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Abreu MM, Chocron AF, Smadja DM. From cold to hot: mechanisms of hyperthermia in modulating tumor immunology for enhanced immunotherapy. Front Immunol 2025; 16:1487296. [PMID: 40092992 PMCID: PMC11906415 DOI: 10.3389/fimmu.2025.1487296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 02/03/2025] [Indexed: 03/19/2025] Open
Abstract
The emergence of immunotherapies has revolutionized cancer treatment by leveraging the immune system to target malignancies, offering new hope where traditional therapies often fall short. Within this context, hyperthermia (HT) has re-emerged as a promising adjunctive treatment, capable of enhancing the effectiveness of radiotherapy, chemotherapy, and immunotherapy. HT influences both the innate and adaptive immune systems, enhancing the activity of immune cells such as neutrophils, NK cells, and dendritic cells, while also modulating the tumor microenvironment (TME) to promote immunogenic cell death (ICD) and reduce immunosuppressive conditions. These effects contribute to the transformation of immunologically "cold" tumors into "hot" tumors, making them more susceptible to immune-mediated destruction. Furthermore, HT can amplify the efficacy of immune checkpoint inhibitors (ICIs) by improving immune cell infiltration, inducing damage-associated molecular pattern (DAMP) release, and enhancing antigen presentation. Preclinical and clinical studies support the combination of HT with ICIs, demonstrating improved outcomes in otherwise resistant tumors. However, the full therapeutic potential of the different technologies allowing to apply HT remains to be fully understood, and further research is needed to optimize treatment protocols, explore the differential impacts of local versus whole-body hyperthermia, and identify biomarkers for patient stratification. This review underscores the multifaceted role of HT in immunity and its potential to significantly enhance the efficacy of immunotherapy.
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Affiliation(s)
- M. Marc Abreu
- Medicine Department, BTT Medical Institute, Aventura, FL, United States
- BTT Engineering Department, BTT Medical Institute, Aventura, FL, United States
| | - Alberto F. Chocron
- Medicine Department, BTT Medical Institute, Aventura, FL, United States
- Research Service, Miami Veteran Administration Medical Center, Miami, FL, United States
| | - David M. Smadja
- Department of Hematology, AP-HP, Georges Pompidou European Hospital, Paris, France
- Université Paris Cité, INSERM, Paris Cardiovascular Research Center, Paris, France
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Xiao T, Sun M, Kang J, Zhao C. Transient Receptor Potential Vanilloid1 (TRPV1) Channel Opens Sesame of T Cell Responses and T Cell-Mediated Inflammatory Diseases. Front Immunol 2022; 13:870952. [PMID: 35634308 PMCID: PMC9130463 DOI: 10.3389/fimmu.2022.870952] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 04/19/2022] [Indexed: 12/11/2022] Open
Abstract
Transient receptor potential vanilloid1 (TRPV1) was primarily expressed in sensory neurons, and could be activated by various physical and chemical factors, resulting in the flow of extracellular Ca2+ into cells. Accumulating data suggest that the TRPV1 is expressed in some immune cells and is a novel regulator of the immune system. In this review, we highlight the structure and biological features of TRPV1 channel. We also summarize recent findings on its role in modulating T cell activation and differentiation as well as its protective effect in T cell-mediated inflammatory diseases and potential mechanisms.
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Affiliation(s)
- Tengfei Xiao
- Department of Clinical Laboratory, The Sixth Affiliated Hospital of Nantong University, Yancheng Third People’s Hospital, Yancheng, China
| | - Mingzhong Sun
- Department of Clinical Laboratory, The Sixth Affiliated Hospital of Nantong University, Yancheng Third People’s Hospital, Yancheng, China
| | - Jingjing Kang
- Department of Clinical Laboratory, Affiliated Hospital of Nanjing University Medical School, Yancheng First People’s Hospital, Yancheng, China
| | - Chuanxiang Zhao
- Institute of Medical Genetics and Reproductive Immunity, School of Medical Science and Laboratory Medicine, Jiangsu College of Nursing, Huai’an, China
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Heterogeneous Heat Absorption Is Complementary to Radiotherapy. Cancers (Basel) 2022; 14:cancers14040901. [PMID: 35205649 PMCID: PMC8870118 DOI: 10.3390/cancers14040901] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/20/2022] [Accepted: 01/30/2022] [Indexed: 12/10/2022] Open
Abstract
Simple Summary This review shows the advantages of heterogeneous heating of selected malignant cells in harmonic synergy with radiotherapy. The main clinical achievement of this complementary therapy is its extreme safety and minimal adverse effects. Combining the two methods opens a bright perspective, transforming the local radiotherapy to the antitumoral impact on the whole body, destroying the distant metastases by “teaching” the immune system about the overall danger of malignancy. Abstract (1) Background: Hyperthermia in oncology conventionally seeks the homogeneous heating of the tumor mass. The expected isothermal condition is the basis of the dose calculation in clinical practice. My objective is to study and apply a heterogenic temperature pattern during the heating process and show how it supports radiotherapy. (2) Methods: The targeted tissue’s natural electric and thermal heterogeneity is used for the selective heating of the cancer cells. The amplitude-modulated radiofrequency current focuses the energy absorption on the membrane rafts of the malignant cells. The energy partly “nonthermally” excites and partly heats the absorbing protein complexes. (3) Results: The excitation of the transmembrane proteins induces an extrinsic caspase-dependent apoptotic pathway, while the heat stress promotes the intrinsic caspase-dependent and independent apoptotic signals generated by mitochondria. The molecular changes synergize the method with radiotherapy and promote the abscopal effect. The mild average temperature (39–41 °C) intensifies the blood flow for promoting oxygenation in combination with radiotherapy. The preclinical experiences verify, and the clinical studies validate the method. (4) Conclusions: The heterogenic, molecular targeting has similarities with DNA strand-breaking in radiotherapy. The controlled energy absorption allows using a similar energy dose to radiotherapy (J/kg). The two therapies are synergistically combined.
