{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T23:21:19Z","timestamp":1794007279295,"version":"4.8.0"},"reference-count":51,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2024,7,5]],"date-time":"2024-07-05T00:00:00Z","timestamp":1720137600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Rinri Therapeutics Ltd"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Pharmacologic immunosuppression regimes are commonly employed in stem cell clinical trials to mitigate host immune rejection and promote survival and viability of transplanted cells. Immunosuppression and cell survival has been extensively studied in retinal and spinal tissues. The applicability of stem cell therapy is rapidly expanding to other sensory organs such as the ear and hearing. As regenerative therapy is directed to new areas, a greater understanding of immunosuppression strategies and their efficacy is required to facilitate translation to organ-specific biologic microenvironments.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Objective<\/jats:title>\n<jats:p>This systematic review appraises the current literature regarding immunosuppression strategies employed in stem cell trials of retinal and neural cells.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Methods<\/jats:title>\n<jats:p>This systematic review was performed in line with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Inclusion criteria included studies presenting data on neural or retinal cells as part of an in-human clinical trial that detailed the immunosuppression regime used. Exclusion criteria included non-English language studies, animal studies, review articles, case reports, editorials, and letters. The databases Medline, Embase, Scopus, Web of Science, and the Cochrane Library were searched from inception to February 2024. Risk of bias was evaluated using the ROBINS-I tool.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Results<\/jats:title>\n<jats:p>Eighteen articles fit the inclusion criteria. Nine articles concerned retinal cells, 5 concerned spinal cord injury, and 4 concerned amyotrophic lateral sclerosis. A multi-drug and short-term immunosuppression regime were commonly employed in the identified studies. Detected immune responses in treated patients were rare. Common immunosuppression paradigms included tacrolimus, mycophenolate mofetil and tapering doses of steroids. Local immunosuppression with steroids was employed in some studies concerning retinal diseases.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec005\">\n<jats:title>Discussion<\/jats:title>\n<jats:p>A short-term course of systemic immunosuppression seemed efficacious for most included studies, with some showing grafted cells viable months to years after immunosuppression had stopped. Longer-term follow-up is required to see if this remains the case. Side effects related to immunosuppression were uncommon.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0304073","type":"journal-article","created":{"date-parts":[[2024,7,5]],"date-time":"2024-07-05T17:43:43Z","timestamp":1720201423000},"page":"e0304073","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["Immunosuppression in stem cell clinical trials of neural and retinal cell types: A systematic review"],"prefix":"10.1371","volume":"19","author":[{"given":"Shravan","family":"Gowrishankar","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew E.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3879-3371","authenticated-orcid":true,"given":"Nathan","family":"Creber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3065-0269","authenticated-orcid":true,"given":"Jameel","family":"Muzaffar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3464-2688","authenticated-orcid":true,"given":"Daniele","family":"Borsetto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,7,5]]},"reference":[{"key":"pone.0304073.ref001","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1186\/s13287-019-1165-5","article-title":"Stem cells: past, present, and future","volume":"10","author":"W Zakrzewski","year":"2019","journal-title":"Stem Cell Research & Therapy"},{"key":"pone.0304073.ref002","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s42003-021-02237-4","article-title":"Immunological considerations and challenges for regenerative cellular therapies","volume":"4","author":"S Petrus-Reurer","year":"2021","journal-title":"Commun Biol"},{"key":"pone.0304073.ref003","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1177\/1545968320935815","article-title":"The Damaged Spinal Cord Is a Suitable Target for Stem Cell Transplantation","volume":"34","author":"A Curt","year":"2020","journal-title":"Neurorehabil Neural Repair"},{"key":"pone.0304073.ref004","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1038\/nbt.4114","article-title":"Phase 1 clinical study of an embryonic stem cell\u2013derived retinal pigment epithelium patch in age-related macular degeneration","volume":"36","author":"L da