevation of cell death and reduction of proliferation of liver NK cells occurred within a range of 5.6-7.2. Interestingly, an acidic extracellular pH only marginally, and not significantly, suppressed IFN-gamma production by liver NK cells. CONCLUSION The sharp morphological and functional differences shown by the two types of NK cells in vitro indicate that liver NK cells are unexpectedly resistant to pH shock.
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Affiliation(s)
- Li-Hong Lv
- Department of Hepatobiliary Surgery, Sun Yat-Sen University, Guangzhou, China
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9
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Cecal Ligation and Puncture Sepsis Is Associated with Attenuated Expression of Adenylyl Cyclase 9 and Increased Mir142-3p. Shock 2011; 36:390-5. [DOI: 10.1097/shk.0b013e318228ec6f] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Abstract
Emerging evidence suggests a strong interaction between the gut microbiota and health and disease. The interactions of the gut microbiota and the liver have only recently been investigated in detail. Receiving approximately 70% of its blood supply from the intestinal venous outflow, the liver represents the first line of defense against gut-derived antigens and is equipped with a broad array of immune cells (i.e., macrophages, lymphocytes, natural killer cells, and dendritic cells) to accomplish this function. In the setting of tissue injury, whereby the liver is otherwise damaged (e.g., viral infection, toxin exposure, ischemic tissue damage, etc.), these same immune cell populations and their interactions with the infiltrating gut bacteria likely contribute to and promote these pathologies. The following paper will highlight recent studies investigating the relationship between the gut microbiota, liver biology, and pathobiology. Defining these connections will likely provide new targets for therapy or prevention of a wide variety of acute and chronic liver pathologies.
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12
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The marginating-pulmonary immune compartment in rats: characteristics of continuous inflammation and activated NK cells. J Immunother 2010; 33:16-29. [PMID: 19952959 DOI: 10.1097/cji.0b013e3181b0b146] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
A significant role has been indicated for cellular immunity in controlling circulating cancer cells, but most autologous tumor cells seem resistant, in vitro, to natural killer cell (NKC) and cytotoxic T lymphocytes cytotoxicity. Addressing this apparent contradiction, we recently identified a unique leukocyte population, marginating-pulmonary (MP)-leukocytes, which exhibit potent natural killer (NK) cytotoxicity. Here, we characterize the MP-compartment in naive and immunostimulated rats, and assessed its cytotoxicity against "NK-resistant" tumors cells. Animals were treated with poly I-C (3x0.2 mg/kg) or saline, and circulating-leukocytes and MP-leukocytes were collected and analyzed in terms of cellular composition, cellular activation markers, and NK cytotoxicity of leukocytes and purified NKCs. Compared with circulating-leukocytes, MP-leukocytes showed greater proportion of granulocytes, monocytes, NKCs, and large NKCs; higher expression of activation and adhesion markers (CD25, CD11a, CD11b, and NKR-P1, IFN-gamma); and elevated NK cytotoxicity of leukocytes and purified NKCs against several syngeneic and xenogeneic NK-resistant target cells (from both F344 and BDX inbred rats). In immunostimulated animals (treated with poly I-C), but not in naive animals, purified NKCs from the MP-compartment showed markedly superior cytotoxicity, suggesting that poly I-C immunostimulation uniquely affect MP-NKCs, and that in naive animals other MP-leukocytes support NK cytotoxicity. Overall, the results suggest that the MP-compartment is characterized by a continuous activated inflammatory microenvironment uniquely affected by immunostimulation. If similarly potent MP-NKCs exist in patients, then circulating autologous tumor cells that are considered "NK-resistant" could actually be controlled by MP-NKCs. Innate immunity may assume greater role in controlling malignant spread, especially after immunostimulation.