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Acharya TK, Sahu RP, Kumar S, Kumar S, Rokade TP, Chakraborty R, Dubey NK, Shikha D, Chawla S, Goswami C. Function and regulation of thermosensitive ion channel TRPV4 in the immune system. CURRENT TOPICS IN MEMBRANES 2022; 89:155-188. [DOI: 10.1016/bs.ctm.2022.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
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Herold Z, Szasz AM, Dank M. Evidence based tools to improve efficiency of currently administered oncotherapies for tumors of the hepatopancreatobiliary system. World J Gastrointest Oncol 2021; 13:1109-1120. [PMID: 34616516 PMCID: PMC8465447 DOI: 10.4251/wjgo.v13.i9.1109] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 04/29/2021] [Accepted: 07/23/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatopancreatobiliary tumors are challenging to treat, and the advanced or metastatic forms have a very low 5-year survival rate. Several drug combinations have been tested, and new therapeutic approaches have been introduced in the last decades, including radiofrequency and heat based methods. Hyperthermia is the artificial heating of tumors by various biophysical methods that may possess immunostimulant, tumoricidal, and chemoradiotherapy sensitizer effects. Both whole-body and regional hyperthermia studies have been conducted since the 1980s after the introduction of deep-seated tumor hyperthermia techniques. Results of the effects of hyperthermia in hepatocellular and pancreatic cancer are known from several studies. Hyperthermia in biliary cancers is a less investigated area. High local and overall responses to treatment, increased progression-free and overall survival, and improved laboratory and quality-of-life results are associated with hyperthermia in all three tumor types. With the evolution of chemotherapeutic agents and the introduction of newer techniques, the combination of adjuvant hyperthermia with those therapies is advantageous and has not been associated with an increase in alarming adverse effects. However, despite the many positive effects of hyperthermia, its use is still only known at the experimental level, and its concomitant utilization in routine cancer treatment is not certain because of the lack of thorough clinical studies.
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Affiliation(s)
- Zoltan Herold
- Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, Budapest H-1083, Hungary
| | - A Marcell Szasz
- Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, Budapest H-1083, Hungary
| | - Magdolna Dank
- Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, Budapest H-1083, Hungary
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Mancilla-Galindo J, Galindo-Sevilla N. Exploring the rationale for thermotherapy in COVID-19. Int J Hyperthermia 2021; 38:202-212. [PMID: 33682604 DOI: 10.1080/02656736.2021.1883127] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Increased transmissibility of the pandemic severe acute respiratory coronavirus 2 (SARS-CoV-2) has been noted to occur at lower ambient temperatures. This is seemingly related to a better replication of most respiratory viruses, including SARS-CoV-2, at lower-than-core body temperatures (i.e., 33 °C vs 37 °C). Also, intrinsic characteristics of SARS-CoV-2 make it a heat-susceptible pathogen. Thermotherapy has successfully been used to combat viral infections in plants which could otherwise result in great economic losses; 90% of viruses causing infections in plants are positive-sense single-stranded ribonucleic acid (+ssRNA) viruses, a characteristic shared by SARS-CoV-2. Thus, it is possible to envision the use of heat-based interventions (thermotherapy or mild-temperature hyperthermia) in patients with COVID-19 for which moderate cycles (every 8-12 h) of mild-temperature hyperthermia (1-2 h) have been proposed. However, there are potential safety and mechanistic concerns which could limit the use of thermotherapy only to patients with mild-to-moderate COVID-19 to prevent disease progression rather than to treat patients who have already progressed to severe-to-critical COVID-19. Here, we review the characteristics of SARS-CoV-2 which make it a heat-susceptible virus, potential host mechanisms which could be enhanced at higher temperatures to aid viral clearance, and how thermotherapy could be investigated as a modality of treatment in patients with COVID-19 while taking into consideration potential risks.
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Affiliation(s)
- Javier Mancilla-Galindo
- Facultad de Medicina, División de Investigación, Unidad de Investigación UNAM-INC, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Norma Galindo-Sevilla
- Departamento de Infectología e Inmunología, Instituto Nacional de Perinatología, Mexico City, Mexico
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Lee SY, Fiorentini G, Szasz AM, Szigeti G, Szasz A, Minnaar CA. Quo Vadis Oncological Hyperthermia (2020)? Front Oncol 2020; 10:1690. [PMID: 33014841 PMCID: PMC7499808 DOI: 10.3389/fonc.2020.01690] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Accepted: 07/29/2020] [Indexed: 12/19/2022] Open
Abstract
Heating as a medical intervention in cancer treatment is an ancient approach, but effective deep heating techniques are lacking in modern practice. The use of electromagnetic interactions has enabled the development of more reliable local-regional hyperthermia (LRHT) techniques whole-body hyperthermia (WBH) techniques. Contrary to the relatively simple physical-physiological concepts behind hyperthermia, its development was not steady, and it has gone through periods of failures and renewals with mixed views on the benefits of heating seen in the medical community over the decades. In this review we study in detail the various techniques currently available and describe challenges and trends of oncological hyperthermia from a new perspective. Our aim is to describe what we believe to be a new and effective approach to oncologic hyperthermia, and a change in the paradigm of dosing. Physiological limits restrict the application of WBH which has moved toward the mild temperature range, targeting immune support. LRHT does not have a temperature limit in the tumor (which can be burned out in extreme conditions) but a trend has started toward milder temperatures with immune-oriented goals, developing toward immune modulation, and especially toward tumor-specific immune reactions by which LRHT seeks to target the malignancy systemically. The emerging research of bystander and abscopal effects, in both laboratory investigations and clinical applications, has been intensified. Our present review summarizes the methods and results, and discusses the trends of hyperthermia in oncology.
