{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:57:57Z","timestamp":1753891077393,"version":"3.41.2"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,11]],"date-time":"2022-03-11T00:00:00Z","timestamp":1646956800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Most allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients receive peripheral blood stem cell grafts resulting in a 30%\u201370% incidence of chronic graft-versus-host disease (cGVHD), a major cause of mortality and morbidity in long-term survivors. While systemic steroids remain the standard of care for first-line therapy, patients may require long-term administration, and those with steroid-resistant or refractory cGVHD have a worse prognosis. Although durable and deep responses with second-line therapies can be achieved in some patients, there remains an urgent need for new therapies. In this study, we evaluated the efficacy of IRX4204, a novel agonist that activates RXRs and is in clinical trials for cancer treatment to prevent and treat cGVHD in two complementary murine models. In a major histocompatibility complex mismatched, non-sclerodermatous multiorgan system model with bronchiolitis obliterans, IRX4204 prevented and reversed cGVHD including associated pulmonary dysfunction with restoration of germinal center T-follicular helper: T-follicular regulatory cell balance. In a minor histocompatibility antigen disparate sclerodermatous model, IRX4204 treatment significantly prevented and ameliorated skin cGVHD by reducing Th1 and Th17 differentiation due to anti-inflammatory properties. Together, these results indicate that IRX4204 is a promising therapeutic option to treat cGVHD with bronchiolitis obliterans or sclerodermatous manifestations.<\/jats:p>","DOI":"10.3389\/fimmu.2022.765319","type":"journal-article","created":{"date-parts":[[2022,3,11]],"date-time":"2022-03-11T10:52:21Z","timestamp":1646995941000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting the Retinoid X Receptor Pathway Prevents and Ameliorates Murine Chronic Graft-Versus-Host Disease"],"prefix":"10.3389","volume":"13","author":[{"given":"Govindarajan","family":"Thangavelu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael C.","family":"Zaiken","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fathima A.","family":"Mohamed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan","family":"Flynn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Du","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie Y.","family":"Rhee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan J.","family":"Riddle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ethan G.","family":"Aguilar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela","family":"Panoskaltsis-Mortari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin E.","family":"Sanders","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruce R.","family":"Blazar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-01-514752","article-title":"Current Issues in Chronic Graft-Versus-Host Disease","volume":"124","author":"Socie","year":"2014","journal-title":"Blood"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1703472","article-title":"Pathophysiology of Chronic Graft-Versus-Host Disease and Therapeutic Targets","volume":"377","author":"Zeiser","year":"2017","journal-title":"N Engl J Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2010.06.015","article-title":"Consensus Conference on Clinical Practice in Chronic Graft-Versus-Host Disease (GVHD): First-Line and Topical Treatment of Chronic GVHD","volume":"16","author":"Wolff","year":"2010","journal-title":"Biol Blood Marrow Transplant"},{"key":"B4","doi-asserted-by":"publisher","first-page":"601953","DOI":"10.1155\/2011\/601953","article-title":"Steroid-Refractory Acute GVHD: Predictors and Outcomes","volume":"2011","author":"Westin","year":"2011","journal-title":"Adv Hematol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2012.04.005","article-title":"First- and Second-Line Systemic Treatment of Acute Graft-Versus-Host Disease: Recommendations of the American Society of Blood and Marrow Transplantation","volume":"18","author":"Martin","year":"2012","journal-title":"Biol Blood Marrow Transplant"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/S1083-8791(03)00242-8","article-title":"Bronchiolitis Obliterans in Chronic Graft-Versus-Host Disease: Analysis of Risk Factors and Treatment Outcomes","volume":"9","author":"Dudek","year":"2003","journal-title":"Biol Blood Marrow Transplant"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-10-464198","article-title":"Incidence, Risk Factors, and Outcomes of Sclerosis in Patients With Chronic Graft-Versus-Host Disease","volume":"121","author":"Inamoto","year":"2013","journal-title":"Blood"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2009.11.002","article-title":"Bronchiolitis Obliterans Syndrome After Allogeneic Hematopoietic Stem Cell Transplantation-an Increasingly Recognized Manifestation of Chronic Graft-Versus-Host