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13
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Gao B, Radaeva S, Park O. Liver natural killer and natural killer T cells: immunobiology and emerging roles in liver diseases. J Leukoc Biol 2009; 86:513-28. [PMID: 19542050 DOI: 10.1189/jlb.0309135] [Citation(s) in RCA: 293] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Hepatic lymphocytes are enriched in NK and NKT cells that play important roles in antiviral and antitumor defenses and in the pathogenesis of chronic liver disease. In this review, we discuss the differential distribution of NK and NKT cells in mouse, rat, and human livers, the ultrastructural similarities and differences between liver NK and NKT cells, and the regulation of liver NK and NKT cells in a variety of murine liver injury models. We also summarize recent findings about the role of NK and NKT cells in liver injury, fibrosis, and repair. In general, NK and NKT cells accelerate liver injury by producing proinflammatory cytokines and killing hepatocytes. NK cells inhibit liver fibrosis via killing early-activated and senescent-activated stellate cells and producing IFN-gamma. In regulating liver fibrosis, NKT cells appear to be less important than NK cells as a result of hepatic NKT cell tolerance. NK cells inhibit liver regeneration by producing IFN-gamma and killing hepatocytes; however, the role of NK cells on the proliferation of liver progenitor cells and the role of NKT cells in liver regeneration have been controversial. The emerging roles of NK/NKT cells in chronic human liver disease will also be discussed.Understanding the role of NK and NKT cells in the pathogenesis of chronic liver disease may help us design better therapies to treat patients with this disease.
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Affiliation(s)
- Bin Gao
- Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892, USA.
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14
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Le Couteur DG, Warren A, Cogger VC, Smedsrød B, Sørensen KK, De Cabo R, Fraser R, McCuskey RS. Old age and the hepatic sinusoid. Anat Rec (Hoboken) 2008; 291:672-83. [PMID: 18484614 DOI: 10.1002/ar.20661] [Citation(s) in RCA: 112] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Morphological changes in the hepatic sinusoid with old age are increasingly recognized. These include thickening and defenestration of the liver sinusoidal endothelial cell, sporadic deposition of collagen and basal lamina in the extracellular space of Disse, and increased numbers of fat engorged, nonactivated stellate cells. In addition, there is endothelial up-regulation of von Willebrand factor and ICAM-1 with reduced expression of caveolin-1. These changes have been termed age-related pseudocapillarization. The effects of old age on Kupffer cells are inconsistent, but impaired responsiveness is likely. There are functional implications of these aging changes in the hepatic sinusoid. There is reduced sinusoidal perfusion, which will impair the hepatic clearance of highly extracted substrates. Blood clearance of a variety of waste macromolecules takes place in liver sinusoidal endothelial cells (LSECs). Previous studies indicated either that aging had no effect, or reduced the endocytic capacity of LSECs. However, a recent study in mice showed reduced endocytosis in pericentral regions of the liver lobules. Reduced endocytosis may increase systemic exposure to potential harmful waste macromolecules such as advanced glycation end products Loss of fenestrations leads to impaired transfer of lipoproteins from blood to hepatocytes. This provides a mechanism for impaired chylomicron remnant clearance and postprandial hyperlipidemia associated with old age. Given the extensive range of substrates metabolized by the liver, age-related changes in the hepatic sinusoid and microcirculation have important systemic implications for aging and age-related diseases.
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Affiliation(s)
- David G Le Couteur
- Centre for Education and Research on Ageing, University of Sydney and Concord RG Hospital, Sydney, NSW, Australia.
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Abstract
Tle liver has a number of important functions in innate and adaptive immunity. Contributions to the innate (nonspecific) immune system include production of acute phase proteins, nonspecific phagocytosis of particles, nonspecific pinocytosis of molecules, and nonspecific cell killing. Hepatic involvement in innate immunity contributes to the systemic response to local inflammation, clearance of particles and soluble molecules from the circulation, and killing of invading cells such as neoplastic cells. Liver involvement in the adaptive (specific) immune system includes deletion of activated T cells, induction of tolerance to ingested and self-antigens, extrathymic proliferation of T cells, and deletion of many of the signaling and effector molecules. Hepatic involvement in adaptive immunity allows clearance of activated T cells and signaling molecules following inflammatory reactions, and promotes immunologic tolerance toward potentially antigenic proteins that are absorbed from the intestinal tract. The liver is a major site of extrathymic T cell development, which assumes increasing significance with aging in mammals. Perturbations in hepatic structure or function can result in significant ramifications in both the innate and adaptive immune systems.