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Affiliation(s)
- Sun-Young Lee
- Department of Radiation Oncology, Chonbuk National University Hospital, Jeonbuk, South Korea
| | | | - Attila Marcell Szasz
- Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, Budapest, Hungary
| | - Gyula Szigeti
- Innovation Center, Semmelweis University, Budapest, Hungary
| | - Andras Szasz
- Biotechnics Department, St. Istvan University, Godollo, Hungary
| | - Carrie Anne Minnaar
- Department of Radiation Oncology, Wits Donald Gordon Medical Center, Johannesburg, South Africa
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Leary R, Gardner RB, Mockbee C, Roychowdhury DF. Boosting Abscopal Response to Radiotherapy with Sargramostim: A Review of Data and Ongoing Studies. Cureus 2019; 11:e4276. [PMID: 31157137 PMCID: PMC6529041 DOI: 10.7759/cureus.4276] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Drug development in oncology today routinely focuses on approaches that utilize the patients’ immune system to destroy the malignancy. Combinatorial approaches of antineoplastic agents, both new and old, are being incorporated in the armamentarium of cancer treatments. The overarching goal of therapy remains the achievement of a complete and durable response with long term remission or cure. One approach in advancing treatment is aimed at strategies that improve immunological memory to induce long lasting immunity against the tumor. Although radiation therapy has not traditionally been thought to elicit an immunological effect, an increasing number of reports document the induction of an immune response against a tumor that kills cancer cells distant to the original site of treatment after local irradiation to a tumor. This phenomenon is called an abscopal effect. Since radiation alone is rarely associated with such a response, it is being combined with immuno-oncology drugs in an attempt to enhance response. One such strategy combines sargramostim, a recombinant human granulocyte macrophage colony stimulating factor (rhu GM-CSF), with radiotherapy. GM-CSF is a cytokine secreted by multiple cells types that promotes maturation of dendritic cells and enables the presentation of tumor-associated antigens to generate a T-cell response. This review article discusses the outcomes of clinical trials and case reports examining the efficacy and safety of combining radiation therapy with this immunomodulatory agent. We will also examine future studies and challenges facing the translation of this therapeutic approach.
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Affiliation(s)
- Robyn Leary
- Oncology, Partner Therapeutics, Lexington, USA
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Gazel D, Yılmaz M. Are infectious diseases and microbiology new fields for thermal therapy research? Int J Hyperthermia 2018; 34:918-924. [PMID: 29448846 DOI: 10.1080/02656736.2018.1440015] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Antimicrobial chemotherapy and surgery are classical methods for treating infectious diseases. However, there is a need for alternative methods to cure infections caused by antibiotic-resistant pathogens, recurrent or chronic infections, and unreachable local infections in which the use of drugs or surgery is anatomically and physically restricted. Several micro-organisms are known to be sensitive to mild hyperthermia, and this sensitivity is one of the potential benefits proposed for the host during an episode of fever. Additionally, some immunological or biophysical changes occur during hyperthermia. These changes may be useful for eliminating thermo-susceptible microbial pathogens using local heat therapy. There are several experimental studies proposing the use of hyperthermia to treat local infections. The infected organs or tissues may be heated up to a temperature that can inhibit invading microorganisms. Here, it is hypothesised that local heat therapy may become an alternative or adjuvant method for curing local infections. Here, we highlight the potential for local hyperthermia in the treatment of bacterial infections caused by thermo-susceptible pathogens in a systematic plan. If the proposed thermal-microbiology concepts and local thermal therapies can be adapted to clinical microbiology and infectiology, new medical fields, such as thermo-microbiology and thermo-infectiology, may be created in the future.
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Affiliation(s)
- Deniz Gazel
- a Department of Medical Microbiology, Faculty of Medicine , Gaziantep University , Gaziantep , Turkey
| | - Mehmet Yılmaz
- b Division of Hematology, Department of Internal Medicine, Faculty of Medicine , Sanko University , Gaziantep , Turkey
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10
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Fan YF, Qin Y, Li DG, Kerr D. Retrospective Clinical Study of Advanced Pancreatic Cancer Treated With Chemotherapy and Abdominal Hyperthermia. J Glob Oncol 2017; 4:1-4. [PMID: 30241198 PMCID: PMC6180841 DOI: 10.1200/jgo.2017.009985] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
PURPOSE Hyperthermia is a mechanistically plausible partner with chemotherapy, although many of the underlying molecular mechanisms of this combination treatment are not yet properly understood. Preclinical studies suggest that there is potential synergy with gemcitabine and that provides the basis for retrospective analysis of a clinical series combining these treatment modalities for patients with advanced pancreatic cancer. PATIENTS AND METHODS Twenty-nine chemotherapy-naive patients with locally advanced or metastatic pancreatic carcinoma with malignant ascites were treated with intraperitoneal cisplatin 30 mg/m2 and gemcitabine 800 to 1,000 mg/m2 intravenously on days 1, 8, and 15 every 28 days until tumor progression. Patients also received regional hyperthermia treatment (41 to 42°C) on the upper abdomen two times per week from days 1 to 21. RESULTS In all, 83 cycles of chemotherapy were administered and were generally well tolerated. No patients had a complete response, 13 had a partial response, seven had stable disease, and 9 had progressive disease. Mean progression-free survival and overall survival were 119 ± 61days and 195 ± 98 days, respectively. CONCLUSION This study provides preliminary evidence that the treatment approach of combined systemic and intraperitoneal chemotherapy plus hyperthermia is well tolerated, is active, and has an acceptable survival profile for patients with stage IV pancreatic cancer and ascites.
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Affiliation(s)
- Yu-Fei Fan
- Yu-Fei Fan, Beijing Yanhua Hospital; Yuan Qin and Ding-Gang Li, Beijing Haidian Hospital, Beijing, China; and David Kerr, University of Oxford, Oxford, United Kingdom
| | - Yuan Qin
- Yu-Fei Fan, Beijing Yanhua Hospital; Yuan Qin and Ding-Gang Li, Beijing Haidian Hospital, Beijing, China; and David Kerr, University of Oxford, Oxford, United Kingdom
| | - Ding-Gang Li
- Yu-Fei Fan, Beijing Yanhua Hospital; Yuan Qin and Ding-Gang Li, Beijing Haidian Hospital, Beijing, China; and David Kerr, University of Oxford, Oxford, United Kingdom
| | - David Kerr
- Yu-Fei Fan, Beijing Yanhua Hospital; Yuan Qin and Ding-Gang Li, Beijing Haidian Hospital, Beijing, China; and David Kerr, University of Oxford, Oxford, United Kingdom
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Shemi D, Azab A, Kaplanski J. The effect of high and low ambient temperatures on PGE2 and TNF-α production by rat glial brain cultures. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/09680519030090030401] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
This study was undertaken to investigate the effect of changes in incubation temperature on PGE 2 and TNF-α production by rat glial brain cultures after LPS stimulation. One-hour incubation at temperatures of 4°C, 37°C, 39°C and 42°C were used. Treatment of cultures with 10 μg/ml LPS from Escherichia coli caused a significant elevation of PGE2 production 24 h after incubation at control temperatures of 37°C and the experimental temperatures of 4°C, 39°C and 42°C. While high ambient temperatures of 39°C and 42°C reduced LPS-stimulated production, compared to exposure to 37°C, exposure to 4°C did not do so. On the other hand, exposure of the cultures to a temperature of 39°C and 42°C for 1 h did not alter LPS-stimulated TNF-α production, while exposure to a temperature of 4°C significantly reduced this elevation.