Disease","volume":"16","author":"Chien","year":"2010","journal-title":"Biol Blood Marrow Transplant"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2011.10.021","article-title":"Fibrotic and Sclerotic Manifestations of Chronic Graft-Versus-Host Disease","volume":"18","author":"Kitko","year":"2012","journal-title":"Biol Blood Marrow Transplant"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.168.6.3088","article-title":"Murine Sclerodermatous Graft-Versus-Host Disease, a Model for Human Scleroderma: Cutaneous Cytokines, Chemokines, and Immune Cell Activation","volume":"168","author":"Zhang","year":"2002","journal-title":"J Immunol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"2993","DOI":"10.1182\/blood-2005-09-3623","article-title":"Donor CD4+ T and B Cells in Transplants Induce Chronic Graft-Versus-Host Disease With Autoimmune Manifestations","volume":"107","author":"Zhang","year":"2006","journal-title":"Blood"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2007.12.002","article-title":"Murine Models of Chronic Graft-Versus-Host Disease: Insights and Unresolved Issues","volume":"14","author":"Chu","year":"2008","journal-title":"Biol Blood Marrow Transplant"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-07-364414","article-title":"Donor B-Cell Alloantibody Deposition and Germinal Center Formation Are Required for the Development of Murine Chronic GVHD and Bronchiolitis Obliterans","volume":"119","author":"Srinivasan","year":"2012","journal-title":"Blood"},{"key":"B14","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1182\/blood-2016-06-686618","article-title":"Chronic Graft-Versus-Host Disease: Biological Insights From Preclinical and Clinical Studies","volume":"129","author":"MacDonald","year":"2017","journal-title":"Blood"},{"key":"B15","doi-asserted-by":"publisher","first-page":"978","DOI":"10.1038\/s41467-017-00880-2","article-title":"Extrafollicular CD4(+) T-B Interactions are Sufficient for Inducing Autoimmune-Like Chronic Graft-Versus-Host Disease","volume":"8","author":"Deng","year":"2017","journal-title":"Nat Commun"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200702-335OC","article-title":"A New Murine Model for Bronchiolitis Obliterans Post-Bone Marrow Transplant","volume":"176","author":"Panoskaltsis-Mortari","year":"2007","journal-title":"Am J Respir Crit Care Med"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-03-562231","article-title":"Increased T Follicular Helper Cells and Germinal Center B Cells Are Required for cGVHD and Bronchiolitis Obliterans","volume":"123","author":"Flynn","year":"2014","journal-title":"Blood"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-01-332478","article-title":"Synthetic Retinoid Am80 Ameliorates Chronic Graft-Versus-Host Disease by Down-Regulating Th1 and Th17","volume":"119","author":"Nishimori","year":"2012","journal-title":"Blood"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90200-7","article-title":"The RXR Heterodimers and Orphan Receptors","volume":"83","author":"Mangelsdorf","year":"1995","journal-title":"Cell"},{"key":"B20","article-title":"Treatment With Retinoid X Receptor Agonist IRX4204 Ameliorates Experimental Autoimmune Encephalomyelitis","volume":"8","author":"Chandraratna","year":"2016","journal-title":"Am J Transl Res"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200535366","article-title":"An Essential Role for Rxr Alpha in the Development of Th2 Responses","volume":"35","author":"Du","year":"2005","journal-title":"Eur J Immunol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1038\/nrd2397","article-title":"RAR and RXR Modulation in Cancer and Metabolic Disease","volume":"6","author":"Altucci","year":"2007","journal-title":"Nat Rev Drug Discovery"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.2337\/db19-1001","article-title":"A Small Molecule, UAB126, Reverses Diet-Induced Obesity and Its Associated Metabolic Disorders","volume":"69","author":"Ren","year":"2020","journal-title":"Diabetes"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1997.15.2.790","article-title":"Initial Clinical Trial of a Selective Retinoid X Receptor Ligand, LGD1069","volume":"15","author":"Miller","year":"1997","journal-title":"J Clin Oncol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1007\/s001250051193","article-title":"The RXR Agonist LG100268 Causes Hepatomegaly, Improves Glycaemic Control and Decreases Cardiovascular Risk and Cachexia in Diabetic Mice Suffering From Pancreatic Beta-Cell Dysfunction","volume":"42","author":"Lenhard","year":"1999","journal-title":"Diabetologia"},{"key":"B26","doi-asserted-by":"publisher","first-page":"94156","DOI":"10.1155\/2007\/94156","article-title":"Therapeutic Potential of Retinoid X Receptor Modulators for the Treatment of the Metabolic Syndrome","volume":"2007","author":"Pinaire","year":"2007","journal-title":"PPAR Res"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1021\/jm00016a018","article-title":"Design and Synthesis of Potent Retinoid X Receptor Selective Ligands That Induce Apoptosis in Leukemia