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Ramadori G, Saile B. Inflammation, damage repair, immune cells, and liver fibrosis: specific or nonspecific, this is the question. Gastroenterology 2004; 127:997-1000. [PMID: 15362057 DOI: 10.1053/j.gastro.2004.07.041] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Vermijlen D, Luo D, Froelich CJ, Medema JP, Kummer JA, Willems E, Braet F, Wisse E. Pit cells exclusively kill P815 tumor cells by the perforin/granzyme pathway. COMPARATIVE HEPATOLOGY 2004; 3 Suppl 1:S58. [PMID: 14960210 PMCID: PMC2410270 DOI: 10.1186/1476-5926-2-s1-s58] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Affiliation(s)
- David Vermijlen
- Laboratory for Cell Biology and Histology, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium
| | - Dianzhong Luo
- Laboratory for Cell Biology and Histology, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium
| | | | - Jan P Medema
- Department of Immunohematology and Bloodtransfusion, Leiden University Medical Center, Leiden, The Netherlands
| | - Jean A Kummer
- Institute for Biochemistry, BIL Biomedical Research Center, University of Lausanne, Epilanges, Switzerland
| | - Erik Willems
- Laboratory for Cell Biology and Histology, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium
| | - Filip Braet
- Laboratory for Cell Biology and Histology, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium
- Present address: Department for Molecular Biomedical Research, Molecular Cell Biology Unit, Ghent University (UGhent), Technologiepark 927, 9052 Zwijnaarde, Belgium
| | - Eddie Wisse
- Laboratory for Cell Biology and Histology, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium
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Lai YC, Shih CY, Jeng CM, Yang SS, Hu JT, Sung YC, Liu HT, Hou SM, Wu CH, Chen TK. Hepatic arterial infusion chemotherapy for hepatocellular carcinoma with tumor thrombosis of the portal vein tumor thrombosis. World J Gastroenterol 2003; 9:2666-70. [PMID: 14669309 PMCID: PMC4612028 DOI: 10.3748/wjg.v9.i12.2666] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) is associated with poor prognosis. The aim of this prospective study was to evaluate the efficacy of hepatic arterial infusion chemotherapy (HAIC) for patients with this disease.
METHODS: Eighteen HCC patients with PVTT were treated with HAIC via a subcutaneously implanted injection port. A course of chemotherapy consisted of daily cisplatin (10 mg for one hour) followed by 5-fluorouracil (250 mg for five hours) for five continuous days within a given week. The patients were scheduled to receive four consecutive courses of HAIC. Responders were defined in whom either a complete or partial response was achieved, while non-responders were defined based on stable or progressive disease status. The prognostic factors associated with survival after treatment were analyzed.
RESULTS: Six patients exhibited partial response to this form of HAIC (response rate = 33%). The 3, 6, 9, 12 and 18-month cumulative survival rates for the 18 patients were 83%, 72%, 50%, 28%, and 7%, respectively. Median survival times for the six responders and 12 non-responders were 15.0 (range, 11-18) and 7.5 (range, 1-13) months, respectively. It was demonstrated by both univariate and multivariate analyses that the therapeutic response and hepatic reserve function were significant prognostic factors.
CONCLUSION: HAIC using low-dose cisplatin and 5-fluorouracil may be a useful alternative for the treatment of patients with advanced HCC complicated with PVTT. There may also be survival-related benefits associated with HAIC.
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Affiliation(s)
- Yung-Chih Lai
- Department of Internal Medicine, Cathay General Hospital, Taipei, Taiwan, China.
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Panigrahi S, Yacovlev E, Gelfand Y, Schuger L, Slavin S, Morecki S. Intraportal and systemic allogeneic cell therapy in a murine model of hepatic metastatic breast cancer. CYTOKINES, CELLULAR & MOLECULAR THERAPY 2003; 7:99-106. [PMID: 12850809 DOI: 10.1080/13684730310001661] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Allogeneic immunocompetent splenocytes were tested for their ability to exert a GVT effect in a murine model of liver metastasis. Mammary carcinoma cells originating from an H-2(d) mouse were inoculated through the PV of F(1) (H-2(d/b)) mice, to mimic clinical hepatic involvement in malignant disease. Cell therapy was given either locally (PV) or systemically by IV inoculation to test differential efficacy of the GVT effect, and the differential expression of GVHD symptoms induced by diverse routes of administration. Livers of mice treated with H-2(b) derived splenocytes given PV or IV remained tumor-free for at least 4 weeks following tumor inoculation. Furthermore, all secondary recipients of adoptively transferred (AT) liver cells were tumor-free for >300 days. In contrast, all livers of untreated control mice or mice treated with syngeneic splenocytes displayed tumor metastases as early as 2 weeks following tumor inoculation, and large local tumors developed in AT secondary recipients. Our data demonstrate the efficacy of allogeneic cell therapy, given either locally or systemically, in the eradication of liver metastases. However, diverse routes of cell therapy administration did not show any difference in the expression and outcome of GVHD.