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Affiliation(s)
- D. Shemi
- Department of Clinical Pharmacology, Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Abed Azab
- Department of Clinical Pharmacology, Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Jacob Kaplanski
- Department of Clinical Pharmacology, Ben-Gurion University of the Negev, Beer Sheva, Israel,
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Majhi RK, Sahoo SS, Yadav M, Pratheek BM, Chattopadhyay S, Goswami C. Functional expression of TRPV channels in T cells and their implications in immune regulation. FEBS J 2015; 282:2661-81. [PMID: 25903376 DOI: 10.1111/febs.13306] [Citation(s) in RCA: 92] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Revised: 03/02/2015] [Accepted: 04/20/2015] [Indexed: 12/11/2022]
Abstract
The importance of Ca(2+) signalling and temperature in the context of T cell activation is well known. However, the molecular identities of key players involved in such critical regulations are still unknown. In this work we explored the endogenous expression of transient receptor potential vanilloid (TRPV) channels, a group of thermosensitive and non-selective cation channels, in T cells. Using flow cytometry and confocal microscopy, we demonstrate that members belonging to the TRPV subfamily are expressed endogenously in the human T cell line Jurkat, in primary human T cells and in primary murine splenic T cells. We also demonstrate that TRPV1- and TRPV4-specific agonists, namely resiniferatoxin and 4α-phorbol-12,13-didecanoate, can cause Ca(2+) influx in T cells. Moreover, our results show that expression of these channels can be upregulated in T cells during concanavalin A-driven mitogenic and anti-CD3/CD28 stimulated TCR activation of T cells. By specific blocking of TRPV1 and TRPV4 channels, we found that these TRPV inhibitors may regulate mitogenic and T cell receptor mediated T cell activation and effector cytokine(s) production by suppressing tumour necrosis factor, interleukin-2 and interferon-γ release. These results may have broad implications in the context of cell-mediated immunity, especially T cell responses and their regulations, neuro-immune interactions and molecular understanding of channelopathies.
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Affiliation(s)
- Rakesh K Majhi
- School of Biological Sciences, National Institute of Science Education and Research, Bhubaneswar, Orissa, India
| | - Subhransu S Sahoo
- School of Biological Sciences, National Institute of Science Education and Research, Bhubaneswar, Orissa, India
| | - Manoj Yadav
- School of Biological Sciences, National Institute of Science Education and Research, Bhubaneswar, Orissa, India
| | - Belluru M Pratheek
- School of Biological Sciences, National Institute of Science Education and Research, Bhubaneswar, Orissa, India
| | - Subhasis Chattopadhyay
- School of Biological Sciences, National Institute of Science Education and Research, Bhubaneswar, Orissa, India
| | - Chandan Goswami
- School of Biological Sciences, National Institute of Science Education and Research, Bhubaneswar, Orissa, India
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Peer AJ, Grimm MJ, Zynda ER, Repasky EA. Diverse immune mechanisms may contribute to the survival benefit seen in cancer patients receiving hyperthermia. Immunol Res 2010; 46:137-54. [PMID: 19756410 DOI: 10.1007/s12026-009-8115-8] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
There is increasing documentation of significant survival benefits achieved in cancer patients treated with hyperthermia in combination with radiation and/or chemotherapy. Most evidence collected regarding the mechanisms by which hyperthermia positively influences tumor control has centered on in vitro data showing the ability of heat shock temperatures (usually above 42 degrees C) to result in radio- or chemosensitization. However, these high temperatures are difficult to achieve in vivo, and new thermometry data in patients reveal that much of the tumor and surrounding region is only heated to 40-41 degrees C or less as a result of vascular drainage from the target zone of the heated tumor. Thus, there is now a growing appreciation of a role for mild hyperthermia in the stimulation of various arms of the immune system in contributing to long term protection from tumor growth. Indeed, a review of recent literature suggests the existence of an array of thermally sensitive functions which may exist naturally to help the organism to establish a new "set point" of immune responsiveness during fever. This review summarizes recent literature identifying complex effects of temperature on immune cells and potential cellular mechanisms by which increased temperature may enhance immune surveillance.
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Affiliation(s)
- Adrienne J Peer
- Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
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Murapa P, Gandhapudi S, Skaggs HS, Sarge KD, Woodward JG. Physiological Fever Temperature Induces a Protective Stress Response in T Lymphocytes Mediated by Heat Shock Factor-1 (HSF1). THE JOURNAL OF IMMUNOLOGY 2007; 179:8305-12. [DOI: 10.4049/jimmunol.179.12.8305] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Harada H, Murakami T, Tea SS, Takeuchi A, Koga T, Okada S, Suico MA, Shuto T, Kai H. Heat shock suppresses human NK cell cytotoxicity via regulation of perforin. Int J Hyperthermia 2007; 23:657-665. [PMID: 18097852 DOI: 10.1080/02656730701822087] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Abstract
Human natural killer (NK) cell, which is an important lymphocyte for immune surveillance, is highly sensitive to heat, but the nature of its response to and its mechanistic regulation by heat remain unclear. Here we determined the effect of in vitro heat shock and in vivo hyperthermia on human NK cell cytotoxicity. Human peripheral blood mononuclear cells (PBMC) obtained from healthy volunteers were subjected to heat shock in vitro (42 degrees C, 1 h). PBMC from cancer patients receiving intentional hyperthermia (42 degrees C, 1 h) for cancer therapy were also obtained. NK cytolytic activity was determined in these samples. NK cell cytotoxicity was down-regulated by heat shock in vitro at 5 h, but at 24 h after heat shock, the NK cytotoxicity was comparable to that with its respective control. Furthermore, we observed that the mRNA and protein expression levels of perforin, which is the cytolytic granule of NK cells, were regulated by heat shock in a similar manner as NK cytotoxicity at 5 h and at 24 h after heat shock. Heat regulation involved the perforin protein in CD56(dim) but not in CD56(bright) NK cell subset. Heat shock neither induced cell death nor altered the expression of some NK activating receptors and adhesion molecules. Moreover, whole-body hyperthermia at 42 degrees C for 1 h of cancer patients also suppressed the cytotoxicity of NK cells but recovered to basal level 1 week after hyperthermia. Heat shock in vitro and in vivo temporarily represses the cytotoxicity of human NK cells.