Cruz","year":"2018","journal-title":"Nat Biotechnol"},{"key":"pone.0304073.ref005","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1212\/WNL.0000000000002889","article-title":"Transplantation of spinal cord-derived neural stem cells for ALS: Analysis of phase 1 and 2 trials","volume":"87","author":"JD Glass","year":"2016","journal-title":"Neurology"},{"key":"pone.0304073.ref006","doi-asserted-by":"crossref","first-page":"e13100","DOI":"10.1111\/cpr.13100","article-title":"A phase I clinical trial of human embryonic stem cell-derived retinal pigment epithelial cells for early-stage Stargardt macular degeneration: 5-years\u2019 follow-up","volume":"54","author":"S-Y Li","year":"2021","journal-title":"Cell Prolif"},{"key":"pone.0304073.ref007","doi-asserted-by":"crossref","first-page":"2891","DOI":"10.1038\/s41598-018-38065-6","article-title":"Critical Functionality Effects from Storage Temperature on Human Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelium Cell Suspensions","volume":"9","author":"S Kitahata","year":"2019","journal-title":"Sci Rep"},{"key":"pone.0304073.ref008","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1080\/14712598.2017.1346079","article-title":"Induced pluripotent stem cell-based therapy for age-related macular degeneration","volume":"17","author":"P Bracha","year":"2017","journal-title":"Expert Opin Biol Ther"},{"key":"pone.0304073.ref009","unstructured":"Tacrolimus | Drugs | BNF content published by NICE [Internet]. [cited 2023 Feb 6]. Available from: https:\/\/bnf.nice.org.uk\/drugs\/tacrolimus\/."},{"key":"pone.0304073.ref010","unstructured":"Prednisolone | Drugs | BNF content published by NICE [Internet]. [cited 2023 Feb 6]. Available from: https:\/\/bnf.nice.org.uk\/drugs\/prednisolone\/."},{"key":"pone.0304073.ref011","doi-asserted-by":"crossref","first-page":"5680","DOI":"10.3390\/ijms20225680","article-title":"The Importance of HLA Assessment in \u201cOff-the-Shelf\u201d Allogeneic Mesenchymal Stem Cells Based-Therapies","volume":"20","author":"M Kot","year":"2019","journal-title":"Int J Mol Sci"},{"key":"pone.0304073.ref012","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1038\/s41591-022-01956-3","article-title":"Transplantation of human neural progenitor cells secreting GDNF into the spinal cord of patients with ALS: a phase 1\/2a trial","volume":"28","author":"RH Baloh","year":"2022","journal-title":"Nat Med"},{"key":"pone.0304073.ref013","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41536-020-00100-4","article-title":"Global trends in clinical trials involving pluripotent stem cells: a systematic multi-database analysis","volume":"5","author":"J Deinsberger","year":"2020","journal-title":"npj Regen Med"},{"key":"pone.0304073.ref014","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.jclinepi.2016.01.021","article-title":"PRESS Peer Review of Electronic Search Strategies: 2015 Guideline Statement","volume":"75","author":"J McGowan","year":"2016","journal-title":"Journal of Clinical Epidemiology"},{"key":"pone.0304073.ref015","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s13643-020-01542-z","article-title":"PRISMA-S: an extension to the PRISMA Statement for Reporting Literature Searches in Systematic Reviews.","volume":"10","author":"ML Rethlefsen","year":"2021","journal-title":"Systematic Reviews"},{"key":"pone.0304073.ref016","doi-asserted-by":"crossref","first-page":"i4919","DOI":"10.1136\/bmj.i4919","article-title":"ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions","volume":"355","author":"JA Sterne","year":"2016","journal-title":"BMJ"},{"key":"pone.0304073.ref017","doi-asserted-by":"crossref","DOI":"10.1167\/iovs.15-18681","article-title":"Subretinal Transplantation of Embryonic Stem Cell-Derived Retinal Pigment Epithelium for the Treatment of Macular Degeneration: An Assessment at 4 Years","volume":"57","author":"SD Schwartz","year":"2016","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"pone.0304073.ref018","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/s41421-018-0053-y","article-title":"Human embryonic stem cell-derived retinal pigment epithelium transplants as a potential treatment for wet age-related macular degeneration","volume":"4","author":"Y Liu","year":"2018","journal-title":"Cell Discov"},{"key":"pone.0304073.ref019","doi-asserted-by":"crossref","first-page":"1765","DOI":"10.1016\/j.ophtha.2018.04.037","article-title":"Transplantation of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells in Macular Degeneration","volume":"125","author":"MS Mehat","year":"2018","journal-title":"Ophthalmology"},{"key":"pone.0304073.ref020","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1136\/bjophthalmol-2020-316225","article-title":"Long-term safety and tolerability of subretinal transplantation of embryonic stem cell-derived retinal pigment epithelium in Asian Stargardt disease patients","volume":"105","author":"Y Sung","year":"2021","journal-title":"Br J