{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T19:41:41Z","timestamp":1792870901827,"version":"4.5.0"},"reference-count":84,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,9,18]],"date-time":"2021-09-18T00:00:00Z","timestamp":1631923200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL111130"],"award-info":[{"award-number":["R01HL111130"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30CA008748"],"award-info":[{"award-number":["P30CA008748"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Recent studies suggest that Th2 cells play a key role in the pathology of secondary lymphedema by elaborating cytokines such as IL4 and IL13. The aim of this study was to test the efficacy of QBX258, a monoclonal IL4\/IL13 neutralizing antibody, in women with breast cancer\u2013related lymphedema (BCRL). We enrolled nine women with unilateral stage I\/II BCRL and treated them once monthly with intravenous infusions of QBX258 for 4 months. We measured limb volumes, bioimpedance, and skin tonometry, and analyzed the quality of life (QOL) using a validated lymphedema questionnaire (Upper Limb Lymphedema 27, ULL-27) before treatment, immediately after treatment, and 4 months following treatment withdrawal. We also obtained 5 mm skin biopsies from the normal and lymphedematous limbs before and after treatment. Treatment was well-tolerated; however, one patient with a history of cellulitis developed cellulitis during the trial and was excluded from further analysis. We found no differences in limb volumes or bioimpedance measurements after drug treatment. However, QBX258 treatment improved skin stiffness (p &lt; 0.001) and improved QOL measurements (Physical p &lt; 0.05, Social p = 0.01). These improvements returned to baseline after treatment withdrawal. Histologically, treatment decreased epidermal thickness, the number of proliferating keratinocytes, type III collagen deposition, infiltration of mast cells, and the expression of Th2-inducing cytokines in the lymphedematous skin. Our limited study suggests that immunotherapy against Th2 cytokines may improve skin changes and QOL of women with BCRL. This treatment appears to be less effective for decreasing limb volumes; however, additional studies are needed.<\/jats:p>","DOI":"10.3390\/biology10090934","type":"journal-article","created":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T07:52:14Z","timestamp":1632124334000},"page":"934","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Pilot Study of Anti-Th2 Immunotherapy for the Treatment of Breast Cancer-Related Upper Extremity Lymphedema"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5717-697X","authenticated-orcid":false,"given":"Babak J.","family":"Mehrara","sequence":"first","affiliation":[{"name":"Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyeung Ju","family":"Park","sequence":"additional","affiliation":[{"name":"Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raghu P.","family":"Kataru","sequence":"additional","affiliation":[{"name":"Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"Bromberg","sequence":"additional","affiliation":[{"name":"Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Coriddi","sequence":"additional","affiliation":[{"name":"Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung Eun","family":"Baik","sequence":"additional","affiliation":[{"name":"Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyeon","family":"Shin","sequence":"additional","affiliation":[{"name":"Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Li","sequence":"additional","affiliation":[{"name":"Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele R.","family":"Cavalli","sequence":"additional","affiliation":[{"name":"Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth M.","family":"Encarnacion","sequence":"additional","affiliation":[{"name":"Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meghan","family":"Lee","sequence":"additional","affiliation":[{"name":"Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly J.","family":"Van Zee","sequence":"additional","affiliation":[{"name":"Breast Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elyn","family":"Riedel","sequence":"additional","affiliation":[{"name":"Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph H.","family":"Dayan","sequence":"additional","affiliation":[{"name":"Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1002\/1097-0142(20010915)92:6<1368::AID-CNCR1459>3.0.CO;2-9","article-title":"Lymphedema in a cohort of breast carcinoma survivors 20 years after diagnosis","volume":"92","author":"Petrek","year":"2001","journal-title":"Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1196\/annals.1413.014","article-title":"Estimating the population burden of lymphedema","volume":"1131","author":"Rockson","year":"2008","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5213","DOI":"10.1200\/JCO.2008.16.3725","article-title":"Prevalence of lymphedema in women with breast cancer 5 years after sentinel lymph node biopsy or axillary dissection: Objective measurements","volume":"26","author":"McLaughlin","year":"2008","journal-title":"J. Clin. