{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T06:48:43Z","timestamp":1781246923331,"version":"3.54.1"},"reference-count":74,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2020,11,24]],"date-time":"2020-11-24T00:00:00Z","timestamp":1606176000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH\/NEI","award":["EY030447"],"award-info":[{"award-number":["EY030447"]}]},{"name":"NEI Training Grant in Vision Sciences","award":["T32 EY007001"],"award-info":[{"award-number":["T32 EY007001"]}]},{"name":"Core Grant for Vision Research Department of Ophthalmology","award":["NIH\/NEI EY002520"],"award-info":[{"award-number":["NIH\/NEI EY002520"]}]},{"name":"NIH Pathology Core","award":["P30CA125123"],"award-info":[{"award-number":["P30CA125123"]}]},{"name":"CPRIT Core Facility Support Award","award":["CPRIT-RP180672"],"award-info":[{"award-number":["CPRIT-RP180672"]}]},{"name":"P30 Cancer Center Support Grant","award":["NCI-CA125123"],"award-info":[{"award-number":["NCI-CA125123"]}]},{"name":"Union BioMetrica BioSorter","award":["NIH-RR024574"],"award-info":[{"award-number":["NIH-RR024574"]}]},{"name":"Union BioMetrica BioSorter","award":["NIH S10 OD025251"],"award-info":[{"award-number":["NIH S10 OD025251"]}]},{"name":"National Institute on Minority Health and Health Disparities of National Institutes of Health","award":["U54 MD007582"],"award-info":[{"award-number":["U54 MD007582"]}]},{"name":"NSF-CREST Center for Complex Materials Design for Multidimensional Additive Processing","award":["1735968"],"award-info":[{"award-number":["1735968"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Dry eye disease (DED), one of the most prevalent conditions among the elderly, is a chronic inflammatory disorder that disrupts tear film stability and causes ocular surface damage. Aged C57BL\/6J mice spontaneously develop DED. Rapamycin is a potent immunosuppressant that prolongs the lifespan of several species. Here, we compared the effects of daily instillation of eyedrops containing rapamycin or empty micelles for three months on the aged mice. Tear cytokine\/chemokine profile showed a pronounced increase in vascular endothelial cell growth factor-A (VEGF-A) and a trend towards decreased concentration of Interferon gamma (IFN)-\u03b3 in rapamycin-treated groups. A significant decrease in inflammatory markers in the lacrimal gland was also evident (IFN-\u03b3, IL-12, CIITA and Ctss); this was accompanied by slightly diminished Unc-51 Like Autophagy Activating Kinase 1 (ULK1) transcripts. In the lacrimal gland and draining lymph nodes, we also observed a significant increase in the CD45+CD4+Foxp3+ cells in the rapamycin-treated mice. More importantly, rapamycin eyedrops increased conjunctival goblet cell density and area compared to the empty micelles. Taken together, evidence from these studies indicates that topical rapamycin has therapeutic efficacy for age-associated ocular surface inflammation and goblet cell loss and opens the venue for new investigations on its role in the aging process of the eye.<\/jats:p>","DOI":"10.3390\/ijms21238890","type":"journal-article","created":{"date-parts":[[2020,11,24]],"date-time":"2020-11-24T09:06:28Z","timestamp":1606208788000},"page":"8890","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Rapamycin Eyedrops Increased CD4+Foxp3+ Cells and Prevented Goblet Cell Loss in the Aged Ocular Surface"],"prefix":"10.3390","volume":"21","author":[{"given":"Claudia M.","family":"Trujillo-Vargas","sequence":"first","affiliation":[{"name":"Grupo de Inmunodeficiencias Primarias, Facultad de Medicina, Universidad de Antioquia, UdeA, Medell\u00edn 050010, Colombia"},{"name":"Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shallu","family":"Kutlehria","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Pharmaceutical Sciences, Florida A&amp;M University, Tallahassee, FL 32307, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Humberto","family":"Hernandez","sequence":"additional","affiliation":[{"name":"Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo G.","family":"de Souza","sequence":"additional","affiliation":[{"name":"Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4079-4813","authenticated-orcid":false,"given":"Andrea","family":"Lee","sequence":"additional","affiliation":[{"name":"Graduate Program in Immunology &amp; Microbiology, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyuan","family":"Yu","sequence":"additional","affiliation":[{"name":"Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen C.","family":"Pflugfelder","sequence":"additional","affiliation":[{"name":"Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mandip","family":"Singh","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Pharmaceutical Sciences, Florida A&amp;M University, Tallahassee, FL 32307, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9057-5494","authenticated-orcid":false,"given":"Cintia S.","family":"de