Ophthalmol"},{"key":"pone.0304073.ref021","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1002\/sctm.18-0154","article-title":"Results from Phase I Clinical Trial with Intraspinal Injection of Neural Stem Cells in Amyotrophic Lateral Sclerosis","volume":"8","author":"L Mazzini","year":"2019","journal-title":"A Long\u2010Term Outcome. Stem Cells Transl Med"},{"key":"pone.0304073.ref022","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1002\/stem.1079","article-title":"Lumbar intraspinal injection of neural stem cells in patients with amyotrophic lateral sclerosis: results of a phase I trial in 12 patients","volume":"30","author":"JD Glass","year":"2012","journal-title":"Stem Cells"},{"key":"pone.0304073.ref023","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1016\/j.stem.2018.05.014","article-title":"A First-in-Human, Phase I Study of Neural Stem Cell Transplantation for Chronic Spinal Cord Injury","volume":"22","author":"E Curtis","year":"2018","journal-title":"Cell Stem Cell"},{"key":"pone.0304073.ref024","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1089\/neu.2018.5843","article-title":"Clinical Outcomes from a Multi-Center Study of Human Neural Stem Cell Transplantation in Chronic Cervical Spinal Cord Injury","volume":"36","author":"AD Levi","year":"2019","journal-title":"J Neurotrauma"},{"key":"pone.0304073.ref025","first-page":"1","article-title":"Ten-year safety of pluripotent stem cell transplantation in acute thoracic spinal cord injury","author":"SL McKenna","year":"2022","journal-title":"J Neurosurg Spine"},{"key":"pone.0304073.ref026","doi-asserted-by":"crossref","first-page":"812","DOI":"10.3171\/2022.5.SPINE22167","article-title":"A phase 1\/2a dose-escalation study of oligodendrocyte progenitor cells in individuals with subacute cervical spinal cord injury","volume":"37","author":"RG Fessler","year":"2022","journal-title":"J Neurosurg Spine"},{"key":"pone.0304073.ref027","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1097\/IAE.0000000000003655","article-title":"TRANSPLANTATION OF SUBRETINAL STEM CELL-DERIVED RETINAL PIGMENT EPITHELIUM FOR STARGARDT DISEASE: A Phase I Clinical Trial","volume":"43","author":"RA Brant Fernandes","year":"2023","journal-title":"Retina"},{"key":"pone.0304073.ref028","article-title":"Long-term Follow-up of a Phase 1\/2a Clinical Trial of a Stem Cell-Derived Bioengineered Retinal Pigment Epithelium Implant for Geographic Atrophy","author":"MS Humayun","year":"2023","journal-title":"Ophthalmology [Internet]"},{"key":"pone.0304073.ref029","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1016\/j.stemcr.2015.04.005","article-title":"Treatment of macular degeneration using embryonic stem cell-derived retinal pigment epithelium: preliminary results in Asian patients","volume":"4","author":"WK Song","year":"2015","journal-title":"Stem Cell Reports"},{"key":"pone.0304073.ref030","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.urology.2017.03.006","article-title":"Urologic Management and Complications in Spinal Cord Injury Patients: A 40- to 50-year Follow-up Study","volume":"104","author":"Y Gao","year":"2017","journal-title":"Urology"},{"key":"pone.0304073.ref031","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1080\/01616412.2021.1893564","article-title":"Overview of stem cells therapy in amyotrophic lateral sclerosis","volume":"43","author":"G Je","year":"2021","journal-title":"Neurological Research"},{"key":"pone.0304073.ref032","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1186\/s12890-016-0297-y","article-title":"Hospitalizations due to respiratory failure in patients with Amyotrophic Lateral Sclerosis and their impact on survival: a population-based cohort study","volume":"16","author":"FE Pisa","year":"2016","journal-title":"BMC Pulm Med"},{"key":"pone.0304073.ref033","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1167\/iovs.17-22467","article-title":"Allogeneic iPSC-Derived RPE Cell Graft Failure Following Transplantation Into the Subretinal Space in Nonhuman Primates","volume":"59","author":"TJ McGill","year":"2018","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"pone.0304073.ref034","doi-asserted-by":"crossref","first-page":"926","DOI":"10.3390\/ijms20040926","article-title":"Human Embryonic Stem Cell-Derived Retinal Pigment Epithelium-Role in Dead Cell Clearance and Inflammation","volume":"20","author":"M Szatm\u00e1ri-T\u00f3th","year":"2019","journal-title":"Int J Mol Sci"},{"key":"pone.0304073.ref035","article-title":"Interaction Between Mesenchymal Stem Cells and Retinal Degenerative Microenvironment","author":"Y Lin","year":"2021","journal-title":"Frontiers in Neuroscience [Internet]"},{"key":"pone.0304073.ref036","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/j.stemcr.2018.07.009","article-title":"Immunological Properties of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells","volume":"11","author":"M Idelson","year":"2018","journal-title":"Stem Cell