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"5138","DOI":"10.1002\/cncr.25458","article-title":"Lymphedema beyond breast cancer: A systematic review and meta-analysis of cancer-related secondary lymphedema","volume":"116","author":"Cormier","year":"2010","journal-title":"Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1111\/j.1075-122X.2004.21411.x","article-title":"Lymphedema of the arm and breast in irradiated breast cancer patients: Risks in an era of dramatically changing axillary surgery","volume":"10","author":"Goffman","year":"2004","journal-title":"Breast J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3536","DOI":"10.1200\/JCO.2007.14.4899","article-title":"Lymphedema after breast cancer: Incidence, risk factors, and effect on upper body function","volume":"26","author":"Hayes","year":"2008","journal-title":"J. Clin. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1111\/j.1524-4741.2006.00342.x","article-title":"Breast cancer-related lymphedema\u2014What are the significant predictors and how they affect the severity of lymphedema?","volume":"12","author":"Soran","year":"2006","journal-title":"Breast J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5689","DOI":"10.1200\/JCO.2008.16.4731","article-title":"Lymphedema and quality of life in breast cancer survivors: The Iowa Women\u2019s Health Study","volume":"26","author":"Ahmed","year":"2008","journal-title":"J. Clin. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2007","DOI":"10.1200\/JCO.2008.18.3517","article-title":"Incidence, treatment costs, and complications of lymphedema after breast cancer among women of working age: A 2-year follow-up study","volume":"27","author":"Shih","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1177\/1358863X9700200408","article-title":"Lymphedema: Anatomy, physiology and pathogenesis","volume":"2","author":"Szuba","year":"1997","journal-title":"Vasc. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1177\/1358836X9800300209","article-title":"Lymphedema: Classification, diagnosis and therapy","volume":"3","author":"Szuba","year":"1998","journal-title":"Vasc. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1200\/JCO.2008.17.9291","article-title":"Lymphedema in breast cancer survivors: Incidence, degree, time course, treatment, and symptoms","volume":"27","author":"Norman","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Nakamura, K., Radhakrishnan, K., Wong, Y.M., and Rockson, S.G. (2009). Anti-inflammatory pharmacotherapy with ketoprofen ameliorates experimental lymphatic vascular insufficiency in mice. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0008380"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1096\/fj.12-222695","article-title":"Th2 differentiation is necessary for soft tissue fibrosis and lymphatic dysfunction resulting from lymphedema","volume":"27","author":"Avraham","year":"2013","journal-title":"FASEB J."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Zampell, J.C., Yan, A., Elhadad, S., Avraham, T., Weitman, E., and Mehrara, B.J. (2012). CD4(+) cells regulate fibrosis and lymphangiogenesis in response to lymphatic fluid stasis. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0049940"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1970","DOI":"10.1038\/s41467-018-04418-y","article-title":"CD4(+) T cells are activated in regional lymph nodes and migrate to skin to initiate lymphedema","volume":"9","author":"Ly","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"14345","DOI":"10.1038\/ncomms14345","article-title":"Topical tacrolimus for the treatment of secondary lymphedema","volume":"8","author":"Gardenier","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"H1065","DOI":"10.1152\/ajpheart.00598.2014","article-title":"Regulation of inflammation and fibrosis by macrophages in lymphedema","volume":"308","author":"Ghanta","year":"2015","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1016\/j.jid.2015.12.001","article-title":"Excess lymphangiogenesis cooperatively induced by macrophages and CD4(+) T cells drives the pathogenesis of lymphedema","volume":"136","author":"Ogata","year":"2016","journal-title":"J. Investig. Dermatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e140853","DOI":"10.1172\/JCI140853","article-title":"Tetracyclines improve experimental lymphatic filariasis pathology by disrupting interleukin-4 receptor-mediated lymphangiogenesis","volume":"131","author":"Cross","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.trsl.2018.12.003","article-title":"T helper 2 differentiation is necessary for development of lymphedema","volume":"206","author":"Ly","year":"2019","journal-title":"Transl. Res."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Savetsky, I.L., Ghanta, S., Gardenier, J.C., Torrisi, J.S., Garcia Nores, G.D., Hespe, G.E., Nitti, M.D., Kataru, R.P., and Mehrara, B.J. (2015). Th2 cytokines inhibit lymphangiogenesis. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0126908"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1172\/JCI31487","article-title":"Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases","volume":"117","author":"Wynn","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"139","DOI":"10.18176\/jiaci.0254","article-title":"Dupilumab: A new paradigm for the treatment of allergic diseases","volume":"28","author":"Sastre","year":"2018","journal-title":"J. Investig. Allergol. Clin. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1001\/jama.2015.19330","article-title":"Effect of subcutaneous dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis: A randomized clinical trial","volume":"315","author":"Bachert","year":"2016","journal-title":"JAMA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1001\/jamadermatol.2018.2526","article-title":"Dupilumab for the treatment of recalcitrant bullous pemphigoid","volume":"154","author":"Kaye","year":"2018","journal-title":"JAMA Dermatol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Executive Committee of the International Society of Lymphology (2020). The diagnosis and treatment of peripheral lymphedema: 2020 Consensus Document of the International Society of Lymphology. Lymphology, 53, 3\u201319.","DOI":"10.2458\/lymph.4649"},{"key":"ref_28","first-page":"26","article-title":"Reliability and limits of agreement of circumferential, water displacement, and optoelectronic volumetry in the measurement of upper limb lymphedema","volume":"40","author":"Deltombe","year":"2007","journal-title":"Lymphology"},{"key":"ref_29","first-page":"77","article-title":"Validation of an optoelectronic limb volumeter (Perometer)","volume":"30","author":"Stanton","year":"1997","journal-title":"Lymphology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1089\/lrb.2006.4.47","article-title":"Bioimpedance analysis: Scientific background","volume":"4","author":"Cornish","year":"2006","journal-title":"Lymphat. Res. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Wiser, I., Mehrara, B.J., Coriddi, M., Kenworthy, E., Cavalli, M., Encarnacion, E., and Dayan, J.H. (2020). Preoperative Assessment of Upper Extremity Secondary Lymphedema. Cancers, 12.","DOI":"10.3390\/cancers12010135"},{"key":"ref_32","first-page":"2","article-title":"Early diagnosis of lymphedema using multiple frequency bioimpedance","volume":"34","author":"Cornish","year":"2001","journal-title":"Lymphology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2803","DOI":"10.1002\/(SICI)1097-0142(19981215)83:12B+<2803::AID-CNCR29>3.0.CO;2-W","article-title":"A review of measures of lymphedema","volume":"83","author":"Gerber","year":"1998","journal-title":"Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1002\/cncr.11641","article-title":"Treatment of postmastectomy lymphedema with low-level laser therapy: A double blind, placebo-controlled trial","volume":"98","author":"Carati","year":"2003","journal-title":"Cancer"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1089\/lrb.2008.1002","article-title":"Reliability of bioimpedance spectroscopy and tonometry after breast conserving cancer treatment","volume":"6","author":"Moseley","year":"2008","journal-title":"Lymphat. Res. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1007\/s11764-012-0247-5","article-title":"Quality of life among breast cancer patients with lymphedema: A systematic review of patient-reported outcome instruments and outcomes","volume":"7","author":"Pusic","year":"2013","journal-title":"J. Cancer Surviv."},{"key":"ref_37","first-page":"131","article-title":"Upper limb lymphedema 27 (ULL27): Dutch translation and validation of an illness-specific health-related quality of life questionnaire for patients with upper limb lymphedema","volume":"41","author":"Viehoff","year":"2008","journal-title":"Lymphology"},{"key":"ref_38","first-page":"181","article-title":"A specific quality of life scale in upper limb lymphedema: The ULL-27 questionnaire","volume":"35","author":"Launois","year":"2002","journal-title":"Lymphology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1080\/028418600750013186","article-title":"Treatment of breast-cancer-related lymphedema with or without manual lymphatic drainage\u2014A randomized study","volume":"39","author":"Andersen","year":"2000","journal-title":"Acta Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2590","DOI":"10.1172\/JCI58978","article-title":"Periostin promotes chronic allergic inflammation in response to Th2 cytokines","volume":"122","author":"Masuoka","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.jaci.2006.02.046","article-title":"Periostin: A novel component of subepithelial fibrosis of bronchial asthma downstream of IL-4 and IL-13 signals","volume":"118","author":"Takayama","year":"2006","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1159\/000487538","article-title":"The staining of mast cells: A historical overview","volume":"176","author":"Ribatti","year":"2018","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1586\/1744666X.2014.967684","article-title":"The importance of TSLP in allergic disease and its role as a potential therapeutic target","volume":"10","author":"Cianferoni","year":"2014","journal-title":"Expert Rev. Clin. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1002\/eji.200737809","article-title":"Mast cell regulation of epithelial TSLP expression plays an important role in the development of allergic rhinitis","volume":"38","author":"Miyata","year":"2008","journal-title":"Eur. J. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1056\/NEJMoa0906312","article-title":"A large-scale, consortium-based genomewide association study of asthma","volume":"363","author":"Moffatt","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Ramasamy, A., Kuokkanen, M., Vedantam, S., Gajdos, Z.K., Couto Alves, A., Lyon, H.N., Ferreira, M.A., Strachan, D.P., Zhao, J.H., and Abramson, M.J. (2012). Genome-wide association studies of asthma in population-based cohorts confirm known and suggested loci and identify an additional association near HLA. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0044008"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1084\/jem.20102131","article-title":"Thymic stromal lymphopoietin fosters human breast tumor growth by promoting type 2 inflammation","volume":"208","author":"Xu","year":"2011","journal-title":"J. Exp. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"130894","DOI":"10.1155\/2014\/130894","article-title":"A role for T-lymphocytes in human breast cancer and in canine mammary tumors","volume":"2014","author":"Carvalho","year":"2014","journal-title":"BioMed Res. Int."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1084\/jem.20061120","article-title":"Breast cancer instructs dendritic cells to prime interleukin 13-secreting CD4+ T cells that facilitate tumor development","volume":"204","author":"Aspord","year":"2007","journal-title":"J. Exp. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/0303-7207(96)03843-9","article-title":"Interleukin-4 and interleukin-13 inhibit estrogen-induced breast cancer cell proliferation and stimulate GCDFP-15 expression in human breast cancer cells","volume":"121","author":"Blais","year":"1996","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1038\/nature03799","article-title":"Genes that mediate breast cancer metastasis to lung","volume":"436","author":"Minn","year":"2005","journal-title":"Nature"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1038\/82771","article-title":"NKT cell-mediated repression of tumor immunosurveillance by IL-13 and the IL-4R-STAT6 pathway","volume":"1","author":"Terabe","year":"2000","journal-title":"Nat. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"5869","DOI":"10.4049\/jimmunol.160.12.5869","article-title":"A pathogenic role of Th2 cells and their cytokine products on the pulmonary metastasis of murine B16 melanoma","volume":"160","author":"Kobayashi","year":"1998","journal-title":"J. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1038\/sj.gt.3301956","article-title":"Potent antitumor activity of IL-13 cytotoxin in human pancreatic tumors engineered to express IL-13 receptor alpha2 chain in vivo","volume":"10","author":"Kawakami","year":"2003","journal-title":"Gene Ther."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1146\/annurev.immunol.21.120601.141142","article-title":"IL-13 effector functions","volume":"21","author":"Wynn","year":"2003","journal-title":"Annu. Rev. Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1089\/lrb.2016.0049","article-title":"Does lymphedema severity affect quality of life? Simple question. Challenging answers","volume":"16","author":"Lee","year":"2018","journal-title":"Lymphat. Res. Biol."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Tabibiazar, R., Cheung, L., Han, J., Swanson, J., Beilhack, A., An, A., Dadras, S.S., Rockson, N., Joshi, S., and Wagner, R. (2006). Inflammatory manifestations of experimental lymphatic insufficiency. PLoS Med., 3.","DOI":"10.1371\/journal.pmed.0030254"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1172\/jci.insight.123775","article-title":"Pilot studies demonstrate the potential benefits of antiinflammatory therapy in human lymphedema","volume":"3","author":"Rockson","year":"2018","journal-title":"JCI Insight"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"eaal3920","DOI":"10.1126\/scitranslmed.aal3920","article-title":"Leukotriene B4 antagonism ameliorates experimental lymphedema","volume":"9","author":"Tian","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1093\/cid\/cis486","article-title":"Doxycycline improves filarial lymphedema independent of active filarial infection: A randomized controlled trial","volume":"55","author":"Mand","year":"2012","journal-title":"Clin. Infect. Dis."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.critrevonc.2014.06.004","article-title":"Lymphedema following breast cancer treatment and impact on quality of life: A review","volume":"92","author":"Taghian","year":"2014","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.1002\/sctm.17-0037","article-title":"Treatment of breast cancer-related lymphedema with adipose-derived regenerative cells and fat grafts: A feasibility and safety study","volume":"6","author":"Toyserkani","year":"2017","journal-title":"Stem Cells Transl. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1089\/lrb.2014.0022","article-title":"Lymphaticovenous bypass decreases pathologic skin changes in upper extremity breast cancer-related lymphedema","volume":"13","author":"Torrisi","year":"2015","journal-title":"Lymphat. Res. Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1038\/jid.2011.446","article-title":"IL-33 and ST2 in atopic dermatitis: Expression profiles and modulation by triggering factors","volume":"132","author":"Savinko","year":"2012","journal-title":"J. Investig. Dermatol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1038\/ng.3033","article-title":"Genome-wide association analysis of eosinophilic esophagitis provides insight into the tissue specificity of this allergic disease","volume":"46","author":"Kottyan","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1084\/jem.20062211","article-title":"Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells","volume":"204","author":"Allakhverdi","year":"2007","journal-title":"J. Exp. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1084\/jem.20081499","article-title":"TSLP regulates intestinal immunity and inflammation in mouse models of helminth infection and colitis","volume":"206","author":"Taylor","year":"2009","journal-title":"J. Exp. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/ni805","article-title":"Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP","volume":"3","author":"Soumelis","year":"2002","journal-title":"Nat. Immunol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1084\/jem.20041503","article-title":"Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin","volume":"202","author":"Yoo","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"4311","DOI":"10.4049\/jimmunol.181.6.4311","article-title":"Intradermal administration of thymic stromal lymphopoietin induces a T cell- and eosinophil-dependent systemic Th2 inflammatory response","volume":"181","author":"Jessup","year":"2008","journal-title":"J. Immunol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1084\/jem.187.6.875","article-title":"Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes","volume":"187","author":"Sallusto","year":"1998","journal-title":"J. Exp. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1056\/NEJMoa1704064","article-title":"Tezepelumab in adults with uncontrolled asthma","volume":"377","author":"Corren","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1016\/j.jaad.2018.11.059","article-title":"Tezepelumab, an anti-thymic stromal lymphopoietin monoclonal antibody, in the treatment of moderate to severe atopic dermatitis: A randomized phase 2a clinical trial","volume":"80","author":"Simpson","year":"2019","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"9773","DOI":"10.1073\/pnas.0901206106","article-title":"The cytokine interleukin-33 mediates anaphylactic shock","volume":"106","author":"Pushparaj","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1690","DOI":"10.1016\/j.jaci.2017.09.046","article-title":"Eosinophilic esophagitis (EoE) genetic susceptibility is mediated by synergistic interactions between EoE-specific and general atopic disease loci","volume":"141","author":"Martin","year":"2018","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.immuni.2005.09.015","article-title":"IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines","volume":"23","author":"Schmitz","year":"2005","journal-title":"Immunity"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1016\/j.jaad.2014.01.867","article-title":"Increased serum levels of interleukin 33 in patients with atopic dermatitis","volume":"70","author":"Okuzawa","year":"2014","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2051","DOI":"10.4049\/jimmunol.179.4.2051","article-title":"Cutting edge: The ST2 ligand IL-33 potently activates and drives maturation of human mast cells","volume":"179","author":"Allakhverdi","year":"2007","journal-title":"J. Immunol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"6941","DOI":"10.1074\/jbc.M111.298703","article-title":"Interleukin 33 as a mechanically responsive cytokine secreted by living cells","volume":"287","author":"Kakkar","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1673","DOI":"10.1073\/pnas.1115884109","article-title":"IL-33 is processed into mature bioactive forms by neutrophil elastase and cathepsin G","volume":"109","author":"Lefrancais","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1016\/S1074-7613(01)00243-6","article-title":"IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo","volume":"15","author":"Fort","year":"2001","journal-title":"Immunity"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2794","DOI":"10.1111\/all.14526","article-title":"Role of IL-25, IL-33, and TSLP in triggering united airway diseases toward type 2 inflammation","volume":"75","author":"Hong","year":"2020","journal-title":"Allergy"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1089\/lrb.2012.0015","article-title":"Systematic review of quality of life and patient reported outcomes in patients with oncologic related lower extremity lymphedema","volume":"11","author":"Cemal","year":"2013","journal-title":"Lymphat. Res. Biol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1097\/NNR.0b013e318283da67","article-title":"Using temporal mining to examine the development of lymphedema in breast cancer survivors","volume":"62","author":"Green","year":"2013","journal-title":"Nurs. Res."}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/10\/9\/934\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:02:03Z","timestamp":1760166123000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/10\/9\/934"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,18]]},"references-count":84,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["biology10090934"],"URL":"https:\/\/doi.org\/10.3390\/biology10090934","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,18]]}}}