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Affiliation(s)
- Hideki Harada
- Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan
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Fukui K, Ostapenko VV, Abe K, Nishide T, Miyano M, Mune M, Yukawa S, Nishide I. Changes in plasma alpha and gamma tocopherol levels before and after long-term local hyperthermia in cancer patients. Free Radic Res 2007; 40:893-9. [PMID: 17015268 DOI: 10.1080/10715760600750396] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Local hyperthermia is one of the heat therapies for cancer patients. The effect of this therapy is recognized to affect the immune function. On the other hand, researchers have recently suggested that vitamin E has not only antioxidant but also other functions including the immune function. However, the association between local hyperthermia therapy and vitamin E level is not yet well understood. Comparing plasma alpha and gamma tocopherol levels before and after the therapy, the basal levels of both tocopherols in the cancer patients did not significantly differ from those in healthy subjects. However, the interindividual difference in the basal levels was very wide in the cancer patients. After long-term local hyperthermia (more than 70 days), the levels of both tocopherols were significantly higher than the basal levels. This result suggests that long-term local hyperthermia therapy influences plasma tocopherol level in cancer patients; thus, an increase in vitamin E level may play an important role in the therapy of cancer patients.
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Affiliation(s)
- Koji Fukui
- Hyperthermia Research Center, Shouseikai Nishide Hospital, Osaka, Japan.
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Dieing A, Ahlers O, Hildebrandt B, Kerner T, Tamm I, Possinger K, Wust P. The effect of induced hyperthermia on the immune system. PROGRESS IN BRAIN RESEARCH 2007; 162:137-52. [PMID: 17645918 DOI: 10.1016/s0079-6123(06)62008-6] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Therapeutical hyperthermia has been considered for cancer therapy since William Coley observed tumour remission after induction of fever by bacterial toxins at the end of the 19th century. Because fever is associated with a variety of immunological reactions, it has been suspected, that therapeutical hyperthermia might also activate the immune system in a reproducible manner and thereby positively influence the course of the disease. During the last decade, new insight has been gained regarding the immunological changes taking place during therapeutic hyperthermia. In this chapter, we review the most relevant data known about the effect of hyperthermia on the immune system with special focus on alterations induced by therapeutical whole-body hyperthermia (WBH) in cancer patients.
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Affiliation(s)
- Annette Dieing
- Department of Oncology and Hematology, Charité Campus Mitte, University Medicine Berlin, Germany, Schumannstrasse 20/21, D-10117 Berlin, Germany.
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18
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Kida Y, Tsuji-Kawahara S, Ostapenko V, Kinoshita S, Kajiwara E, Kawabata H, Yuasa T, Nishide I, Yukawa S, Ichinose M, Miyazawa M. Increased liver temperature efficiently augments human cellular immune response: T-cell activation and possible monocyte translocation. Cancer Immunol Immunother 2006; 55:1459-69. [PMID: 16491400 PMCID: PMC11030585 DOI: 10.1007/s00262-006-0146-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2005] [Accepted: 01/25/2006] [Indexed: 10/25/2022]
Abstract
Hyperthermia (HT), in combination with other conventional therapeutic modalities, has become a promising approach in cancer therapy. In addition to heat-induced apoptosis, an augmented immunological effect is considered to be a benefit of hyperthermic treatment over chemo- or radiotherapy. Here, we investigated the effect of regional HT targeting the liver on immune cells, especially T cells and antigen-presenting cells, which are important in recognizing and eliminating tumor cells and pathogens such as viruses. In healthy volunteers exposed to such regional HT, both CD4(+) and CD8(+) T cells that express an activation marker CD69 increased transiently at 1 h post-treatment, with a subsequent decrease to base levels at 6 h after the treatment. At 24 h post-treatment, the percentage of CD69-positive cells significantly increased again but only among CD8(+) T cells. IFN-gamma production from PHA-stimulated peripheral blood mononuclear cells was gradually and significantly increased in the 2 days following the heating procedure, peaking at 36 h post-treatment. Furthermore, we found marked increases in plasma levels of IL-1beta and IL-6 starting at 24 h post-treatment. With regard to the number of each leukocyte subpopulation, a transient and dramatic decrease in the number of a subset of monocytes, CD14(+) CD16(-) cells, was observed at 1 h after the hyperthermic treatment, suggesting that the regional HT aimed at the liver may have influenced the extravasation of blood monocytes. No significant changes in T-cell activities or monocyte counts were observed in the volunteers exposed to heating of the lungs or the legs. These results suggest that heating of the liver may efficiently induce cellular immune responses to liver cancers.
