{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:39:34Z","timestamp":1753889974517,"version":"3.41.2"},"reference-count":45,"publisher":"IMR Press","issue":"7","license":[{"start":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T00:00:00Z","timestamp":1657238400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000104","name":"NASA","doi-asserted-by":"crossref","award":["NNX16AB29G","80NSSC19K1059"],"award-info":[{"award-number":["NNX16AB29G","80NSSC19K1059"]}],"id":[{"id":"10.13039\/100000104","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background: We have previously shown that the anti-tumor activity of human lymphocytes is diminished in vitro after 12-hours pre-exposure to simulated microgravity (SMG). Here we used an immunocompromised mouse model to determine if this loss of function would extend in vivo, and to also test the efficacy of IL-2 and zoledronic acid (ZOL) therapy as a potential countermeasure against SMG-induced immune dysfunction. We adoptively transferred human lymphocytes that were exposed to either SMG or 1G-control into NSG-Tg (Hu-IL15) mice 1-week after they were injected with a luciferase-tagged human chronic myeloid leukemia (K562) cell line. Tumor growth was monitored 2x weekly with bioluminescence imaging (BLI) for up to 6-weeks. Results: Mice that received lymphocytes exposed to SMG showed greater tumor burden compared to those receiving lymphocytes exposed to 1G (week 6 BLI: 1.8e10 \u00b1 8.07e9 versus 2.22e8 \u00b1 1.39e8 photons\/second; p &lt; 0.0001). Peak BLI was also higher in the SMG group compared to 1G-control (2.34e10 \u00b1 1.23e10 versus 3.75e8 \u00b1 1.56e8 photons\/second; p = 0.0062). Exposure to SMG did not affect the ability of human lymphocytes to engraft or evoke xeno-graft-versus-host disease in the mice. Additionally, we injected the mice with IL-2 and zoledronic acid (ZOL) to expand and activate the anti-tumor activity of NK cells and \u03b3 \u03b4-T cells, respectively. This treatment was found to revive the loss of anti-leukemic function observed in vivo when lymphocytes were pre-exposed to SMG. Conclusions: Microgravity plays a contributory role in loss of tumor control in vivo. Immuno-stimulating agents like ZOL+IL-2 may offer an important countermeasure for immune dysregulation during prolonged spaceflight.<\/jats:p>","DOI":"10.31083\/j.fbl2707215","type":"journal-article","created":{"date-parts":[[2022,7,14]],"date-time":"2022-07-14T09:25:48Z","timestamp":1657790748000},"source":"Crossref","is-referenced-by-count":2,"title":["IL-2 and Zoledronic Acid Therapy Restores the In Vivo Anti-Leukemic Activity of Human Lymphocytes Pre-Exposed to Simulated Microgravity"],"prefix":"10.31083","volume":"27","author":[{"given":"Preteesh L.","family":"Mylabathula","sequence":"first","affiliation":[{"name":"School of Nutritional Sciences and Wellness, The University of Arizona, Tucson, AZ 85721, USA"},{"name":"Department of Pediatrics, The University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Douglass M.","family":"Diak","sequence":"first","affiliation":[{"name":"School of Nutritional Sciences and Wellness, The University of Arizona, Tucson, AZ 85721, USA"},{"name":"Department of Pediatrics, The University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Forrest L.","family":"Baker","sequence":"first","affiliation":[{"name":"School of Nutritional Sciences and Wellness, The University of Arizona, Tucson, AZ 85721, USA"},{"name":"Department of Pediatrics, The University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Grace M.","family":"Niemiro","sequence":"first","affiliation":[{"name":"Department of Pediatrics, The University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melissa M.","family":"Markofski","sequence":"first","affiliation":[{"name":"Laboratory of Integrated Physiology, Department