Reports"},{"key":"pone.0304073.ref037","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1007\/s12015-019-09908-0","article-title":"The Immunomodulatory Potential of Mesenchymal Stem Cells in a Retinal Inflammatory Environment","volume":"15","author":"B Hermankova","year":"2019","journal-title":"Stem Cell Rev and Rep"},{"key":"pone.0304073.ref038","doi-asserted-by":"crossref","first-page":"1885","DOI":"10.1038\/eye.2008.382","article-title":"Ocular immune privilege","volume":"23","author":"AW Taylor","year":"2009","journal-title":"Eye"},{"key":"pone.0304073.ref039","first-page":"I166","article-title":"Embryonic stem cell immunogenicity increases upon differentiation after transplantation into ischemic myocardium","volume":"112","author":"R-J Swijnenburg","year":"2005","journal-title":"Circulation"},{"key":"pone.0304073.ref040","doi-asserted-by":"crossref","first-page":"20920","DOI":"10.1073\/pnas.0710265105","article-title":"Embryonic stem cell-derived tissues are immunogenic but their inherent immune privilege promotes the induction of tolerance","volume":"104","author":"NJ Robertson","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pone.0304073.ref041","doi-asserted-by":"crossref","first-page":"12991","DOI":"10.1073\/pnas.0805802105","article-title":"Immunosuppressive therapy mitigates immunological rejection of human embryonic stem cell xenografts","volume":"105","author":"R-J Swijnenburg","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pone.0304073.ref042","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1038\/sj.bmt.1703076","article-title":"Mycophenolate mofetil for the prevention and treatment of graft-versus-host disease following stem cell transplantation: preliminary findings","volume":"27","author":"GB Vogelsang","year":"2001","journal-title":"Bone Marrow Transplant"},{"key":"pone.0304073.ref043","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/S0162-3109(00)00188-0","article-title":"Mycophenolate mofetil and its mechanisms of action","volume":"47","author":"AC Allison","year":"2000","journal-title":"Immunopharmacology"},{"key":"pone.0304073.ref044","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1097\/00007691-199512000-00007","article-title":"Mode of action of tacrolimus (FK506): molecular and cellular mechanisms","volume":"17","author":"AW Thomson","year":"1995","journal-title":"Ther Drug Monit"},{"key":"pone.0304073.ref045","doi-asserted-by":"crossref","first-page":"7S","DOI":"10.1016\/S0041-1345(03)00211-2","article-title":"Sirolimus: its discovery, biological properties, and mechanism of action","volume":"35","author":"SN Sehgal","year":"2003","journal-title":"Transplant Proc"},{"key":"pone.0304073.ref046","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.stem.2011.01.012","article-title":"Short-term Immunosuppression Promotes Engraftment of Embryonic and Induced Pluripotent Stem Cells","volume":"8","author":"JI Pearl","year":"2011","journal-title":"Cell Stem Cell"},{"key":"pone.0304073.ref047","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/j.cell.2006.07.024","article-title":"Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors","volume":"126","author":"K Takahashi","year":"2006","journal-title":"Cell"},{"key":"pone.0304073.ref048","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.stem.2015.01.018","article-title":"Successful function of autologous iPSC-derived dopamine neurons following transplantation in a non-human primate model of Parkinson\u2019s disease","volume":"16","author":"PJ Hallett","year":"2015","journal-title":"Cell Stem Cell"},{"key":"pone.0304073.ref049","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.stem.2017.09.014","article-title":"Human Trials of Stem Cell-Derived Dopamine Neurons for Parkinson\u2019s Disease: Dawn of a New Era","volume":"21","author":"RA Barker","year":"2017","journal-title":"Cell Stem Cell"},{"key":"pone.0304073.ref050","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/j.celrep.2012.04.009","article-title":"Generation of regionally specified neural progenitors and functional neurons from human embryonic stem cells under defined conditions","volume":"1","author":"A Kirkeby","year":"2012","journal-title":"Cell Rep"},{"key":"pone.0304073.ref051","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/nature10648","article-title":"Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson\u2019s disease","volume":"480","author":"S Kriks","year":"2011","journal-title":"Nature"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0304073","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,5]],"date-time":"2024-07-05T17:44:16Z","timestamp":1720201456000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0304073"}},"subtitle":[],"editor":[{"given":"Nazmul","family":"Haque","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,7,5]]},"references-count":51,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2024,7,5]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0304073","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,5]]}}}