title: Interleukin-21 receptor blockade inhibits secondary humoral responses and halts the progression of preestablished disease in the (NZB × NZW)F1 systemic lupus erythematosus model.
abstract: OBJECTIVE
  Systemic lupus erythematosus (SLE) is a complex autoimmune disease that is driven in part by chronic B and T lymphocyte hyperresponsiveness to self antigens. A deficiency of interleukin-21 (IL-21) or IL-21 receptor (IL-21R) in mice dramatically reduces inflammation and B and T cell activation in models of autoimmunity, including SLE. However, whether IL-21 is essential for the maintenance and amplification of preestablished inflammation has not been widely examined in various animal models. The purpose of this study was to examine the impact of novel mouse IL-21R neutralizing antibodies on recall responses to antigen challenge and on disease progression in the (NZB × NZW)F1 (NZB/NZW) mouse model of SLE.
  
  
  METHODS
  Humoral and cellular immune responses to immunization with sheep red blood cells (SRBCs) were measured in mice dosed with IL-21R blocking antibodies. Progression of nephritis and markers of immune activation was monitored in NZB/NZW mice following different anti-IL-21R treatment regimens.
  
  
  RESULTS
  IL-21R blockade specifically inhibited secondary IgG responses to SRBC immunization. In NZB/NZW mice, IL-21R blockade completely inhibited the onset of nephritis, which was associated with dramatic reductions in splenomegaly and in B cell and T cell activation. When administered to mice with preexisting disease, anti-IL-21R antibody halted the disease progression and mortality and reversed the nephritis in a subset of mice. Furthermore, treatment cessation was not followed by rapid reemergence of disease.
  
  
  CONCLUSIONS
  Our results highlight the importance of IL-21 in promoting humoral recall responses and in sustaining autoimmune inflammation.
authors.affiliation: Amgen, Inc., Thousand Oaks, California.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Amgen, Inc., Thousand Oaks, California.
authors.forename: Gang
authors.initials: G
authors.lastname: Yu
authors.affiliation: Amgen, Inc., Burnaby, British Columbia, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: Chan
authors.affiliation: Amgen, Inc., Seattle, Washington.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Pearson
authors.affiliation: Amgen, Inc., Burnaby, British Columbia, Canada.
authors.forename: Palaniswami
authors.initials: P
authors.lastname: Rathanaswami
authors.affiliation: Amgen, Inc., Seattle, Washington.
authors.forename: John
authors.initials: J
authors.lastname: Delaney
authors.affiliation: Amgen, Inc., Seattle, Washington.
authors.forename: Ai
authors.initials: A
authors.lastname: Ching Lim
authors.affiliation: Amgen, Inc., Burnaby, British Columbia, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Babcook
authors.affiliation: Amgen, Inc., Thousand Oaks, California.
authors.forename: Hailing
authors.initials: H
authors.lastname: Hsu
authors.affiliation: Amgen, Inc., Seattle, Washington.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Gavin
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D015551:Autoimmunity / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D056724:Immunity, Humoral / Q000187:drug effects / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008814:Mice, Inbred NZB; D053655:Receptors, Interleukin-21 / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000276:immunology; D012756:Sheep / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D019138:Antibodies, Blocking; D007074:Immunoglobulin G; D053655:Receptors, Interleukin-21