title: Loss of intra-islet CD20 expression may complicate efficacy of B-cell-directed type 1 diabetes therapies.
abstract: OBJECTIVE
  Consistent with studies in NOD mice, early clinical trials addressing whether depletion of B cells by the Rituximab CD20-specific antibody provides an effective means for type 1 diabetes reversal have produced promising results. However, to improve therapeutic efficacy, additional B-cell-depleting agents, as well as attempts seeking diabetes prevention, are being considered.
  
  
  METHODS
  Autoantibodies, including those against insulin (IAAs), are used to identify at-risk subjects for inclusion in diabetes prevention trials. Therefore, we tested the ability of anti-CD20 to prevent diabetes in NOD mice when administered either before or after IAA onset.
  
  
  RESULTS
  The murine CD20-specific 18B12 antibody that like Rituximab, depletes the follicular (FO) but not marginal zone subset of B cells, efficiently inhibited diabetes development in NOD mice in a likely regulatory T-cell-dependent manner only when treatment was initiated before IAA detection. One implication of these results is that the FO subset of B cells preferentially contributes to early diabetes initiation events. However, most important, the inefficient ability of anti-CD20 treatment to exert late-stage diabetes prevention was found to be attributable to downregulation of CD20 expression upon B cell entry into pancreatic islets.
  
  
  CONCLUSIONS
  These findings provide important guidance for designing strategies targeting B cells as a potential means of diabetes intervention.
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, USA. dave.serreze@jax.org
authors.forename: David V
authors.initials: DV
authors.lastname: Serreze
authors.forename: Harold D
authors.initials: HD
authors.lastname: Chapman
authors.forename: Marijke
authors.initials: M
authors.lastname: Niens
authors.forename: Robert
authors.initials: R
authors.lastname: Dunn
authors.forename: Marilyn R
authors.initials: MR
authors.lastname: Kehry
authors.forename: John P
authors.initials: JP
authors.lastname: Driver
authors.forename: Michael
authors.initials: M
authors.lastname: Haller
authors.forename: Clive
authors.initials: C
authors.lastname: Wasserfall
authors.forename: Mark A
authors.initials: MA
authors.lastname: Atkinson
mesh_terms: D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use*; D018951:Antigens, CD20 / Q000737:chemistry / Q000378:metabolism*; D001323:Autoantibodies / Q000032:analysis; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000276:immunology / Q000378:metabolism* / Q000517:prevention & control; D018450:Disease Progression; D005260:Female; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D008212:Lymphocyte Depletion; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D010950:Plasma Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D011236:Prediabetic State / Q000097:blood / Q000276:immunology / Q000378:metabolism; D000069283:Rituximab
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D001323:Autoantibodies; D007004:Hypoglycemic Agents; D000069283:Rituximab