title: Abatacept does not induce direct gene expression changes in antigen-presenting cells.
abstract: BACKGROUND
  It has been proposed that ligation of CD80 and CD86 induces reverse signaling into antigen-presenting cells. In this study, we tested the ability of abatacept, a soluble human fusion protein comprising the extracellular domain of cytotoxic T lymphocyte antigen 4 and a fragment of the Fc domain of IgG(1), to activate antigen-presenting cells by measuring changes in global transcriptional responses.
  
  
  METHODS
  Affymetrix chips were used to measure gene expression levels using mRNA isolated from immature and mature human dendritic cells and a B cell line following 6 h of treatment with abatacept.
  
  
  RESULTS
  In contrast to robust transcriptional responses induced by the control treatment phorbol-12-myristate-13-acetate, abatacept induced minimal gene changes in three different populations of antigen-presenting cells. Furthermore, no gene changes were observed in response to belatacept, a modified version of abatacept that binds with higher avidity to CD80 and CD86.
  
  
  CONCLUSIONS
  We conclude that reverse signaling in antigen-presenting cells is unlikely to occur in response to either abatacept or belatacept, thereby supporting the modulation of CD28 signaling on T cells as the main mechanism of action for these therapeutics.
authors.affiliation: Discovery Biology, Bristol-Myers Squibb, Princeton, NJ, USA. julie.carman@bms.com
authors.forename: Julie A
authors.initials: JA
authors.lastname: Carman
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Davis
authors.forename: Wen-Pin
authors.initials: WP
authors.lastname: Yang
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.forename: Han
authors.initials: H
authors.lastname: Chang
authors.forename: Aiqing
authors.initials: A
authors.lastname: He
authors.forename: Amy
authors.initials: A
authors.lastname: Truong
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Suchard
authors.forename: Steven G
authors.initials: SG
authors.lastname: Nadler
mesh_terms: D000069594:Abatacept; D017951:Antigen Presentation / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism*; D051940:B7-2 Antigen / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D010703:Phorbol Esters / Q000494:pharmacology
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D016207:Cytokines; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D010703:Phorbol Esters; C119222:phorbol-12-myristate; D000069594:Abatacept