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dc.contributor.authorVuckovic, Slavica
dc.contributor.authorMinnie, Simone A
dc.contributor.authorSmith, David
dc.contributor.authorGartlan, Kate H
dc.contributor.authorWatkins, Thomas S
dc.contributor.authorMarkey, Kate A
dc.contributor.authorMukhopadhyay, Pamela
dc.contributor.authorGuillerey, Camille
dc.contributor.authorKuns, Rachel D
dc.contributor.authorLocke, Kelly R
dc.contributor.authorPritchard, Antonia L
dc.contributor.authorJohansson, Peter A
dc.contributor.authorVarelias, Antiopi
dc.contributor.authorZhang, Ping
dc.contributor.authoret al.
dc.date.accessioned2021-01-15T04:10:11Z
dc.date.available2021-01-15T04:10:11Z
dc.date.issued2019
dc.identifier.issn0021-9738
dc.identifier.doi10.1172/JCI98888
dc.identifier.urihttp://hdl.handle.net/10072/401147
dc.description.abstractTransplantation with autologous hematopoietic progenitors remains an important consolidation treatment for patients with multiple myeloma (MM) and is thought to prolong the disease plateau phase by providing intensive cytoreduction. However, transplantation induces inflammation in the context of profound lymphodepletion that may cause hitherto unexpected immunological effects. We developed preclinical models of bone marrow transplantation (BMT) for MM using Vk*MYC myeloma-bearing recipient mice and donor mice that were myeloma naive or myeloma experienced to simulate autologous transplantation. Surprisingly, we demonstrated broad induction of T cell-dependent myeloma control, most efficiently from memory T cells within myeloma-experienced grafts, but also through priming of naive T cells after BMT. CD8+ T cells from mice with controlled myeloma had a distinct T cell receptor (TCR) repertoire and higher clonotype overlap relative to myeloma-free BMT recipients. Furthermore, T cell-dependent myeloma control could be adoptively transferred to secondary recipients and was myeloma cell clone specific. Interestingly, donor-derived IL-17A acted directly on myeloma cells expressing the IL-17 receptor to induce a transcriptional landscape that promoted tumor growth and immune escape. Conversely, donor IFN-γ secretion and signaling were critical to protective immunity and were profoundly augmented by CD137 agonists. These data provide new insights into the mechanisms of action of transplantation in myeloma and provide rational approaches to improving clinical outcomes.
dc.description.peerreviewedYes
dc.languageEnglish
dc.publisherAmerican Society for Clinical Investigation (ASCI)
dc.relation.ispartofpagefrom106
dc.relation.ispartofpageto121
dc.relation.ispartofissue1
dc.relation.ispartofjournalJournal of Clinical Investigation
dc.relation.ispartofvolume129
dc.subject.fieldofresearchClinical Sciences
dc.subject.fieldofresearchMedical and Health Sciences
dc.subject.fieldofresearchcode1103
dc.subject.fieldofresearchcode11
dc.subject.keywordsScience & Technology
dc.subject.keywordsLife Sciences & Biomedicine
dc.subject.keywordsMedicine, Research & Experimental
dc.subject.keywordsResearch & Experimental Medicine
dc.subject.keywordsANTI-INTERLEUKIN-17 MONOCLONAL-ANTIBODY
dc.titleBone marrow transplantation generates T cell-dependent control of myeloma in mice
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationVuckovic, S; Minnie, SA; Smith, D; Gartlan, KH; Watkins, TS; Markey, KA; Mukhopadhyay, P; Guillerey, C; Kuns, RD; Locke, KR; Pritchard, AL; Johansson, PA; Varelias, A; Zhang, P; et al., Bone marrow transplantation generates T cell-dependent control of myeloma in mice, Journal of Clinical Investigation, 2019, 129 (1), pp. 106-121
dcterms.dateAccepted2018-10-02
dc.date.updated2021-01-15T03:42:41Z
dc.description.versionVersion of Record (VoR)
gro.rights.copyright© 2019 American Society for Clinical Investigation (ASCI). The attached file is reproduced here in accordance with the copyright policy of the publisher. Please refer to the journal's website for access to the definitive, published version.
gro.hasfulltextFull Text
gro.griffith.authorZhang, Ping


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