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Affiliation(s)
- Soumya Panigrahi
- Department of Bone Marrow Transplantation, The Cancer Immunotherapy and Immunobiology Research Center, Hadassah University Hospital Jerusalem
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20
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Vermijlen D, Timmers M, Wisse E. Comments on augmentation of local antitumor immunity in liver by interleukin-2 gene transfer via portal vein: a possible explanation for contradictory in vivo and vitro results of interleukin-2 treatment in a rat model of colon carcinoma metastasis. Cancer Gene Ther 2003; 10:432-3. [PMID: 12719713 DOI: 10.1038/sj.cgt.7700582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Luo D, Vermijlen D, Kuppen PJK, Wisse E. MHC class I expression protects rat colon carcinoma cells from hepatic natural killer cell-mediated apoptosis and cytolysis, by blocking the perforin/granzyme pathway. COMPARATIVE HEPATOLOGY 2002; 1:2. [PMID: 12495445 PMCID: PMC149428 DOI: 10.1186/1476-5926-1-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/28/2002] [Accepted: 11/20/2002] [Indexed: 01/28/2023]
Abstract
BACKGROUND: Hepatic natural killer (NK) cells, the most cytotoxic cells of the natural occurring NK cells, are located in the liver sinusoids and are thus in a strategic position to kill arriving metastasising tumour cells, like colon carcinoma cells. It is known that major histocompatibility complex (MHC) class I on tumour cells negatively regulates NK cell-mediated cytolysis, but this is found using blood- or spleen-derived NK cells. Therefore, using isolated rat hepatic NK cells and the syngeneic colon carcinoma cell line CC531s, we investigated whether this protective role of MHC class I is also operative in hepatic NK cells, and addressed the mechanism of MHC class I protection. RESULTS: When MHC class I on CC531s cells was masked by preincubation with monoclonal antibody OX18, hepatic NK cell-mediated cytolysis (51Cr release) as well as apoptosis (DNA fragmentation, nucleus condensation and fragmentation) increased. When hepatic NK cells were preincubated with the granzyme inhibitor 3,4-dichloroisocoumarin, or when extracellular Ca2+ was chelated by ethylene glycol-bis(beta-aminoethyl ether)-N, N-tetraacetic acid, the enhanced cytolysis and apoptosis were completely inhibited. The involvement of the perforin/granzyme pathway was confirmed by showing that the enhanced cytolysis was caspase-independent. CONCLUSIONS: MHC class I expression protects CC531s colon carcinoma cells from hepatic NK cell-mediated apoptosis and cytolysis, by blocking the perforin/granzyme pathway.
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Affiliation(s)
- Dianzhong Luo
- Laboratory for Cell Biology and Histology, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium.
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22
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Vermijlen D, Luo D, Froelich CJ, Medema JP, Kummer JA, Willems E, Braet F, Wisse E. Hepatic natural killer cells exclusively kill splenic/blood natural killer‐resistant tumor cells by the perforin/granzyme pathway. J Leukoc Biol 2002. [DOI: 10.1189/jlb.72.4.668] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Affiliation(s)
- David Vermijlen
- Laboratory for Cell Biology and Histology, Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Dianzhong Luo
- Laboratory for Cell Biology and Histology, Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | | | - Jan Paul Medema
- Department of Immunohematology and Bloodtransfusion, Leiden University Medical Center, The Netherlands; and
| | - Jean Alain Kummer
- Institute for Biochemistry, BIL Biomedical Research Center, University of Lausanne, Epilanges, Switzerland
| | - Erik Willems
- Laboratory for Cell Biology and Histology, Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Filip Braet
- Laboratory for Cell Biology and Histology, Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Eddie Wisse
- Laboratory for Cell Biology and Histology, Vrije Universiteit Brussel (VUB), Brussels, Belgium
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Vermijlen D, Luo D, Kruhøffer M, ØRntoft TF, Kuppen PJK, Wisse E. Is the presence of interleukin-2 receptor alpha in the serum of colorectal liver metastases patients derived from hepatic natural killer cells? Cancer Immunol Immunother 2002; 51:291-2. [PMID: 12070716 PMCID: PMC11032833 DOI: 10.1007/s00262-002-0289-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2002] [Accepted: 03/14/2002] [Indexed: 11/24/2022]
Affiliation(s)
- David Vermijlen
- Laboratory for Cell Biology and Histology, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium.
