{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T17:11:48Z","timestamp":1767373908436},"reference-count":52,"publisher":"American Society of Hematology","issue":"4","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,1,26]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Aspergillus fumigatus is a model fungal pathogen and a common cause of severe infections and diseases. CD8+ T cells are present in the human and murine T-cell repertoire to the fungus. However, CD8+ T-cell function in infection and the molecular mechanisms that control their priming and differentiation into effector and memory cells in vivo remain elusive. In the present study, we report that both CD4+ and CD8+ T cells mediate protective memory responses to the fungus contingent on the nature of the fungal vaccine. Mechanistically, class I MHC-restricted, CD8+ memory T cells were activated through TLR3 sensing of fungal RNA by cross-presenting dendritic cells. Genetic deficiency of TLR3 was associated with susceptibility to aspergillosis and concomitant failure to activate memory-protective CD8+ T cells both in mice and in patients receiving stem-cell transplantations. Therefore, TLR3 essentially promotes antifungal memory CD8+ T-cell responses and its deficiency is a novel susceptibility factor for aspergillosis in high-risk patients.<\/jats:p>","DOI":"10.1182\/blood-2011-06-362582","type":"journal-article","created":{"date-parts":[[2011,12,7]],"date-time":"2011-12-07T06:36:11Z","timestamp":1323239771000},"page":"967-977","update-policy":"http:\/\/dx.doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":116,"title":["TLR3 essentially promotes protective class I\u2013restricted memory CD8+ T-cell responses to Aspergillus fumigatus in hematopoietic transplanted patients"],"prefix":"10.1182","volume":"119","author":[{"given":"Agostinho","family":"Carvalho","sequence":"first","affiliation":[{"name":"Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy;"},{"name":"Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal;"},{"name":"ICVS\/3B's, PT Government Associate Laboratory, Braga\/Guimar\u00e3es, Portugal;"}]},{"given":"Antonella","family":"De Luca","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy;"}]},{"given":"Silvia","family":"Bozza","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy;"}]},{"given":"Cristina","family":"Cunha","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy;"}]},{"given":"Carmen","family":"D'Angelo","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy;"}]},{"given":"Silvia","family":"Moretti","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy;"}]},{"given":"Katia","family":"Perruccio","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy; and"}]},{"given":"Rossana G.","family":"Iannitti","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy;"}]},{"given":"Francesca","family":"Fallarino","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy;"}]},{"given":"Antonio","family":"Pierini","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy; and"}]},{"given":"Jean-Paul","family":"Latg\u00e9","sequence":"additional","affiliation":[{"name":"Unit\u00e9 des Aspergillus, Institut Pasteur, Paris, France"}]},{"given":"Andrea","family":"Velardi","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy; and"}]},{"given":"Franco","family":"Aversa","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy; and"}]},{"given":"Luigina","family":"Romani","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy;"}]}],"member":"234","reference":[{"issue":"6857","key":"2019111808143699200_B1","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1038\/35099560","article-title":"Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3.","volume":"413","author":"Alexopoulou","year":"2001","journal-title":"Nature"},{"issue":"13","key":"2019111808143699200_B2","doi-asserted-by":"crossref","first-page":"12542","DOI":"10.1074\/jbc.M310175200","article-title":"mRNA is an endogenous ligand for Toll-like receptor 3.","volume":"279","author":"Karik\u00f3","year":"2004","journal-title":"J Biol Chem"},{"issue":"11","key":"2019111808143699200_B3","doi-asserted-by":"crossref","first-page":"2609","DOI":"10.1084\/jem.20081370","article-title":"TLR3 is an endogenous sensor of tissue necrosis during acute inflammatory