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Costimulation blockade alters germinal center responses and prevents antibody-mediated rejection.

dc.contributor.author Kim, EJ
dc.contributor.author Kwun, J
dc.contributor.author Gibby, AC
dc.contributor.author Hong, JJ
dc.contributor.author Farris III, AB
dc.contributor.author Iwakoshi, NN
dc.contributor.author Villinger, F
dc.contributor.author Kirk, AD
dc.contributor.author Knechtle, SJ
dc.coverage.spatial United States
dc.date.accessioned 2015-05-16T11:58:01Z
dc.date.issued 2014-01
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/24354871
dc.identifier.uri https://hdl.handle.net/10161/10063
dc.description.abstract De novo donor-specific antibody (DSA) after organ transplantation promotes antibody-mediated rejection (AMR) and causes late graft loss. Previously, we demonstrated that depletion using anti-CD3 immunotoxin combined with tacrolimus and alefacept (AMR regimen) reliably induced early DSA production with AMR in a nonhuman primate kidney transplant model. Five animals were assigned as positive AMR controls, four received additional belatacept and four received additional anti-CD40 mAb (2C10R4). Notably, production of early de novo DSA was completely attenuated with additional belatacept or 2C10R4 treatment. In accordance with this, while positive controls experienced a decrease in peripheral IgM(+) B cells, bela- and 2C10R4-added groups maintained a predominant population of IgM(+) B cells, potentially indicating decreased isotype switching. Central memory T cells (CD4(+) CD28(+) CD95(+)) as well as PD-1(hi) CD4(+) T cells were decreased in both bela-added and 2C10R4-added groups. In analyzing germinal center (GC) reactions in situ, lymph nodes further revealed a reduction of B cell clonal expansion, GC-follicular helper T (Tfh) cells, and IL-21 production inside GCs with additional belatacept or 2C10R4 treatment. Here we provide evidence that belatacept and 2C10R4 selectively suppresses the humoral response via regulating Tfh cells and prevents AMR in this nonhuman primate model.
dc.language eng
dc.publisher Wiley
dc.relation.ispartof Am J Transplant
dc.relation.isversionof 10.1111/ajt.12526
dc.subject Antibody-mediated rejection
dc.subject costimulation blockade
dc.subject follicular helper T cells
dc.subject germinal center reaction
dc.subject Abatacept
dc.subject Animals
dc.subject Antibodies
dc.subject B-Lymphocytes
dc.subject CD4-Positive T-Lymphocytes
dc.subject Germinal Center
dc.subject Graft Rejection
dc.subject Immunoconjugates
dc.subject Kidney Transplantation
dc.subject Lymph Nodes
dc.subject Macaca mulatta
dc.subject Male
dc.subject Recombinant Fusion Proteins
dc.subject T-Lymphocytes, Helper-Inducer
dc.subject Tacrolimus
dc.title Costimulation blockade alters germinal center responses and prevents antibody-mediated rejection.
dc.type Journal article
duke.contributor.id Kwun, J|0669479
duke.contributor.id Kirk, AD|0071767
duke.contributor.id Knechtle, SJ|0167915
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/24354871
pubs.begin-page 59
pubs.end-page 69
pubs.issue 1
pubs.organisational-group Basic Science Departments
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke
pubs.organisational-group Duke Cancer Institute
pubs.organisational-group Duke Clinical Research Institute
pubs.organisational-group Immunology
pubs.organisational-group Institutes and Centers
pubs.organisational-group Pediatrics
pubs.organisational-group School of Medicine
pubs.organisational-group Surgery
pubs.organisational-group Surgery, Abdominal Transplant Surgery
pubs.publication-status Published
pubs.volume 14
dc.identifier.eissn 1600-6143
duke.contributor.orcid Kwun, J|0000-0002-8563-5472
duke.contributor.orcid Kirk, AD|0000-0003-2004-5962
duke.contributor.orcid Knechtle, SJ|0000-0002-1625-385X


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