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Affiliation(s)
- Yohei Kida
- Department of Immunology, Kinki University School of Medicine, Osaka-Sayama, Osaka Japan
- Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Sachiyo Tsuji-Kawahara
- Department of Immunology, Kinki University School of Medicine, Osaka-Sayama, Osaka Japan
| | - Valentina Ostapenko
- Laboratory of Clinical Hyperthermia, Shousei-kai Nishide Hospital, Kaizuka, Osaka Japan
| | - Saori Kinoshita
- Department of Immunology, Kinki University School of Medicine, Osaka-Sayama, Osaka Japan
| | - Eiji Kajiwara
- Department of Immunology, Kinki University School of Medicine, Osaka-Sayama, Osaka Japan
| | - Hiroyuki Kawabata
- Department of Immunology, Kinki University School of Medicine, Osaka-Sayama, Osaka Japan
| | - Takae Yuasa
- Department of Immunology, Kinki University School of Medicine, Osaka-Sayama, Osaka Japan
| | - Iwao Nishide
- Laboratory of Clinical Hyperthermia, Shousei-kai Nishide Hospital, Kaizuka, Osaka Japan
| | - Susumu Yukawa
- Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Masakazu Ichinose
- Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Masaaki Miyazawa
- Department of Immunology, Kinki University School of Medicine, Osaka-Sayama, Osaka Japan
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Koga T, Harada H, Shi TS, Okada S, Suico MA, Shuto T, Kai H. Hyperthermia suppresses the cytotoxicity of NK cells via down-regulation of perforin/granzyme B expression. Biochem Biophys Res Commun 2005; 337:1319-1323. [PMID: 16236268 DOI: 10.1016/j.bbrc.2005.09.184] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2005] [Accepted: 09/28/2005] [Indexed: 10/25/2022]
Abstract
Hyperthermia, which is used as an adjunctive therapy for cancer, is known to modulate the activity of natural killer (NK) cells in vitro, but its effect in vivo is unclear. In the present study, we used a whole body hyperthermia (WBH) device heated by infrared rays to evaluate the effect of WBH on mice models. We demonstrate here that wild type C57BL/6J mice exposed to 42 degrees C for 60min had reduced NK cell cytolytic activity against YAC-1 target cells as determined by cytolytic assay. This result was confirmed using Rag-2 knockout mice, which possess functional NK but not cytolytic T or NK-T cells. Moreover, WBH decreased the mRNA expression of perforin and granzyme B in spleens of mice. But the expression of TNF cytokines (Fas ligand and TRAIL) was unchanged. These data suggest that the suppression of NK cell activity induced by WBH could be mediated through the perforin/granzyme pathway.
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Affiliation(s)
- Tomoaki Koga
- Department of Molecular Medicine, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan
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Ahlers O, Hildebrandt B, Dieing A, Deja M, Böhnke T, Wust P, Riess H, Gerlach H, Kerner T. Stress induced changes in lymphocyte subpopulations and associated cytokines during whole body hyperthermia of 41.8-42.2 degrees C. Eur J Appl Physiol 2005; 95:298-306. [PMID: 16096838 DOI: 10.1007/s00421-005-0009-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/06/2005] [Indexed: 12/31/2022]
Abstract
Extreme acute physical stress leads to transient impairment of T-lymphocytes, which are essential for tumor defence and prevention of infectious diseases. Radiant whole body hyperthermia (WBH) at 41.8-42.2 degrees C may enhance the efficacy of systemic chemotherapy in patients with advanced malignancies, but is associated with marked physical stress. Aim of this study was to demonstrate stress induced short-time effects on lymphocyte subpopulations and associated cytokines during WBH. Total leukocyte count, white blood cell differential blood count, lymphocyte subpopulations (T-helper-/T4-cells, T-suppressor-/T8-cells, natural-killer-/NK-cells, gammadelta-T-cells) as well as plasma levels of Interleukin(IL)-10, IL-12 and Interferon-gamma (IFN-gamma) were measured in ten patients treated with WBH and additional cytostatic chemotherapy. Blood samples were drawn before treatment, at three temperature points during WBH, and 24 h after start of treatment. Results were compared with those obtained from a control group consisting of six patients receiving chemotherapy alone. Numbers of T4-cells decreased significantly during WBH, while numbers of NK-cells and gammadelta-T-cells increased, resulting in transient impairments of total lymphocyte counts and T4/T8-ratio. IL-12 plasma levels as well as IFN-gamma/IL-10-ratio also decreased during WBH. No significant changes were found in T8-cells of WBH patients. Changes were reversible within 24 h and could not been found in control patients. Our results support the hypothesis that WBH combined with chemo therapy induces a strong but reversible anti-inflammatory stress response in cancer patients during therapy. Further studies are necessary to examine the pathophysiological details and to evaluate the meaning of these transient immunological changes for patient's outcome.
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Affiliation(s)
- Olaf Ahlers
- Klinik für Anästhesiologie und operative Intensivmedizin, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, 13344, Berlin, Germany.
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21
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Dieing A, Ahlers O, Kerner T, Wust P, Felix R, Löffel J, Riess H, Hildebrandt B. Whole body hyperthermia induces apoptosis in subpopulations of blood lymphocytes. Immunobiology 2004; 207:265-73. [PMID: 12952349 DOI: 10.1078/0171-2985-00236] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Whole Body Hyperthermia (WBH) has been shown to induce alterations of lymphocyte subpopulations in peripheral blood: T-cells decrease and NK-cells increase in number in the course of this therapy. As elevated temperature induces programmed cell death in healthy lymphocytes in vitro, we intended to determine the role of lymphocyte apoptosis in WBH by measuring the rate of apoptosis in blood lymphocytes in the course of this treatment. Blood was taken from cancer patients, treated with whole body hyperthermia and chemotherapy, before, during and the day after treatment. Apoptosis rates of the whole lymphocyte population, as well as, of B-, T-, CD4 + -T-, CD8 + -T-, and Natural-Killer (NK)-cell-subpopulations were determined by staining with AnnexinV-FITC and FACS flow analysis. A significant rise of apoptosis in the whole lymphocyte population, in CD4 + -T- and in CD8 + -T-cells occurred during treatment. In contrast, an elevated rate of apoptosis in NK-cells was observed 20 hours after termination of WBH. These differences were similar when the cells were incubated at 37 degrees C for 24 hours. Our results suggest, that apoptosis is one reason for the previously described decrease of T-cells during WBH and of NK-cells after WBH, and that the hyperthermia-related apoptosis-inducing mechanism is different in T-cells and NK-cells.
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Affiliation(s)
- Annette Dieing
- Medical Clinic, Department of Hematology and Oncology, Charité Medical School, Humboldt-University, Campus Mitte, Berlin, Germany.