of Health and Human Performance, University of Houston, Houston, TX 77004, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian E.","family":"Crucian","sequence":"first","affiliation":[{"name":"NASA Johnson Space Center, Houston, TX 77058, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emmanuel","family":"Katsanis","sequence":"first","affiliation":[{"name":"Department of Pediatrics, The University of Arizona, Tucson, AZ 85721, USA"},{"name":"Department of Immunobiology, The University of Arizona, Tucson, AZ 85721, USA"},{"name":"The University of Arizona Cancer Center, Tucson, AZ, 85721, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard J.","family":"Simpson","sequence":"first","affiliation":[{"name":"School of Nutritional Sciences and Wellness, The University of Arizona, Tucson, AZ 85721, USA"},{"name":"Department of Pediatrics, The University of Arizona, Tucson, AZ 85721, USA"},{"name":"Department of Immunobiology, The University of Arizona, Tucson, AZ 85721, USA"},{"name":"The University of Arizona Cancer Center, Tucson, AZ, 85721, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"16242","published-online":{"date-parts":[[2022,7,8]]},"reference":[{"doi-asserted-by":"crossref","unstructured":"Crucian B, Stowe R, Mehta S, Uchakin P, Quiriarte H, Pierson D, et al. Immune System Dysregulation Occurs during Short Duration Spaceflight on Board the Space Shuttle. Journal of Clinical Immunology. 2013; 33: 456\u2013465.","key":"ref1","DOI":"10.1007\/s10875-012-9824-7"},{"doi-asserted-by":"crossref","unstructured":"Crucian B, Stowe R, Quiriarte H, Pierson D, Sams C. Monocyte phenotype and cytokine production profiles are dysregulated by short-duration spaceflight. Aviation, Space, and Environmental Medicine. 2011; 82: 857\u2013862.","key":"ref2","DOI":"10.3357\/ASEM.3047.2011"},{"doi-asserted-by":"crossref","unstructured":"Crucian BE, Stowe RP, Pierson DL, Sams CF. Immune system dysregulation following short- vs long-duration spaceflight. Aviation, Space, and Environmental Medicine. 2008; 79: 835\u2013843.","key":"ref3","DOI":"10.3357\/ASEM.2276.2008"},{"doi-asserted-by":"crossref","unstructured":"Mehta SK, Laudenslager ML, Stowe RP, Crucian BE, Sams CF, Pierson DL. Multiple latent viruses reactivate in astronauts during Space Shuttle missions. Brain, Behavior, and Immunity. 2014; 41: 210\u2013217.","key":"ref4","DOI":"10.1016\/j.bbi.2014.05.014"},{"doi-asserted-by":"crossref","unstructured":"Crucian B, Stowe RP, Mehta S, Quiriarte H, Pierson D, Sams C. Alterations in adaptive immunity persist during long-duration spaceflight. Npj Microgravity. 2015; 1: 15013.","key":"ref5","DOI":"10.1038\/npjmgrav.2015.13"},{"doi-asserted-by":"crossref","unstructured":"Mehta SK, Laudenslager ML, Stowe RP, Crucian BE, Feiveson AH, Sams CF, et al. Latent virus reactivation in astronauts on the international space station. Npj Microgravity. 2017; 3: 11.","key":"ref6","DOI":"10.1038\/s41526-017-0015-y"},{"doi-asserted-by":"crossref","unstructured":"Rooney BV, Crucian BE, Pierson DL, Laudenslager ML, Mehta SK. Herpes Virus Reactivation in Astronauts During Spaceflight and Its Application on Earth. Frontiers in Microbiology. 2019; 10: 16.","key":"ref7","DOI":"10.3389\/fmicb.2019.00016"},{"doi-asserted-by":"crossref","unstructured":"Bigley AB, Agha NH, Baker FL, Spielmann G, Kunz HE, Mylabathula PL, et al. NK cell function is impaired during long-duration spaceflight. Journal of Applied Physiology. 2019; 126: 842\u2013853.","key":"ref8","DOI":"10.1152\/japplphysiol.00761.2018"},{"doi-asserted-by":"crossref","unstructured":"Mylabathula PL, Li L, Bigley AB, Markofski MM, Crucian BE, Mehta SK, et al. Simulated microgravity disarms human NK-cells and inhibits anti-tumor cytotoxicity in vitro. Acta Astronautica. 