Paiva","sequence":"additional","affiliation":[{"name":"Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1167\/iovs.18-25822","article-title":"InflammAging at Ocular Surface: Clinical and Biomolecular Analyses in Healthy Volunteers","volume":"60","author":"Micera","year":"2019","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2024","DOI":"10.1167\/iovs.17-23358","article-title":"Age-Related Changes to Human Tear Composition","volume":"59","author":"Micera","year":"2018","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/s12948-017-0077-0","article-title":"Immunosenescence in aging: Between immune cells depletion and cytokines up-regulation","volume":"15","author":"Ventura","year":"2017","journal-title":"Clin. Mol. Allergy CMA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1089\/jwh.2018.7041","article-title":"Dry Eye Disease: Consideration for Women\u2019s Health","volume":"28","author":"Matossian","year":"2019","journal-title":"J. Women\u2019s Health"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1136\/bjophthalmol-2015-307848","article-title":"Ageing and ocular surface immunity","volume":"101","author":"Mashaghi","year":"2017","journal-title":"Br. J. Ophthalmol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3653","DOI":"10.4049\/jimmunol.1101442","article-title":"Ocular surface APCs are necessary for autoreactive T cell-mediated experimental autoimmune lacrimal keratoconjunctivitis","volume":"187","author":"Schaumburg","year":"2011","journal-title":"J. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2553","DOI":"10.1167\/iovs.07-0069","article-title":"Dry eye-induced conjunctival epithelial squamous metaplasia is modulated by interferon-gamma","volume":"48","author":"Villarreal","year":"2007","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1038\/mi.2009.5","article-title":"IL-17 disrupts corneal barrier following desiccating stress","volume":"2","author":"Chotikavanich","year":"2009","journal-title":"Mucosal Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1038\/mi.2016.83","article-title":"Age-related spontaneous lacrimal keratoconjunctivitis is accompanied by dysfunctional T regulatory cells","volume":"10","author":"Coursey","year":"2017","journal-title":"Mucosal Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/j.ajpath.2013.11.019","article-title":"Ocular surface disease and dacryoadenitis in aging C57BL\/6 mice","volume":"184","author":"McClellan","year":"2014","journal-title":"Am. J. Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"64605","DOI":"10.18632\/oncotarget.11872","article-title":"Interferon-gamma deficiency protects against aging-related goblet cell loss","volume":"7","author":"Volpe","year":"2016","journal-title":"Oncotarget"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e3","DOI":"10.4110\/in.2019.19.e3","article-title":"Age-related Autoimmune Changes in Lacrimal Glands","volume":"19","author":"Alves","year":"2019","journal-title":"Immune Netw."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1038\/s41385-018-0127-z","article-title":"Age-associated antigen-presenting cell alterations promote dry-eye inducing Th1 cells","volume":"12","author":"Bian","year":"2019","journal-title":"Mucosal Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2705","DOI":"10.1167\/iovs.19-26631","article-title":"The Effects of Aging on Corneal and Ocular Surface Homeostasis in Mice","volume":"60","author":"Hill","year":"2019","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1126\/science.1215135","article-title":"Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity","volume":"335","author":"Lamming","year":"2012","journal-title":"Science"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1139\/y77-007","article-title":"Inhibition of the immune response by rapamycin, a new antifungal antibiotic","volume":"55","author":"Martel","year":"1977","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1177\/0961203307088289","article-title":"Rapamycin prevents the development of nephritis in lupus-prone NZB\/W F1 mice","volume":"17","author":"Lui","year":"2008","journal-title":"Lupus"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1097\/00007890-199501000-00005","article-title":"Prolongation of renal allograft survival in a large animal model by oral rapamycin monotherapy","volume":"59","author":"Granger","year":"1995","journal-title":"Transplantation"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.3389\/fphar.2018.01520","article-title":"Rapamycin: A Bacteria-Derived Immunosuppressant That Has Anti-atherosclerotic Effects and Its Clinical Application","volume":"9","author":"Liu","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"7824","DOI":"10.1038\/s41598-019-44106-5","article-title":"Rapamycin modulates tissue aging and lifespan independently of the gut microbiota in Drosophila","volume":"9","author":"Schinaman","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_21","first-page":"1024","article-title":"Meta-Analysis of 29 Experiments Evaluating the Effects of Rapamycin on Life Span in the Laboratory Mouse","volume":"72","author":"Swindell","year":"2017","journal-title":"J. Gerontol. Ser. A Biol. Sci. Med. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1111\/j.1474-9726.2011.00722.x","article-title":"Rapamycin and other longevity-promoting compounds enhance the generation of mouse induced pluripotent stem cells","volume":"10","author":"Chen","year":"2011","journal-title":"Aging Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1089\/rej.2018.2070","article-title":"Rapamycin Confers Neuroprotection Against Aging-Induced Oxidative Stress, Mitochondrial Dysfunction, and Neurodegeneration in Old Rats Through Activation of Autophagy","volume":"22","author":"Singh","year":"2019","journal-title":"Rejuvenation Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.ajpath.2012.04.018","article-title":"Prevention of age-related macular degeneration-like retinopathy by rapamycin in rats","volume":"181","author":"Kolosova","year":"2012","journal-title":"Am. J. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1007\/s00417-010-1420-z","article-title":"Influence of combined treatment of low dose rapamycin and cyclosporin A on corneal allograft survival","volume":"248","author":"Stanojlovic","year":"2010","journal-title":"Graefe\u2019s Arch. Clin. Exp. Ophthalmol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1097\/01.tp.0000191291.71003.1b","article-title":"An open prospective pilot study on the use of rapamycin after penetrating high-risk keratoplasty","volume":"81","author":"Birnbaum","year":"2006","journal-title":"Transplantation"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"40308","DOI":"10.1038\/srep40308","article-title":"Rapamycin Prolongs the Survival of Corneal Epithelial Cells in Culture","volume":"7","author":"Gidfar","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"44876","DOI":"10.18632\/oncotarget.10381","article-title":"Rapamycin in aging and disease: Maximizing efficacy while minimizing side effects","volume":"7","author":"Johnson","year":"2016","journal-title":"Oncotarget"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1647746","DOI":"10.1080\/20010001.2019.1647746","article-title":"Rapamycin increases breast tumor burden in young wheel-running mice","volume":"9","author":"Wang","year":"2019","journal-title":"Pathobiol. Aging Age Relat. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Zhang, Z., Wu, X., Duan, J., Hinrichs, D., Wegmann, K., Zhang, G.L., Hall, M., and Rosenbaum, J.T. (2012). Low dose rapamycin exacerbates autoimmune experimental uveitis. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0036589"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9269","DOI":"10.1038\/s41598-019-45759-y","article-title":"Delivery of Rapamycin Using In Situ Forming Implants Promotes Immunoregulation and Vascularized Composite Allograft Survival","volume":"9","author":"Sutter","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"43299","DOI":"10.1038\/srep43299","article-title":"Progressive slowdown\/prevention of cellular senescence by CD9-targeted delivery of rapamycin using lactose-wrapped calcium carbonate nanoparticles","volume":"7","author":"Thapa","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"9718","DOI":"10.18632\/oncotarget.3929","article-title":"Rapatar, a nanoformulation of rapamycin, decreases chemically-induced benign prostate hyperplasia in rats","volume":"6","author":"Lesovaya","year":"2015","journal-title":"Oncotarget"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1111\/jphp.12089","article-title":"Rapamycin-loaded poly(epsilon-caprolactone)-poly(ethylene glycol)-poly(epsilon-caprolactone) nanoparticles: Preparation, characterization and potential application in corneal transplantation","volume":"66","author":"Zhang","year":"2014","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.jconrel.2013.07.016","article-title":"A rapamycin-binding protein polymer nanoparticle shows potent therapeutic activity in suppressing autoimmune dacryoadenitis in a mouse model of Sjogren\u2019s syndrome","volume":"171","author":"Shah","year":"2013","journal-title":"J. Control. Rel. Off. J. Control. Release Soc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1167\/iovs.16-19159","article-title":"Rapamycin Eye Drops Suppress Lacrimal Gland Inflammation In a Murine Model of Sjogren\u2019s Syndrome","volume":"58","author":"Shah","year":"2017","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1080\/09273948.2018.1527369","article-title":"Effect of Rapamycin Microspheres in Sjogren Syndrome Dry Eye: Preparation and Outcomes","volume":"27","author":"Wang","year":"2019","journal-title":"Ocul. Immunol. Inflamm."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"8048","DOI":"10.18632\/aging.102355","article-title":"Rapamycin for longevity: Opinion article","volume":"11","author":"Blagosklonny","year":"2019","journal-title":"Aging"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.ajo.2008.08.032","article-title":"Tear cytokine profiles in dysfunctional tear syndrome","volume":"147","author":"Lam","year":"2009","journal-title":"Am. J. Ophthalmol."