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22
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Gothard LQ, Ruffner ME, Woodward JG, Park-Sarge OK, Sarge KD. Lowered temperature set point for activation of the cellular stress response in T-lymphocytes. J Biol Chem 2003; 278:9322-6. [PMID: 12519785 DOI: 10.1074/jbc.m209412200] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The induction of heat shock protein gene expression in response to stress is critical for the ability of organisms to cope with and survive exposure to these stresses. However, most studies on HSF1-mediated induction of hsp70 gene expression have utilized immortalized cell lines and temperatures above the physiologically relevant range. For these reasons much less is known about the heat shock response as it occurs in mammalian cells within tissues in the intact organism. To gain insight into this area we determined the temperature thresholds for activation of HSF1 DNA binding in different mouse tissues. We have found that HSF1 DNA binding activity and hsp70 synthesis are induced in spleen cells at significantly lower temperatures relative to cells of other tissues, with a temperature threshold for activation (39 degrees C) that is within the physiological range for fever. Furthermore, we found that the lowered temperature set point for induction of the stress response in spleen is specific to T-lymphocytes residing within this tissue and is not exhibited by B-lymphocytes. This lowered threshold is also observed in T-lymphocytes isolated from lymph nodes, suggesting that it is a general property of T-lymphocytes, and is seen in different mouse strains. Fever is an early event in the immune response to infection, and thus activation of the cellular stress response in T-lymphocytes by fever temperatures could serve as a way to give these cells enough time to express hsps in anticipation of their function in the coming immune response. The induced hsps likely protect these cells from the stressful conditions that can exist during the immune response, for example increasing their protection against stress-induced apoptosis.
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Affiliation(s)
- Lisa Q Gothard
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Chandler Medical Center, Lexington, Kentucky 40536-0294, USA
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23
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Wust P, Hildebrandt B, Sreenivasa G, Rau B, Gellermann J, Riess H, Felix R, Schlag PM. Hyperthermia in combined treatment of cancer. Lancet Oncol 2002; 3:487-97. [PMID: 12147435 DOI: 10.1016/s1470-2045(02)00818-5] [Citation(s) in RCA: 1155] [Impact Index Per Article: 50.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Hyperthermia, the procedure of raising the temperature of tumour-loaded tissue to 40-43 degrees C, is applied as an adjunctive therapy with various established cancer treatments such as radiotherapy and chemotherapy. The potential to control power distributions in vivo has been significantly improved lately by the development of planning systems and other modelling tools. This increased understanding has led to the design of multiantenna applicators (including their transforming networks) and implementation of systems for monitoring of E-fields (eg, electro-optical sensors) and temperature (particularly, on-line magnetic resonance tomography). Several phase III trials comparing radiotherapy alone or with hyperthermia have shown a beneficial effect of hyperthermia (with existing standard equipment) in terms of local control (eg, recurrent breast cancer and malignant melanoma) and survival (eg, head and neck lymph-node metastases, glioblastoma, cervical carcinoma). Therefore, further development of existing technology and elucidation of molecular mechanisms are justified. In recent molecular and biological investigations there have been novel applications such as gene therapy or immunotherapy (vaccination) with temperature acting as an enhancer, to trigger or to switch mechanisms on and off. However, for every particular temperature-dependent interaction exploited for clinical purposes, sophisticated control of temperature, spatially as well as temporally, in deep body regions will further improve the potential.
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Affiliation(s)
- P Wust
- Department of Radiation Oncology, Charité Medical School, Campus Virchow Klinikum, Berlin, Germany.
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24
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Schrott LM, Sparber SB. Embryonic "binge" cocaine exposure alters neural-immune and neural-endocrine interactions in young chickens: involvement of serotonin(2) receptors. BRAIN RESEARCH. DEVELOPMENTAL BRAIN RESEARCH 2001; 130:99-107. [PMID: 11557098 DOI: 10.1016/s0165-3806(01)00217-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
As part of our characterization of the developmental consequences of prenatal cocaine exposure, cocaine was injected into eggs containing viable chicken embryos on embryonic day (E) 18 and the fever response to the endotoxin lipopolysaccharide (LPS) and a delayed-type hypersensitivity response to phytohemagglutinin (PHA) were assessed postnatally. E18 cocaine exposure did not affect basal body temperature. LPS induced a fever in the chicks at 4 h post-injection on post-hatch day (D) 4 and 2 h post-injection on D24. E18 cocaine exposure suppressed the peak LPS-induced fever by 50% at both ages. E18 cocaine exposure also suppressed the hypersensitivity reaction to an intradermal injection of PHA on D17, while having no effect on the response to a saline injection. To determine the importance of serotonin(2) (5-HT(2)) receptors in the developmental toxicity of cocaine, varying doses of the 5-HT(2) antagonist ritanserin were injected on E17 followed by cocaine on E18. Ritanserin, like cocaine, did not alter basal temperature, but it dose-relatedly attenuated or blocked cocaine's effect on LPS-induced fever on both D4 and D24. Ritanserin pretreatment was also able to block the blunted isolation stress response seen in D16 chicks following E18 cocaine exposure. Thus, late prenatal cocaine exposure significantly alters adaptive fever and hypersensitivity responses, and embryonic 5-HT(2) receptors played a mediating role in the fever effect.
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Affiliation(s)
- L M Schrott
- Department of Pharmacology, University of Minnesota Medical School, 6-120 Jackson Hall, 321 Church St. S.E., Minneapolis, MN 55455-0217, USA.
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25
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Payne J, Nair MP, Ambrus JL, Chadha KC. Mild hyperthermia modulates biological activities of interferons. Int J Hyperthermia 2000; 16:492-507. [PMID: 11129261 DOI: 10.1080/02656730050199340] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022] Open
Abstract
A significant enhancement of antiviral activity of human IFN-alpha, -beta and -gamma and murine IFN-gamma is observed when cells are treated with mild hyperthermia (39 degrees C) during antiviral assays. Treatment of primary human fibroblast cells with mild hyperthermia for 4 and 24 hours prior to interferon antiviral assays (pre-assay hyperthermia) further enhances interferon antiviral activity. An enhancement of interferon induced enzyme, 2,5-oligoadenylate synthetase, is also observed in cells treated with interferon and mild hyperthermia. This increase in enzyme activity is, in part, responsible for the observed increase in interferon antiviral activity with hyperthermia. Besides antiviral activity, mild hyperthermia also increases interferon antiproliferative activity on different tumour cells beyond its effect at normal physiological temperatures. On the other hand, mild hyperthermia decreases human interferon production in both human and murine cells when challenged with a viral or non-viral inducer. Also, mild hyperthermia suppresses interferon-mediated enhancement of natural killer (NK) cell activity in human and murine cells. The findings demonstrate that, although mild hyperthermia has suppressive effects upon interferon production and NK cell activity, it significantly increases both antiviral and antiproliferative activities of all three human interferons. These observations have direct bearing upon clinical utilization of exogenously administered interferons to late stage cancer patients who for the most part have a weaker immune system. In these patients, the antiviral and antiproliferative efficacies of administered interferon can be enhanced by combining interferon and hyperthermia.