2020; 174: 32\u201340.","key":"ref9","DOI":"10.1016\/j.actaastro.2020.03.023"},{"doi-asserted-by":"crossref","unstructured":"Bosma GC, Custer RP, Bosma MJ. A severe combined immunodeficiency mutation in the mouse. Nature. 1983; 301: 527\u2013530.","key":"ref10","DOI":"10.1038\/301527a0"},{"doi-asserted-by":"crossref","unstructured":"Shultz LD, Lyons BL, Burzenski LM, Gott B, Chen X, Chaleff S, et al. Human Lymphoid and Myeloid Cell Development in NOD\/LtSz-scid IL2R null Mice Engrafted with Mobilized Human Hemopoietic Stem Cells. Journal of Immunology. 2005; 174: 6477\u20136489.","key":"ref11","DOI":"10.4049\/jimmunol.174.10.6477"},{"doi-asserted-by":"crossref","unstructured":"Cao X, Shores EW, Hu-Li J, Anver MR, Kelsall BL, Russell SM, et al. Defective lymphoid development in mice lacking expression of the common cytokine receptor \u03b3 chain. Immunity. 1995; 2: 223\u2013238.","key":"ref12","DOI":"10.1016\/1074-7613(95)90047-0"},{"doi-asserted-by":"crossref","unstructured":"Shultz LD, Ishikawa F, Greiner DL. Humanized mice in translational biomedical research. Nature Reviews Immunology. 2007; 7: 118\u2013130.","key":"ref13","DOI":"10.1038\/nri2017"},{"doi-asserted-by":"crossref","unstructured":"Cooper MA, Bush JE, Fehniger TA, VanDeusen JB, Waite RE, Liu Y, et al. In vivo evidence for a dependence on interleukin 15 for survival of natural killer cells. Blood. 2002; 100: 3633\u20133638.","key":"ref14","DOI":"10.1182\/blood-2001-12-0293"},{"doi-asserted-by":"crossref","unstructured":"Crucian BE, Chouk\u00e8r A, Simpson RJ, Mehta S, Marshall G, Smith SM, et al. Immune system dysregulation during spaceflight: Potential countermeasures for deep space exploration missions. Frontiers in Immunology. 2018; 9: 1437.","key":"ref15","DOI":"10.3389\/fimmu.2018.01437"},{"doi-asserted-by":"crossref","unstructured":"Cheever MA, Greenberg PD, Fefer A, Gillis S. Augmentation of the anti-tumor therapeutic efficacy of long-term cultured T lymphocytes by in vivo administration of purified interleukin 2. Journal of Experimental Medicine. 1982; 155: 968\u2013980.","key":"ref16","DOI":"10.1084\/jem.155.4.968"},{"doi-asserted-by":"crossref","unstructured":"Mazumder A, Rosenberg SA. Successful immunotherapy of natural killer-resistant established pulmonary melanoma metastases by the intravenous adoptive transfer of syngeneic lymphocytes activated in vitro by interleukin 2. Journal of Experimental Medicine. 1984; 159: 495\u2013507.","key":"ref17","DOI":"10.1084\/jem.159.2.495"},{"doi-asserted-by":"crossref","unstructured":"Rosenberg SA. IL-2: the first effective immunotherapy for human cancer. Journal of Immunology. 2014; 192: 5451\u20135458.","key":"ref18","DOI":"10.4049\/jimmunol.1490019"},{"doi-asserted-by":"crossref","unstructured":"Muntasell A, Ochoa MC, Cordeiro L, Berraondo P, L\u00f3pez-D\u00edaz de Cerio A, Cabo M, et al. Targeting NK-cell checkpoints for cancer immunotherapy. Current Opinion in Immunology. 2017; 45: 73\u201381.","key":"ref19","DOI":"10.1016\/j.coi.2017.01.003"},{"doi-asserted-by":"crossref","unstructured":"Kimpo MS, Oh B, Lee S. The Role of Natural Killer Cells as a Platform for Immunotherapy in Pediatric Cancers. Current Oncology Reports. 2019; 21: 93.","key":"ref20","DOI":"10.1007\/s11912-019-0837-8"},{"doi-asserted-by":"crossref","unstructured":"Fobelo Lozano MJ, S\u00e1nchez-Fidalgo S. Adherence and preference of intravenous zoledronic acid for osteoporosis versus other bisphosphonates. European Journal of Hospital Pharmacy. 2019; 26: 4\u20139.","key":"ref21","DOI":"10.1136\/ejhpharm-2017-001258"},{"doi-asserted-by":"crossref","unstructured":"Mei M, Xiang Z, Yang J, Xiang R. Efficacy of zoledronic acid for prevention of bone loss in early-stage breast cancer patients receiving adjuvant therapy: a meta-analysis of 13 randomized controlled trials. Current Problems in Cancer. 