},{"key":"ref_40","first-page":"862","article-title":"Tear cytokine and chemokine analysis and clinical correlations in evaporative-type dry eye disease","volume":"16","author":"Castellanos","year":"2010","journal-title":"Mol. Vis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2239","DOI":"10.1038\/onc.2014.164","article-title":"mTORC1 drives HIF-1\u03b1 and VEGF-A signalling via multiple mechanisms involving 4E-BP1, S6K1 and STAT3","volume":"34","author":"Dodd","year":"2015","journal-title":"Oncogene"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/S1542-0124(12)70177-5","article-title":"The aging lacrimal gland: Changes in structure and function","volume":"6","author":"Rocha","year":"2008","journal-title":"Ocul. Surf."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1016\/S0161-6420(95)30971-2","article-title":"Histopathologic study of human lacrimal gland. Statistical analysis with special reference to aging","volume":"102","author":"Obata","year":"1995","journal-title":"Ophthalmology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1042\/EBC20170021","article-title":"The mammalian ULK1 complex and autophagy initiation","volume":"61","author":"Zachari","year":"2017","journal-title":"Essays Biochem."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Yoon, C.H., Ryu, J.S., Hwang, H.S., and Kim, M.K. (2020). Comparative Analysis of Age-Related Changes in Lacrimal Glands and Meibomian Glands of a C57BL\/6 Male Mouse Model. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21114169"},{"key":"ref_46","first-page":"636812","article-title":"Modulation of conjunctival goblet cell function by inflammatory cytokines","volume":"2013","author":"Shatos","year":"2013","journal-title":"Mediat. Inflamm."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1093\/intimm\/dxy045","article-title":"Goblet cell-produced retinoic acid suppresses CD86 expression and IL-12 production in bone marrow-derived cells","volume":"30","author":"Xiao","year":"2018","journal-title":"Int. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.jtos.2019.12.006","article-title":"Immune\u2014Goblet cell interaction in the conjunctiva","volume":"18","author":"Alam","year":"2020","journal-title":"Ocul. Surf."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/mi.2010.82","article-title":"Homeostatic control of conjunctival mucosal goblet cells by NKT-derived IL-13","volume":"4","author":"Raince","year":"2011","journal-title":"Mucosal Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1111\/j.1474-9726.2011.00791.x","article-title":"Lifelong rapamycin administration ameliorates age-dependent cognitive deficits by reducing IL-1beta and enhancing NMDA signaling","volume":"11","author":"Majumder","year":"2012","journal-title":"Aging Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"5019","DOI":"10.1167\/iovs.09-4523","article-title":"Increased expression of cathepsins and obesity-induced proinflammatory cytokines in lacrimal glands of male NOD mouse","volume":"51","author":"Li","year":"2010","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1016\/j.intimp.2007.08.027","article-title":"Rapamycin inhibits differentiation of Th17 cells and promotes generation of FoxP3+ T regulatory cells","volume":"7","author":"Kopf","year":"2007","journal-title":"Int. Immunopharmacol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"5794","DOI":"10.4049\/jimmunol.180.9.5794","article-title":"Cutting edge: Foxp3-mediated induction of pim 2 allows human T regulatory cells to preferentially expand in rapamycin","volume":"180","author":"Basu","year":"2008","journal-title":"J. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"8338","DOI":"10.4049\/jimmunol.177.12.8338","article-title":"Rapamycin promotes expansion of functional CD4+CD25+FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients","volume":"177","author":"Battaglia","year":"2006","journal-title":"J. Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"7018","DOI":"10.4049\/jimmunol.178.11.7018","article-title":"Rapamycin-conditioned dendritic cells are poor stimulators of allogeneic CD4+ T cells, but enrich for antigen-specific Foxp3+ T regulatory cells and promote organ transplant tolerance","volume":"178","author":"Turnquist","year":"2007","journal-title":"J. Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"5756","DOI":"10.4049\/jimmunol.1102133","article-title":"Rapamycin attenuates airway hyperreactivity, goblet cells, and IgE in experimental allergic asthma","volume":"187","author":"Mushaben","year":"2011","journal-title":"J. Immunol."