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Affiliation(s)
- M Bishr Omary
- Department of Medicine, VA Palo Alto Health Care System, Palo Alto, CA 94304, USA
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Matthews AE, Weiss SR, Shlomchik MJ, Hannum LG, Gombold JL, Paterson Y. Antibody is required for clearance of infectious murine hepatitis virus A59 from the central nervous system, but not the liver. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2001; 167:5254-63. [PMID: 11673540 DOI: 10.4049/jimmunol.167.9.5254] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Intracerebral inoculation with mouse hepatitis virus strain A59 results in viral replication in the CNS and liver. To investigate whether B cells are important for controlling mouse hepatitis virus strain A59 infection, we infected muMT mice who lack membrane-bound IgM and therefore mature B lymphocytes. Infectious virus peaked and was cleared from the livers of muMT and wild-type mice. However, while virus was cleared from the CNS of wild-type mice, virus persisted in the CNS of muMT mice. To determine how B cells mediate viral clearance, we first assessed CD4(+) T cell activation in the absence of B cells as APC. CD4(+) T cells express wild-type levels of CD69 after infection in muMT mice. IFN-gamma production in response to viral Ag in muMT mice was also normal during acute infection, but was decreased 31 days postinfection compared with that in wild-type mice. The role of Ab in viral clearance was also assessed. In wild-type mice plasma cells appeared in the CNS around the time that virus is cleared. The muMT mice that received A59-specific Ab had decreased virus, while mice with B cells deficient in Ab secretion did not clear virus from the CNS. Viral persistence was not detected in FcR or complement knockout mice. These data suggest that clearance of infectious mouse hepatitis virus strain A59 from the CNS requires Ab production and perhaps B cell support of T cells; however, virus is cleared from the liver without the involvement of Abs or B cells.
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Affiliation(s)
- A E Matthews
- Microbiology Department, University of Pennsylvania, Philadelphia, PA, 19104, USA
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26
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Kikkawa H, Tsukada H, Oku N. Usefulness of positron emission tomographic visualization for examination of in vivo susceptibility to metastasis. Cancer 2000; 89:1626-33. [PMID: 11013379 DOI: 10.1002/1097-0142(20001001)89:7<1626::aid-cncr28>3.0.co;2-t] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Immune surveillance may play a role in protecting against the establishment of metastasis. The authors previously observed that the injection of as few as 10(4) lung metastatic B16BL6 melanoma cells/0.2 mL resulted in no metastasis and in a reduced rate of cell accumulation in the lung, the target organ. In the current study, the authors examined the correlation between metastatic potential and tumor cell trafficking by using a liver-metastatic model. METHODS The liver-metastatic potential of RAW117-H10 cells was examined by varying the number of cells injected into mice through the portal vein. To investigate the trafficking of the cells, the authors performed positron emission tomography (PET) analysis, because advances in this technology now enable the use of PET to investigate the real-time trafficking of as few as 10(4) cells/0.2 mL. Furthermore, to clarify the role of the immune defense system, metastatic potential and cell trafficking also were examined by using macrophage-depleted mice. RESULTS When 10(6) or 10(5) RAW117-H10 cells/0.2 mL were injected into mice, both quantities of cells caused liver metastasis, cells accumulated in the liver at a similar rate, and there was an approximately 10-fold difference in the number of accumulated cells between the two doses. However, the injection of 10(4) cells/0.2 mL did not produce metastasis, and the accumulation rate in the liver was less than one-tenth of that after the injection of 10(5) cells/0.2 mL. The treatment of mice with 2-chloroadenosine for depleting macrophages prior to the injection of 10(4) cells/0.2 mL resulted in the suppression of the fast elimination of the cells from the liver. Corresponding to this change in PET images, the injection of 10(4) cells/0.2 mL into 2-chloroadenosine-pretreated mice resulted in metastasis. CONCLUSIONS The current study suggests that immune surveillance suppresses accumulation of tumor cells to the target and suppresses metastasis, and this effect is obvious when small numbers of tumor cells are used for the challenge. Furthermore, the immune defense system plays a role in the early stage of the metastatic process.