2020; 44: 100507.","key":"ref22","DOI":"10.1016\/j.currproblcancer.2019.100507"},{"doi-asserted-by":"crossref","unstructured":"Liu H, Wang SH, Chen SC, Chen CY, Lo JL, Lin TM. Immune modulation of CD4(+) CD25(+) regulatory T cells by zoledronic acid. BMC Immunology. 2016; 17: 45.","key":"ref23","DOI":"10.1186\/s12865-016-0183-7"},{"doi-asserted-by":"crossref","unstructured":"Salaroglio IC, Campia I, Kopecka J, Gazzano E, Orecchia S, Ghigo D, et al. Zoledronic acid overcomes chemoresistance and immunosuppression of malignant mesothelioma. Oncotarget. 2015; 6: 1128\u20131142.","key":"ref24","DOI":"10.18632\/oncotarget.2731"},{"doi-asserted-by":"crossref","unstructured":"M\u00f6nkk\u00f6nen H, Ottewell PD, Kuokkanen J, M\u00f6nkk\u00f6nen J, Auriola S, Holen I. Zoledronic acid-induced IPP\/ApppI production in vivo. Life Sciences. 2007; 81: 1066\u20131070.","key":"ref25","DOI":"10.1016\/j.lfs.2007.08.007"},{"doi-asserted-by":"crossref","unstructured":"Caccamo N, Meraviglia S, Scarpa F, La Mendola C, Santini D, Bonanno CT, et al. Aminobisphosphonate-activated gammadelta T cells in immunotherapy of cancer: doubts no more. Expert Opinion on Biological Therapy. 2008; 8: 875\u2013883.","key":"ref26","DOI":"10.1517\/14712598.8.7.875"},{"doi-asserted-by":"crossref","unstructured":"Hamilton E, Clay TM, Blackwell KL. New perspectives on zoledronic acid in breast cancer: potential augmentation of anticancer immune response. Cancer Investigation. 2011; 29: 533\u2013541.","key":"ref27","DOI":"10.3109\/07357907.2011.605413"},{"doi-asserted-by":"crossref","unstructured":"Paley MA, Prescher JA. Bioluminescence: a versatile technique for imaging cellular and molecular features. MedChemComm. 2014; 5: 255\u2013267.","key":"ref28","DOI":"10.1039\/C3MD00288H"},{"doi-asserted-by":"crossref","unstructured":"Duda J, Karimi M, Negrin RS, Contag CH. Methods for imaging cell fates in hematopoiesis. Methods in Molecular Medicine. 2007; 134: 17\u201334.","key":"ref29","DOI":"10.1007\/978-1-59745-223-6_2"},{"doi-asserted-by":"crossref","unstructured":"Lai H, Chou T, Tzeng C, Lee OK. Cytokine Profiles in Various Graft-Versus-Host Disease Target Organs following Hematopoietic Stem Cell Transplantation. Cell Transplantation. 2012; 21: 2033\u20132045.","key":"ref30","DOI":"10.3727\/096368912X653110"},{"doi-asserted-by":"crossref","unstructured":"Naserian S, Leclerc M, Thiolat A, Pilon C, Le Bret C, Belkacemi Y, et al. Simple, reproducible, and efficient clinical grading system for murine models of acute graft-versus-host disease. Frontiers in Immunology. 2018; 9: 10.","key":"ref31","DOI":"10.3389\/fimmu.2018.00010"},{"doi-asserted-by":"crossref","unstructured":"Stokes J, Hoffman EA, Zeng Y, Larmonier N, Katsanis E. Post-transplant bendamustine reduces GvHD while preserving GvL in experimental haploidentical bone marrow transplantation. British Journal of Haematology. 2016; 174: 102\u2013116.","key":"ref32","DOI":"10.1111\/bjh.14034"},{"doi-asserted-by":"crossref","unstructured":"Fisher JP, Heuijerjans J, Yan M, Gustafsson K, Anderson J. \u0393\u03b4 T cells for cancer immunotherapy: A systematic review of clinical trials. OncoImmunology. 2014; 3: e27572.","key":"ref33","DOI":"10.4161\/onci.27572"},{"doi-asserted-by":"crossref","unstructured":"Tam YK, Klingemann H. Antileukemic effect of interleukin-2-transduced murine bone marrow after autologous transplantation. Biology of Blood and Marrow Transplantation. 1999; 5: 231\u2013242.","key":"ref34","DOI":"10.1053\/bbmt.1999.v5.pm10465103"},{"doi-asserted-by":"crossref","unstructured":"Weiss L, Reich S, Slavin S. Use of recombinant human interleukin-2 in conjunction with bone marrow transplantation as a model for control of minimal residual disease in malignant hematological disorders: I. Treatment of murine leukemia in conjunction with allogeneic bone marrow transplantation and IL-2-activated cell-mediated immunotherapy. Cancer Investigation. 