events.","volume":"205","author":"Cavassani","year":"2008","journal-title":"J Exp Med"},{"issue":"6","key":"2019111808143699200_B4","doi-asserted-by":"crossref","first-page":"2751","DOI":"10.4049\/jimmunol.0903201","article-title":"Cutting edge: polyinosinic:polycytidylic acid boosts the generation of memory CD8 T cells through melanoma differentiation-associated protein 5 expressed in stromal cells.","volume":"184","author":"Wang","year":"2010","journal-title":"J Immunol"},{"issue":"7028","key":"2019111808143699200_B5","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1038\/nature03326","article-title":"Toll-like receptor 3 promotes cross-priming to virus-infected cells.","volume":"433","author":"Schulz","year":"2005","journal-title":"Nature"},{"issue":"4","key":"2019111808143699200_B6","doi-asserted-by":"crossref","first-page":"2422","DOI":"10.4049\/jimmunol.1002845","article-title":"TLR3-specific double-stranded RNA oligonucleotide adjuvants induce dendritic cell cross-presentation, CTL responses, and antiviral protection.","volume":"186","author":"Jelinek","year":"2011","journal-title":"J Immunol"},{"issue":"10","key":"2019111808143699200_B7","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1038\/ni978","article-title":"Cross-priming of CD8+ T cells stimulated by virus-induced type I interferon.","volume":"4","author":"Le Bon","year":"2003","journal-title":"Nat Immunol"},{"issue":"12","key":"2019111808143699200_B8","doi-asserted-by":"crossref","first-page":"5318","DOI":"10.1182\/blood-2006-10-053256","article-title":"TLR3 ligand stimulates fully functional memory CD8+ T cells in the absence of CD4+ T-cell help.","volume":"109","author":"Hervas-Stubbs","year":"2007","journal-title":"Blood"},{"issue":"3","key":"2019111808143699200_B9","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.immuni.2010.08.014","article-title":"Human TRAF3 adaptor molecule deficiency leads to impaired Toll-like receptor 3 response and susceptibility to herpes simplex encephalitis.","volume":"33","author":"P\u00e9rez de Diego","year":"2010","journal-title":"Immunity"},{"issue":"5844","key":"2019111808143699200_B10","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1126\/science.1139522","article-title":"TLR3 deficiency in patients with herpes simplex encephalitis.","volume":"317","author":"Zhang","year":"2007","journal-title":"Science"},{"issue":"30","key":"2019111808143699200_B11","doi-asserted-by":"crossref","first-page":"23208","DOI":"10.1074\/jbc.M109.047464","article-title":"A role for Toll-like receptor 3 variants in host susceptibility to enteroviral myocarditis and dilated cardiomyopathy.","volume":"285","author":"Gorbea","year":"2010","journal-title":"J Biol Chem"},{"issue":"7259","key":"2019111808143699200_B12","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1038\/nature08264","article-title":"Surface hydrophobin prevents immune recognition of airborne fungal spores.","volume":"460","author":"Aimanianda","year":"2009","journal-title":"Nature"},{"issue":"2","key":"2019111808143699200_B13","doi-asserted-by":"crossref","first-page":"e9036","DOI":"10.1371\/journal.pone.0009036","article-title":"Healthy human T-Cell responses to Aspergillus fumigatus antigens.","volume":"5","author":"Chaudhary","year":"2010","journal-title":"PLoS One"},{"issue":"13","key":"2019111808143699200_B14","doi-asserted-by":"crossref","first-page":"4521","DOI":"10.1182\/blood-2002-01-0265","article-title":"Analysis of T-cell responses to Aspergillus fumigatus antigens in healthy individuals and patients with hematologic malignancies.","volume":"100","author":"Hebart","year":"2002","journal-title":"Blood"},{"issue":"13","key":"2019111808143699200_B15","doi-asserted-by":"crossref","first-page":"4397","DOI":"10.1182\/blood-2005-05-1775","article-title":"Transferring functional immune responses to pathogens after haploidentical hematopoietic transplantation.","volume":"106","author":"Perruccio","year":"2005","journal-title":"Blood"},{"issue":"6","key":"2019111808143699200_B16","doi-asserted-by":"crossref","first-page":"2562","DOI":"10.1182\/blood-2005-04-1660","article-title":"Generation of highly purified and functionally active human TH1 cells against Aspergillus