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Affiliation(s)
- J Payne
- Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
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26
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Oglesbee MJ, Diehl K, Crawford E, Kearns R, Krakowka S. Whole body hyperthermia: effects upon canine immune and hemostatic functions. Vet Immunol Immunopathol 1999; 69:185-99. [PMID: 10507304 DOI: 10.1016/s0165-2427(99)00053-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
In this study, the effects of induced whole body hyperthermia (WBH; 42.3 degrees C for 90 min) on peripheral blood mononuclear cell (PBMC) phenotype distribution, in vitro blastogenic responsiveness and selected parameters of hemostasis were determined in dogs. Hyperthermia was induced by heating venous blood during extracorporeal circulation (EC); induction of WBH by peritoneal lavage (PL) and perfusion without heating (i.e. euthermic EC and euthermic PL) were used as controls. Whole body hyperthermia was associated with lymphopenia and thrombocytopenia that persisted throughout the eight-day post-treatment observation interval. The lymphopenia was selective in that CD5-positive T lymphocytes were more sensitive than were sIg-positive B cells and, within the T-cell compartment, suppressor (CD8-positive) cells were more sensitive to hyperthermic stress than helper (CD4 positive) lymphocytes. Lymphopenia was also observed in EC and PL euthermic controls, although that lymphopenia was transient and nonselective. Persistent suppression of T-cell phytomitogen-induced blastogenesis was induced by WBH in contrast to transient suppression in euthermic controls. For all treatment groups, lymphopenia and suppressed blastogenesis were correlated to elevated plasma cortisol levels. Induction of WBH by EC resulted in coagulopathy characterized by thrombocytopenia, increased plasma fibrin degradation products, prolonged clotting times, and evidence of spontaneous bleeding. These hemostatic alterations were correlated temporally to increased serum levels of liver enzymes. However, there was no evidence of hepatic injury when WBH was induced by PL, where transient thrombocytopenia was the only significant hemostatic alteration. These results indicate that 42.3 degrees C whole body hyperthermia can be well-tolerated and, although associated with suppression of general indexes of immunocompetence, is not associated with opportunistic infections.
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Affiliation(s)
- M J Oglesbee
- Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus 43210-1089, USA.
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27
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Lee TK, O'Brien K, Christie K, Wiley AL, Karlsson UL. Effect of ex vivo hyperthermia on radiation-induced micronuclei in lymphocytes of cancer patients before and during radiotherapy. Mutat Res 1998; 417:1-8. [PMID: 9729237 DOI: 10.1016/s1383-5718(98)00086-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
To investigate the effect of ex vivo hyperthermia (HT) and 137Cs-irradiation on micronucleus (MN) production in cytokinesis-blocked lymphocytes, we obtained the peripheral blood samples from the same cancer patients (n=6) before and during fractionated partial-body radiotherapy (xRT). The whole blood cultures were heated at 43.5 degrees C for 60 min, followed by 137Cs irradiation (0-4 Gy). The control cultures from the same patients were incubated at 37 degreesC after being exposed to radiation. The lymphocytes were then stimulated with PHA. Cytochalasin B was applied at 44 h, and lymphocytes were harvested at 72 h. MN frequency was determined on Giemsa-stained slides. We found that in patients before xRT, HT (43.5 degrees C) significantly increased the MN yield (mean+/-SEM) in unirradiated lymphocytes from 15.6+/-2.8 (37 degrees C) to 39.7+/-10.9. Further, in patients either before or during xRT, when the lymphocytes were treated with HT (43.5 degrees C) and combined with ex vivo irradiation, the MN yield (Y) could be estimated by a linear equation Y=C+alphaD. Our findings indicate that as measured by the MN production in cytokinesis-blocked lymphocytes, HT alone at 43.5 degrees C++ induced DNA damage. Moreover, it enhanced the radiation-induced cytogenetic damage. Therefore, the application of HT may impair the T-cell function in cancer patients who are receiving radiotherapy. 1998 Elsevier Science B.V.
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Affiliation(s)
- T K Lee
- Department of Radiation Oncology, Leo W. Jenkins Cancer Center, East Carolina University School of Medicine, Greenville, NC 27858, USA.
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Abstract
Cytokine responses to lipopolysaccharides in neuroendocrine tissues are age- and tissue-dependent in neonatal pigs. Developmental differences in serum and tissue-specific responses are not necessarily equivalent. Lower levels of cytokine gene expression in neuroendocrine tissues of early neonates potentially could influence neuroendocrine and immune responses to infection. The limited information on neuroendocrine-immune responses and interactions in neonatal farm animals presents significant challenges, as well as opportunities for new discoveries and improvements of livestock production.
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Affiliation(s)
- R L Matteri
- Animal Physiology Research Unit, United States Department of Agriculture, Columbia, MO 65211, USA
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29
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de Boer AG, Breimer DD. Cytokines and blood-brain barrier permeability. PROGRESS IN BRAIN RESEARCH 1998; 115:425-51. [PMID: 9632945 DOI: 10.1016/s0079-6123(08)62045-2] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- A G de Boer
- Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University, Sylvius Laboratories, The Netherlands
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30
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Shemi D, Kaplanski J, Knyszynski A, Globerson A. The effect of hyperthermia on PGE2 production by primary brain culture after exposure to LPS. Ann N Y Acad Sci 1997; 813:310-3. [PMID: 9100899 DOI: 10.1111/j.1749-6632.1997.tb51711.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
- D Shemi
- Department of Clinical Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beersheva, Israel
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31
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Clinical Practice of Whole-Body Hyperthermia: New Directions. THERMORADIOTHERAPY AND THERMOCHEMOTHERAPY 1996. [DOI: 10.1007/978-3-642-60938-1_18] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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