title: Anti-CD20 antibody suppresses anti-HLA antibody formation in a HLA-A2 transgenic mouse model of sensitization.
abstract: BACKGROUND
  B cell depletion by anti-CD20 antibody is used in desensitization protocols and for treatment of antibody-mediated rejection (AMR). However, little is known about the efficacy and the mechanism(s) of action.
  
  
  METHODS
  A mouse model of HLA sensitization was used to study the effectiveness of anti-CD20 treatment on B cell depletion and anti-HLA antibody suppression.
  
  
  RESULTS
  Immunization of C57BL/6 mice with skin grafts from a transgenic C57BL.Tg/HLA-A2.1 mouse resulted in robust production of anti-HLA IgM and IgG antibodies, and accelerated rejection of a secondary skin allograft (within 3 days) featured by intragraft IgG and C4d deposition. Both IgM and IgG alloantibodies are specific to HLA-A2 as well as to a panel of class I HLA, including A1, A3, A25, A26, A29, and A30. These alloantibodies were complement-dependently cytotoxic (CDC) against HLA-A2 expressing target cells. Administration of 2 doses of a mouse-anti-mouse CD20 monoclonal antibody significantly reduced the levels of anti-HLA IgG2a antibodies, suppressed serum CDC, and prolonged survival of the secondary skin allografts. Suppression of anti-HLA IgG antibodies was associated with significant depletion of B220(+)/CD5(-) B cells from the blood, the spleen and the bone marrow of the treated animals.
  
  
  CONCLUSIONS
  Anti-CD20 treatment effectively depletes B220(+)/CD5(-) B cells, resulting in potent suppression of anti-HLA IgG and prolongation of skin graft survival. The data are in support for the use of anti-CD20 antibodies in highly-HLA sensitized patients undergoing desensitization and for the treatment of AMR.
authors.affiliation: Comprehensive Transplant Center at Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States. gordon.wu@cshs.org
authors.forename: Gordon D
authors.initials: GD
authors.lastname: Wu
authors.forename: Yao
authors.initials: Y
authors.lastname: He
authors.forename: Ning-ning
authors.initials: NN
authors.lastname: Chai
authors.forename: Mieko
authors.initials: M
authors.lastname: Toyoda
authors.forename: Robert
authors.initials: R
authors.lastname: Dunn
authors.forename: Marilyn R
authors.initials: MR
authors.lastname: Kehry
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Klein
authors.forename: Stanley C
authors.initials: SC
authors.lastname: Jordan
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D000917:Antibody Formation / Q000187:drug effects*; D000936:Antigen-Antibody Complex / Q000276:immunology; D018951:Antigens, CD20 / Q000276:immunology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D006084:Graft Rejection / Q000097:blood / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007116:Immunization, Passive; D007136:Immunoglobulins / Q000097:blood; D007518:Isoantibodies / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016038:Skin Transplantation / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D018951:Antigens, CD20; D015789:HLA-A2 Antigen; D007136:Immunoglobulins; D007518:Isoantibodies