fumigatus.","volume":"107","author":"Beck","year":"2006","journal-title":"Blood"},{"issue":"3","key":"2019111808143699200_B17","doi-asserted-by":"crossref","first-page":"e1001315","DOI":"10.1371\/journal.ppat.1001315","article-title":"The danger signal S100B integrates pathogen- and danger-sensing pathways to restrain inflammation.","volume":"7","author":"Sorci","year":"2011","journal-title":"PLoS Pathog"},{"issue":"6","key":"2019111808143699200_B18","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/cmi.2010.43","article-title":"Non-hematopoietic cells contribute to protective tolerance to Aspergillus fumigatus via a TRIF pathway converging on IDO.","volume":"7","author":"de Luca","year":"2010","journal-title":"Cell Mol Immunol"},{"issue":"2","key":"2019111808143699200_B19","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/mi.2009.130","article-title":"Intranasally delivered siRNA targeting PI3K\/Akt\/mTOR inflammatory pathways protects from aspergillosis.","volume":"3","author":"Bonifazi","year":"2010","journal-title":"Mucosal Immunol"},{"issue":"11","key":"2019111808143699200_B20","doi-asserted-by":"crossref","first-page":"1405","DOI":"10.1084\/jem.20030109","article-title":"Vaccine immunity to pathogenic fungi overcomes the requirement for CD4 help in exogenous antigen presentation to CD8+ T cells: implications for vaccine development in immune-deficient hosts.","volume":"197","author":"Wuthrich","year":"2003","journal-title":"J Exp Med"},{"issue":"12","key":"2019111808143699200_B21","doi-asserted-by":"crossref","first-page":"7920","DOI":"10.4049\/jimmunol.174.12.7920","article-title":"Generation of antifungal effector CD8+ T cells in the absence of CD4+ T cells during Cryptococcus neoformans infection.","volume":"174","author":"Lindell","year":"2005","journal-title":"J Immunol"},{"issue":"7","key":"2019111808143699200_B22","doi-asserted-by":"crossref","first-page":"3491","DOI":"10.4049\/jimmunol.152.7.3491","article-title":"Role of CD8+ T cells in host resistance to systemic infection with Histoplasma capsulatum in mice.","volume":"152","author":"Deepe","year":"1994","journal-title":"J Immunol"},{"issue":"4","key":"2019111808143699200_B23","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1084\/jem.173.4.793","article-title":"Immunity to a pulmonary Cryptococcus neoformans infection requires both CD4+ and CD8+ T cells.","volume":"173","author":"Huffnagle","year":"1991","journal-title":"J Exp Med"},{"issue":"4","key":"2019111808143699200_B24","doi-asserted-by":"crossref","first-page":"2407","DOI":"10.4049\/jimmunol.0900961","article-title":"Immune sensing of Aspergillus fumigatus proteins, glycolipids, and polysaccharides and the impact on Th immunity and vaccination.","volume":"183","author":"Bozza","year":"2009","journal-title":"J Immunol"},{"issue":"1","key":"2019111808143699200_B25","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1111\/j.1365-2249.2005.02738.x","article-title":"Generation of cytotoxic T cell responses directed to human leucocyte antigen class I restricted epitopes from the Aspergillus f16 allergen.","volume":"140","author":"Ramadan","year":"2005","journal-title":"Clin Exp Immunol"},{"issue":"10","key":"2019111808143699200_B26","doi-asserted-by":"crossref","first-page":"3807","DOI":"10.1182\/blood-2003-03-0748","article-title":"A dendritic cell vaccine against invasive aspergillosis in allogeneic hematopoietic transplantation.","volume":"102","author":"Bozza","year":"2003","journal-title":"Blood"},{"issue":"24","key":"2019111808143699200_B27","doi-asserted-by":"crossref","first-page":"5394","DOI":"10.1182\/blood-2010-04-279307","article-title":"Dectin-1 Y238X polymorphism associates with susceptibility to invasive aspergillosis in hematopoietic transplantation through impairment of both recipient- and donor-dependent mechanisms of antifungal immunity.","volume":"116","author":"Cunha","year":"2010","journal-title":"Blood"},{"issue":"12","key":"2019111808143699200_B28","doi-asserted-by":"crossref","first-page":"3436","DOI":"10.1002\/eji.200838629","article-title":"TLR3 modulates immunopathology during a Schistosoma mansoni egg-driven Th2 response in the lung.","volume":"38","author":"Joshi","year":"2008","journal-title":"Eur J Immunol"},{"issue":"13","key":"2019111808143699200_B29","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1016\/S1286-4579(02)00007-2","article-title":"Vaccination