1992; 10: 19\u201326.","key":"ref35","DOI":"10.3109\/07357909209032785"},{"unstructured":"Yamasaki A, Onishi H, Morisaki T, Katano M. Induction of cytotoxic T lymphocytes by CEA peptide-pulsed \u03b3\u03b4 T-cells isolated from patients with advanced cancer. Anticancer Research. 2011; 31: 2419\u20132424.","key":"ref36"},{"doi-asserted-by":"crossref","unstructured":"Nada MH, Wang H, Workalemahu G, Tanaka Y, Morita CT. Enhancing adoptive cancer immunotherapy with V\u03b32V\u03b42 T cells through pulse zoledronate stimulation. Journal for ImmunoTherapy of Cancer. 2017; 5: 9.","key":"ref37","DOI":"10.1186\/s40425-017-0209-6"},{"doi-asserted-by":"crossref","unstructured":"Cui Q, Shibata H, Oda A, Amou H, Nakano A, Yata K, et al. Targeting myeloma\u2013osteoclast interaction with V\u03b39V\u03b42 T cells. International Journal of Hematology. 2011; 94: 63\u201370.","key":"ref38","DOI":"10.1007\/s12185-011-0885-9"},{"doi-asserted-by":"crossref","unstructured":"Galley HF, Lowes DA, Thompson K, Wilson ND, Wallace CA, Webster NR. Characterisation of gamma delta (\u03b3\u03b4) T cell populations in patients with sepsis. Cell Biology International. 2015; 39: 210\u2013216.","key":"ref39","DOI":"10.1002\/cbin.10361"},{"doi-asserted-by":"crossref","unstructured":"Zoine JT, Knight KA, Fleischer LC, Sutton KS, Goldsmith KC, Doering CB, et al. Ex vivo expanded patient-derived \u03b3\u03b4 T-cell immunotherapy enhances neuroblastoma tumor regression in a murine model. Oncoimmunology. 2019; 8: 1593804.","key":"ref40","DOI":"10.1080\/2162402X.2019.1593804"},{"doi-asserted-by":"crossref","unstructured":"Bergamaschi C, Bear J, Rosati M, Beach RK, Alicea C, Sowder R, et al. Circulating IL-15 exists as heterodimeric complex with soluble IL-15R\u03b1 in human and mouse serum. Blood. 2012; 120: e1\u2013e8.","key":"ref41","DOI":"10.1182\/blood-2011-10-384362"},{"doi-asserted-by":"crossref","unstructured":"Hauschild S, Tauber S, Lauber B, Thiel CS, Layer LE, Ullrich O. T cell regulation in microgravity \u2013 the current knowledge from in vitro experiments conducted in space, parabolic flights and ground-based facilities. Acta Astronautica. 2014; 104: 365\u2013377.","key":"ref42","DOI":"10.1016\/j.actaastro.2014.05.019"},{"doi-asserted-by":"crossref","unstructured":"Miller JS, Soignier Y, Panoskaltsis-Mortari A, McNearney SA, Yun GH, Fautsch SK, et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood. 2005; 105: 3051\u20133057.","key":"ref43","DOI":"10.1182\/blood-2004-07-2974"},{"unstructured":"Cavanagh PR, Licata AA, Rice AJ. Exercise and pharmacological countermeasures for bone loss during long-duration space flight. Gravitational and Space Biology Bulletin. 2005; 18: 39\u201358.","key":"ref44"},{"doi-asserted-by":"crossref","unstructured":"Bertaina A, Zorzoli A, Petretto A, Barbarito G, Inglese E, Merli P, et al. Zoledronic acid boosts \u03b3\u03b4 T-cell activity in children receiving \u03b1 \u03b2 + T and CD19 + cell-depleted grafts from an HLA-haplo-identical donor. Oncoimmunology. 2016; 6: e1216291.","key":"ref45","DOI":"10.1080\/2162402X.2016.1216291"}],"container-title":["Frontiers in Bioscience-Landmark"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/27\/7\/10.31083\/j.fbl2707215","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T12:05:42Z","timestamp":1732709142000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/27\/7\/10.31083\/j.fbl2707215"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,8]]},"references-count":45,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2022]]}},"alternative-id":["S2768-6701(22)00575-5"],"URL":"https:\/\/doi.org\/10.31083\/j.fbl2707215","relation":{},"ISSN":["2768-6701","2768-6698"],"issn-type":[{"type":"print","value":"2768-6701"},{"type":"electronic","value":"2768-6698"}],"subject":[],"published":{"date-parts":[[2022,7,8]]},"article-number":"215"}}