},{"key":"ref_57","first-page":"1263","article-title":"mTOR disruption causes intestinal epithelial cell defects and intestinal atrophy postinjury in mice","volume":"30","author":"Sampson","year":"2016","journal-title":"FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1002\/cne.24454","article-title":"Morphological and functional changes in TRPM8-expressing corneal cold thermoreceptor neurons during aging and their impact on tearing in mice","volume":"526","author":"Alcalde","year":"2018","journal-title":"J. Comp. Neurol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"283","DOI":"10.3389\/fimmu.2017.00283","article-title":"Old Mice Accumulate Activated Effector CD4 T Cells Refractory to Regulatory T Cell-Induced Immunosuppression","volume":"8","author":"Harpaz","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/978-1-59745-157-4_4","article-title":"LC3 and Autophagy","volume":"445","author":"Tanida","year":"2008","journal-title":"Meth. Mol. Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1167\/iovs.18-25583","article-title":"Rapamycin Rescues Endoplasmic Reticulum Stress-Induced Dry Eye Syndrome in Mice","volume":"60","author":"Cho","year":"2019","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Zhang, X., Chen, W., Gao, Q., Yang, J., Yan, X., Zhao, H., Su, L., Yang, M., Gao, C., and Yao, Y. (2019). Rapamycin directly activates lysosomal mucolipin TRP channels independent of mTOR. PLoS Biol., 17.","DOI":"10.1371\/journal.pbio.3000252"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"17272","DOI":"10.1073\/pnas.1407227111","article-title":"VEGF-B selectively regenerates injured peripheral neurons and restores sensory and trophic functions","volume":"111","author":"Guaiquil","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1016\/j.ajpath.2010.12.001","article-title":"IL-17 and VEGF are necessary for efficient corneal nerve regeneration","volume":"178","author":"Li","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"3024","DOI":"10.1021\/acs.molpharmaceut.9b00263","article-title":"Berunda Polypeptides: Biheaded Rapamycin Carriers for Subcutaneous Treatment of Autoimmune Dry Eye Disease","volume":"16","author":"Lee","year":"2019","journal-title":"Mol. Pharm."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2358","DOI":"10.1021\/acs.bioconjchem.9b00462","article-title":"Molecular Targeting of Immunosuppressants Using a Bifunctional Elastin-Like Polypeptide","volume":"30","author":"Ju","year":"2019","journal-title":"Bioconjug. Chem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2245","DOI":"10.18632\/aging.101319","article-title":"Towards natural mimetics of metformin and rapamycin","volume":"9","author":"Aliper","year":"2017","journal-title":"Aging"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1002\/med.21535","article-title":"Mechanistic\/mammalian target of rapamycin: Recent pathological aspects and inhibitors","volume":"39","author":"Benhalilou","year":"2019","journal-title":"Med. Res. Rev."},{"key":"ref_69","unstructured":"National Research Council Committee for the Update of the Guide for the Care, and Use of Laboratory Animals (2011). The National Academies Collection: Reports funded by National Institutes of Health. Guide for the Care and Use of Laboratory Animals, National Academies Press (US)."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/1476-9255-6-31","article-title":"Cleavage of functional IL-2 receptor alpha chain (CD25) from murine corneal and conjunctival epithelia by MMP-9","volume":"6","author":"Yoon","year":"2009","journal-title":"J. Inflamm."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"5264","DOI":"10.4049\/jimmunol.1400016","article-title":"Desiccating stress-induced chemokine expression in the epithelium is dependent on upregulation of NKG2D\/RAE-1 and release of IFN-gamma in experimental dry eye","volume":"193","author":"Coursey","year":"2014","journal-title":"J. Immunol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.jaut.2018.06.004","article-title":"Protective role of commensal bacteria in Sjogren Syndrome","volume":"93","author":"Zaheer","year":"2018","journal-title":"J. Autoimmun."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2224","DOI":"10.1167\/iovs.14-15668","article-title":"Age-Related Conjunctival Disease in the C57BL\/6.NOD-Aec1Aec2 Mouse Model of Sjogren Syndrome Develops Independent of Lacrimal Dysfunction","volume":"56","author":"You","year":"2015","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Wang, C., Zaheer, M., Bian, F., Quach, D., Swennes, A.G., Britton, R.A., Pflugfelder, S.C., and de Paiva, C.S. (2018). Sjogren-Like Lacrimal Keratoconjunctivitis in Germ-Free Mice. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19020565"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/23\/8890\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:36:34Z","timestamp":1760178994000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/23\/8890"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,24]]},"references-count":74,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["ijms21238890"],"URL":"https:\/\/doi.org\/10.3390\/ijms21238890","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,24]]}}}