Cells","volume":"38","author":"Boehm","year":"1995","journal-title":"J Med Chem"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.109.189506","article-title":"Rexinoid Bexarotene Modulates Triglyceride But Not Cholesterol Metabolism via Gene-Specific Permissivity of the RXR\/LXR Heterodimer in the Liver","volume":"29","author":"Lalloyer","year":"2009","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aal2332","article-title":"PPARdelta Activation by Bexarotene Promotes Neuroprotection by Restoring Bioenergetic and Quality Control Homeostasis","volume":"9","author":"Dickey","year":"2017","journal-title":"Sci Transl Med"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.7191","article-title":"Selective Brain Penetrable Nurr1 Transactivator for Treating Parkinson\u2019s Disease","volume":"7","author":"Wang","year":"2016","journal-title":"Oncotarget"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020005628","article-title":"Repurposing a Novel Anti-Cancer RXR Agonist to Attenuate Acute GVHD and Maintain Graft-Versus-Leukemia Responses","volume":"137","author":"Thangavelu","year":"2020","journal-title":"Blood"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-01-758854","article-title":"Pirfenidone Ameliorates Murine Chronic GVHD Through Inhibition of Macrophage Infiltration and TGF-Beta Production","volume":"129","author":"Du","year":"2017","journal-title":"Blood"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0903006","article-title":"STAT3 Signaling in CD4+ T Cells Is Critical for the Pathogenesis of Chronic Sclerodermatous Graft-Versus-Host Disease in a Murine Model","volume":"184","author":"Radojcic","year":"2010","journal-title":"J Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq046","article-title":"EBImage\u2013an R Package for Image Processing With Applications to Cellular Phenotypes","volume":"26","author":"Pau","year":"2010","journal-title":"Bioinformatics"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-2498-1_13","article-title":"In Vitro Assay to Sensitively Measure T(FR) Suppressive Capacity and T(FH) Stimulation of B Cell Responses","volume":"1291","author":"Sage","year":"2015","journal-title":"Methods Mol Biol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1021\/jm0100584","article-title":"Enantioselective Syntheses of Potent Retinoid X Receptor Ligands: Differential Biological Activities of Individual Antipodes","volume":"44","author":"Vuligonda","year":"2001","journal-title":"J Med Chem"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V92.10.3949.422k26_3949_3959","article-title":"Engraftment of Severe Combined Immune Deficient Mice Receiving Allogeneic Bone Marrow via In Utero or Postnatal Transfer","volume":"92","author":"Blazar","year":"1998","journal-title":"Blood"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2425","article-title":"Foxp3+ Follicular Regulatory T Cells Control the Germinal Center Response","volume":"17","author":"Linterman","year":"2011","journal-title":"Nat Med"},{"key":"B39","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/0008-8749(85)90086-3","article-title":"Chronic Graft-Versus-Host Disease as a Model for Scleroderma. II. Mast Cell Depletion With Deposition of Immunoglobulins in the Skin and Fibrosis","volume":"94","author":"Claman","year":"1985","journal-title":"Cell Immunol"},{"key":"B40","doi-asserted-by":"crossref","DOI":"10.4049\/jimmunol.163.10.5693","article-title":"Anti-TGF-Beta Treatment Prevents Skin and Lung Fibrosis in Murine Sclerodermatous Graft-Versus-Host Disease: A Model for Human Scleroderma","volume":"163","author":"McCormick","year":"1999","journal-title":"J Immunol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.jtbi.2016.02.036","article-title":"Bistability Analyses of CD4+ T Follicular Helper and Regulatory Cells During Helicobacter Pylori Infection","volume":"398","author":"Leber","year":"2016","journal-title":"J Theor Biol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1111\/all.14581","article-title":"Vitamin A Controls the Allergic Response Through T Follicular Helper Cell as Well as Plasmablast Differentiation","volume":"76","author":"Scholz","year":"2021","journal-title":"Allergy"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-03-1257","article-title":"Reduced Frequency of FOXP3+ CD4+CD25+ Regulatory T Cells in Patients With Chronic Graft-Versus-Host Disease","volume":"106","author":"Zorn","year":"2005","journal-title":"Blood"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3005265","article-title":"Low-Dose Interleukin-2 Therapy Restores Regulatory T Cell Homeostasis in Patients With Chronic Graft-Versus-Host Disease","volume":"5","author":"Matsuoka","year":"2013","journal-title":"Sci Transl Med"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-05-715896","article-title":"Therapeutic Regulatory T-Cell Adoptive Transfer Ameliorates Established Murine Chronic GVHD in a CXCR5-Dependent Manner","volume":"128","author":"McDonald-Hyman","year":"2016","journal-title":"Blood"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1108188","article-title":"Interleukin-2 