of mice against invasive aspergillosis with recombinant Aspergillus proteins and CpG oligodeoxynucleotides as adjuvants.","volume":"4","author":"Bozza","year":"2002","journal-title":"Microbes Infect"},{"issue":"11","key":"2019111808143699200_B30","doi-asserted-by":"crossref","first-page":"6861","DOI":"10.4049\/jimmunol.178.11.6861","article-title":"CD103- and CD103+ bronchial lymph node dendritic cells are specialized in presenting and cross-presenting innocuous antigen to CD4+ and CD8+ T cells.","volume":"178","author":"del Rio","year":"2007","journal-title":"J Immunol"},{"issue":"10","key":"2019111808143699200_B31","doi-asserted-by":"crossref","first-page":"6984","DOI":"10.4049\/jimmunol.181.10.6984","article-title":"CD4+ and CD8+ T cells exhibit differential requirements for CCR7-mediated antigen transport during influenza infection.","volume":"181","author":"Heer","year":"2008","journal-title":"J Immunol"},{"issue":"3","key":"2019111808143699200_B32","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.1128\/IAI.74.3.1480-1489.2006","article-title":"Human dendritic cells following Aspergillus fumigatus infection express the CCR7 receptor and a differential pattern of interleukin-12 (IL-12), IL-23, and IL-27 cytokines, which lead to a Th1 response.","volume":"74","author":"Gafa","year":"2006","journal-title":"Infect Immun"},{"issue":"1","key":"2019111808143699200_B33","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1074\/jbc.M411223200","article-title":"Double-stranded RNAs from the helminth parasite Schistosoma activate TLR3 in dendritic cells.","volume":"280","author":"Aksoy","year":"2005","journal-title":"J Biol Chem"},{"issue":"17","key":"2019111808143699200_B34","doi-asserted-by":"crossref","first-page":"7915","DOI":"10.1073\/pnas.89.17.7915","article-title":"Cationic lipids direct a viral glycoprotein into the class I major histocompatibility complex antigen-presentation pathway.","volume":"89","author":"Walker","year":"1992","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"2019111808143699200_B35","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.coi.2010.01.022","article-title":"Intracellular mechanisms of antigen cross presentation in dendritic cells.","volume":"22","author":"Amigorena","year":"2010","journal-title":"Curr Opin Immunol"},{"issue":"1","key":"2019111808143699200_B36","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.immuni.2006.04.017","article-title":"Migratory dendritic cells transfer antigen to a lymph node-resident dendritic cell population for efficient CTL priming.","volume":"25","author":"Allan","year":"2006","journal-title":"Immunity"},{"issue":"6","key":"2019111808143699200_B37","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1084\/jem.20092140","article-title":"Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens.","volume":"207","author":"Jongbloed","year":"2010","journal-title":"J Exp Med"},{"issue":"6","key":"2019111808143699200_B38","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1084\/jem.20092618","article-title":"Characterization of human DNGR-1+ BDCA3+ leukocytes as putative equivalents of mouse CD8alpha+ dendritic cells.","volume":"207","author":"Poulin","year":"2010","journal-title":"J Exp Med"},{"issue":"4","key":"2019111808143699200_B39","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1002\/eji.200323797","article-title":"Toll-like receptor expression in murine DC subsets: lack of TLR7 expression by CD8 alpha+ DC correlates with unresponsiveness to imidazoquinolines.","volume":"33","author":"Edwards","year":"2003","journal-title":"Eur J Immunol"},{"issue":"10","key":"2019111808143699200_B40","doi-asserted-by":"crossref","first-page":"6282","DOI":"10.4049\/jimmunol.174.10.6282","article-title":"Dendritic cells cross-present exogenous fungal antigens to stimulate a protective CD8 T cell response in infection by Histoplasma capsulatum.","volume":"174","author":"Lin","year":"2005","journal-title":"J Immunol"},{"issue":"4","key":"2019111808143699200_B41","doi-asserted-by":"crossref","first-page":"e18777","DOI":"10.1371\/journal.pone.0018777","article-title":"Role of germination in murine airway CD8 T-cell responses to Aspergillus conidia.","volume":"6","author":"Templeton","year":"2011","journal-title":"PLoS