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Affiliation(s)
- H Kikkawa
- Department of Radiobiochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
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Luo DZ, Vermijlen D, Ahishali BL, Triantis V, Vanderkerken K, Kuppen PJKK, Wisse E. Participation of CD45, NKR-P1A and ANK61 antigen in rat hepatic NK cell (pit cell)-mediated target cell cytotoxicity. World J Gastroenterol 2000; 6:546-552. [PMID: 11819644 PMCID: PMC4723554 DOI: 10.3748/wjg.v6.i4.546] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Several triggering receptors have been described to be involved in natural killer (NK) cell-mediated target cytotoxicity. In these studies, NK cells derive d from blood or spleen were used. Pit cells are liver-specific NK cells that possess a higher level of natural cytotoxicity and a different morphology when com pared to blood NK cells. The aim of this study was to characterize the role of t he NK-triggeringmoleculesNKR-P1A,ANK61antigen,and CD45 in pit cell-media ted killing of target cells.
METHODS: 51Cr-release and DNA fragmentation were used to quantify target cell lysis and apoptosis, respectively.
RESULTS: Flow cytometric analysis showed that pit cells expressed CD45, NK R-P1A, and ANK61 antigen. Treatment of pit cells with monoclonal antibody (mAb) to CD45 (ANK74) not only inhibited CC531s or YAC-1 target lysis but also apopto sis induced by pit cells. The mAbs to NKR-P1A (3.2.3) and ANK61 antigen (ANK61) had no effect on pit cell-mediated CC531s or YAC-1 target cytolysis or apoptosis, while they did increase the Fcγ receptor positive (Fcγ R+) P815 cytolysis and apoptosis. This enhanced cytotoxicity could be inhibited by 3,4-dichloroi socoumarin, an inhibitor of granzymes.
CONCLUSION: These results indicate that CD45 participates in pit cell-med iated CC531s and YAC-1 target cytolysis and apoptosis. NKR-P1A and ANK61 antig en on pit cells function as activation structures against Fcγ R+ P 815 cells, which was mediated by the perforin/granzyme pathway.
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Gavelli A, Baqué P, Mala M, Saint-Paul MC, Staccini P, Brossette N, Chazal M, Milano G, Gugenheim J, Benchimol D, Bourgeon A, Huguet C, Rossi B, Pierrefite-Carle V. [Vaccination by suicide gene therapy against a model of hepatic metastasis from colon cancer in the rat]. ANNALES DE CHIRURGIE 2000; 125:552-9. [PMID: 10986767 DOI: 10.1016/s0003-3944(00)00240-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
UNLABELLED Suicide gene therapy consists of transferring into tumor cells a viral or bacterial gene encoding for an enzyme which converts a non-toxic product into a lethal drug. STUDY AIM To analyze the therapeutic potential of vaccination with tumor cells expressing the bacterial cytosine deaminase (CD) gene and 5-fluorocytosine (5-FC) treatment in a rat liver metastasis model. MATERIAL AND METHOD We used a rat colon carcinoma cell line which, after subcapsular or intraportal injection in syngenic animals, generates single or multiple experimental liver metastases, respectively. We have shown that introduction of a vector expressing the CD gene in this colon carcinoma cell line results in 5-FC sensitivity (PRObCD). RESULTS Intrahepatic subcapsular injection of PRObCD tumor cells, followed by 5-FC treatment, induces total regression of a wild-type tumor pre-established in the contralateral liver lobe in 45% of animals with a 96% decrease in mean volume (p < 0.0001), demonstrating the existence of a distant bystander effect. This vaccination significantly increased the survival of rats with single (log-rank p < 0.0001) or multiple (log-rank p = 0.01) liver metastasis CONCLUSIONS These results suggest that suicide gene-modified tumor cells can act as potent therapeutic vaccines against liver metastasis from colon carcinoma.