and Regulatory T Cells in Graft-Versus-Host Disease","volume":"365","author":"Koreth","year":"2011","journal-title":"N Engl J Med"},{"key":"B47","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1038\/ncomms1272","article-title":"The Nuclear Orphan Receptor Nr4a2 Induces Foxp3 and Regulates Differentiation of CD4+ T Cells","volume":"2","author":"Sekiya","year":"2011","journal-title":"Nat Commun"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2015.05.005","article-title":"T Follicular Regulatory Cells in the Regulation of B Cell Responses","volume":"36","author":"Sage","year":"2015","journal-title":"Trends Immunol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-07-368027","article-title":"Blocking IL-21 Signaling Ameliorates Xenogeneic GVHD Induced by Human Lymphocytes","volume":"119","author":"Hippen","year":"2012","journal-title":"Blood"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.2.732","article-title":"IL-21 Counteracts the Regulatory T Cell-Mediated Suppression of Human CD4+ T Lymphocytes","volume":"178","author":"Peluso","year":"2007","journal-title":"J Immunol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.8.5393","article-title":"Release From Regulatory T Cell-Mediated Suppression During the Onset of Tissue-Specific Autoimmunity Is Associated With Elevated IL-21","volume":"180","author":"Clough","year":"2008","journal-title":"J Immunol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1182\/asheducation-2008.1.134","article-title":"Recognizing and Managing Chronic Graft-Versus-Host Disease","volume":"2008","author":"Lee","year":"2008","journal-title":"Hematol Am Soc Hematol Educ Program"},{"key":"B53","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1182\/blood.2019000032","article-title":"Inhibition of Inositol Kinase B Controls Acute and Chronic Graft-Versus-Host Disease","volume":"135","author":"Thangavelu","year":"2020","journal-title":"Blood"},{"key":"B54","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1016\/j.immuni.2015.02.003","article-title":"Retinoic Acid is Essential for Th1 Cell Lineage Stability and Prevents Transition to a Th17 Cell Program","volume":"42","author":"Brown","year":"2015","journal-title":"Immunity"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-08-445130","article-title":"A Critical Role for the Retinoic Acid Signaling Pathway in the Pathophysiology of Gastrointestinal Graft-Versus-Host Disease","volume":"121","author":"Chen","year":"2013","journal-title":"Blood"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-11-470252","article-title":"Inhibiting Retinoic Acid Signaling Ameliorates Graft-Versus-Host Disease by Modifying T-Cell Differentiation and Intestinal Migration","volume":"122","author":"Aoyama","year":"2013","journal-title":"Blood"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1800899","article-title":"Dendritic Cell Expression of Retinal Aldehyde Dehydrogenase-2 Controls Graft-Versus-Host Disease Lethality","volume":"202","author":"Thangavelu","year":"2019","journal-title":"J Immunol"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1300032","article-title":"Retinoid X Receptor Agonists Modulate Foxp3(+) Regulatory T Cell and Th17 Cell Differentiation With Differential Dependence on Retinoic Acid Receptor Activation","volume":"191","author":"Takeuchi","year":"2013","journal-title":"J Immunol"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.10.015","article-title":"Th17 Cells Induce Ectopic Lymphoid Follicles in Central Nervous System Tissue Inflammation","volume":"35","author":"Peters","year":"2011","journal-title":"Immunity"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0901499","article-title":"Cyclooxygenase-1 Orchestrates Germinal Center Formation and Antibody Class-Switch via Regulation of IL-17","volume":"183","author":"Blaho","year":"2009","journal-title":"J Immunol"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1038\/ni1552","article-title":"Interleukin 17-Producing T Helper Cells and Interleukin 17 Orchestrate Autoreactive Germinal Center Development in Autoimmune BXD2 Mice","volume":"9","author":"Hsu","year":"2008","journal-title":"Nat Immunol"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.92111","article-title":"An Activated Th17-Prone T Cell Subset Involved in Chronic Graft-Versus-Host Disease Sensitive to Pharmacological Inhibition","volume":"2","author":"Forcade","year":"2017","journal-title":"JCI Insight"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.765319\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,28]],"date-time":"2023-01-28T21:14:42Z","timestamp":1674940482000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.765319\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,11]]},"references-count":62,"alternative-id":["10.3389\/fimmu.2022.765319"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.765319","relation":{},"ISSN":["1664-3224"],"issn-type":[{"type":"electronic","value":"1664-3224"}],"subject":[],"published":{"date-parts":[[2022,3,11]]},"article-number":"765319"}}