One"},{"issue":"22","key":"2019111808143699200_B42","doi-asserted-by":"crossref","first-page":"5881","DOI":"10.1182\/blood-2010-12-325084","article-title":"Cross-protective TH1 immunity against Aspergillus fumigatus and Candida albicans.","volume":"117","author":"Stuehler","year":"2011","journal-title":"Blood"},{"issue":"28","key":"2019111808143699200_B43","doi-asserted-by":"crossref","first-page":"10729","DOI":"10.1073\/pnas.0601956103","article-title":"The dominant role of CD8+ dendritic cells in cross-presentation is not dictated by antigen capture.","volume":"103","author":"Schnorrer","year":"2006","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"12","key":"2019111808143699200_B44","doi-asserted-by":"crossref","first-page":"7335","DOI":"10.4049\/jimmunol.176.12.7335","article-title":"Efficient immunization and cross-priming by vaccine adjuvants containing TLR3 or TLR9 agonists complexed to cationic liposomes.","volume":"176","author":"Zaks","year":"2006","journal-title":"J Immunol"},{"issue":"6779","key":"2019111808143699200_B45","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1038\/35008096","article-title":"Rapid degradation of a large fraction of newly synthesized proteins by proteasomes.","volume":"404","author":"Schubert","year":"2000","journal-title":"Nature"},{"issue":"8","key":"2019111808143699200_B46","doi-asserted-by":"crossref","first-page":"5171","DOI":"10.4049\/jimmunol.0901027","article-title":"CCR7 deficiency on dendritic cells enhances fungal clearance in a murine model of pulmonary invasive aspergillosis.","volume":"183","author":"Hartigan","year":"2009","journal-title":"J Immunol"},{"issue":"5","key":"2019111808143699200_B47","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/j.chom.2009.10.007","article-title":"Inflammatory monocytes facilitate adaptive CD4 T cell responses during respiratory fungal infection.","volume":"6","author":"Hohl","year":"2009","journal-title":"Cell Host Microbe"},{"issue":"1","key":"2019111808143699200_B48","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.immuni.2008.05.008","article-title":"Engagement of the type I interferon receptor on dendritic cells inhibits T helper 17 cell development: role of intracellular osteopontin.","volume":"29","author":"Shinohara","year":"2008","journal-title":"Immunity"},{"issue":"3","key":"2019111808143699200_B49","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1084\/jem.20061706","article-title":"CCR7 ligands stimulate the intranodal motility of T lymphocytes in vivo.","volume":"204","author":"Worbs","year":"2007","journal-title":"J Exp Med"},{"issue":"7","key":"2019111808143699200_B50","doi-asserted-by":"crossref","first-page":"4137","DOI":"10.4049\/jimmunol.1000677","article-title":"Inefficient lymph node sensitization during respiratory viral infection promotes IL-17-mediated lung pathology.","volume":"185","author":"Kallal","year":"2010","journal-title":"J Immunol"},{"issue":"9","key":"2019111808143699200_B51","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1016\/j.exphem.2009.06.004","article-title":"Polymorphisms in Toll-like receptor genes and susceptibility to infections in allogeneic stem cell transplantation.","volume":"37","author":"Carvalho","year":"2009","journal-title":"Exp Hematol"},{"issue":"10","key":"2019111808143699200_B52","doi-asserted-by":"crossref","first-page":"7865","DOI":"10.1074\/jbc.M110.191452","article-title":"Kaposi sarcoma-associated herpesvirus degrades cellular Toll-interleukin-1 receptor domain-containing adaptor-inducing beta-interferon (TRIF).","volume":"286","author":"Ahmad","year":"2011","journal-title":"J Biol Chem"}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/119\/4\/967\/1355307\/zh800412000967.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/119\/4\/967\/1355307\/zh800412000967.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,11]],"date-time":"2023-06-11T14:40:17Z","timestamp":1686494417000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/119\/4\/967\/29722\/TLR3-essentially-promotes-protective-class"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,1,26]]},"references-count":52,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2012,1,26]]}},"URL":"https:\/\/doi.org\/10.1182\/blood-2011-06-362582","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,1,26]]}}}