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Affiliation(s)
- A Gavelli
- Unité Inserm 364, faculté de médecine, Nice, France
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Luo DZ, Vermijlen D, Ahishali B, Triantis V, Plakoutsi G, Braet F, Vanderkerken K, Wisse E. On the cell biology of pit cells, the liver-specific NK cells. World J Gastroenterol 2000; 6:1-11. [PMID: 11819514 PMCID: PMC4723571 DOI: 10.3748/wjg.v6.i1.1] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/1999] [Revised: 11/02/1999] [Accepted: 11/15/1999] [Indexed: 02/06/2023] Open
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Lentsch AB, Yoshidome H, Kato A, Warner RL, Cheadle WG, Ward PA, Edwards MJ. Requirement for interleukin-12 in the pathogenesis of warm hepatic ischemia/reperfusion injury in mice. Hepatology 1999; 30:1448-53. [PMID: 10573524 DOI: 10.1002/hep.510300615] [Citation(s) in RCA: 93] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Abstract
Hepatic ischemia and reperfusion causes neutrophil-dependent liver injury. Although the mechanisms of ischemia/reperfusion-induced liver neutrophil recruitment are somewhat understood, less is known regarding the early events that initiate the inflammatory injury. Using a murine model of partial hepatic ischemia and reperfusion, we evaluated the role of endogenous interleukin (IL)-12 in this inflammatory response. Hepatic ischemia for 90 minutes and reperfusion for up to 4 hours resulted in hepatocyte expression of IL-12. By 8 hours of reperfusion there were large increases in serum levels of interferon-gamma (IFNgamma) and tumor necrosis factor-alpha (TNFalpha). In addition, hepatic ischemia/reperfusion caused significant increases in liver neutrophil recruitment, hepatocellular injury, and liver edema, as defined by liver myeloperoxidase content, serum alanine aminotransferase, and liver wet to dry weight ratios, respectively. In mice treated with neutralizing antibody to IL-12 and in mice deficient in the IL-12 p40 gene, ischemia/reperfusion-induced increases in IFNgamma and TNFalpha were greatly diminished. These conditions also caused significant reductions in liver myeloperoxidase content and attenuated the parameters of liver injury. The data suggest that IL-12 is required for the full induction of injury after hepatic ischemia and reperfusion.
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Affiliation(s)
- A B Lentsch
- Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40202, USA.
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Senaldi G, Shaklee CL, Mak TW, Ulich TR. Corynebacterium parvum- and Mycobacterium bovis Bacillus Calmette and Guerin-induced granuloma formation in mice lacking CD4 and CD8. Cell Immunol 1999; 193:155-61. [PMID: 10222057 DOI: 10.1006/cimm.1999.1461] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Granuloma formation is a T-cell-dependent inflammatory response that is important in the host defense against intracellular bacteria. The role of CD4 and CD8 molecules in the development of Corynebacterium parvum- and Mycobacterium bovis Bacillus Calmette and Guerin (BCG)-induced granulomas was examined in CD4/CD8 knockout (KO) mice. CD4/CD8 KO mice developed a greater granulomatous response to heat-killed C. parvum and heat-killed BCG than did control mice. Thus, granuloma formation is not dependent upon the presence of CD4 and CD8. On the other hand, CD4/CD8 KO mice challenged with live BCG showed initially fewer and smaller granulomas but later more and larger granulomas than control mice. CD4/CD8 KO mice had a greater BCG load than control mice. The absence of CD4 and CD8 therefore impaired the host defense against infection with BCG. alphabeta T-cells were present in the granulomas of both CD4/CD8 KO and control mice in similar numbers. Also the production of IFN-gamma mRNA was similar in the two groups. In conclusion, CD4 and CD8 are not essential to the granulomatous response against C. parvum and BCG, but contribute to the host defense against live BCG infection.
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Affiliation(s)
- G Senaldi
- Amgen, Inc., Thousand Oaks, California 91320, USA
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