title: Reduction of alloantibody response to class I major histocompatibility complex by targeting synthetic allopeptides for presentation by B cells.
abstract: BACKGROUND
  PVG.RT1(u) rats develop a strong CD4 T cell-dependent alloantibody response to class I major histocompatibility complex (MHC) A(a) antigen, during which CD4 T helper cells recognize and respond to A(a)-derived peptides presented by recipient class II MHC (indirect allorecognition). On the basis of evidence that CD4 T cells that encounter antigen presented by resting B cells become tolerant, we have targeted synthetic A(a)-derived allopeptides for in vivo presentation to class I MHC-disparate CD4 T cells by resting recipient B cells.
  
  
  METHODS
  PVG.RT1(u) rats were treated with two peptides, P1 and P2, corresponding to the alpha-helical regions of A(a) (residues 57-80 and 143-163), which were conjugated via an N-terminal cysteine residue to monovalent Fab fragments of OX60 monoclonal antibody, which labels membrane IgD-positive B cells.
  
  
  RESULTS
  RT1(u) rats primed with free (nonconjugated) P1 or P2 emulsified in complete Freund's adjuvant produced strong peptide-specific antibody responses and a heightened anti-A(a) antibody response to an A(a)-disparate PVG.R8 heart graft, confirming that each peptide encompasses one or more major T cell determinant for B cell help. Pretreatment of PVG.RT1(u) rats with a mixture of OX60-Fab-P1/P2 conjugates markedly reduced their ability to mount an A(a) antibody response when challenged with either A(a)-disparate blood transfusion or an A(a)-disparate heart graft, although PVG.R8 heart graft survival was not prolonged.
  
  
  CONCLUSIONS
  In this report, we show that synthetic A(a)-derived allopeptides are able, when targeted for in vivo presentation to CD4 T cells by resting B cells, to impair the ability of RT1(u) rats to mount an antibody response to A(a) antigen. All subclasses of IgG anti-A(a) alloantibody were profoundly reduced, suggesting that the responsible mechanism is more likely to be CD4 T helper cell unresponsiveness rather than Th1/Th2 T cell polarization.
authors.affiliation: Division of Immunological Science, University of Glasgow, Scotland.
authors.forename: C M
authors.initials: CM
authors.lastname: MacDonald
authors.forename: E M
authors.initials: EM
authors.lastname: Bolton
authors.forename: B C
authors.initials: BC
authors.lastname: Jaques
authors.forename: K G
authors.initials: KG
authors.lastname: Walker
authors.forename: J A
authors.initials: JA
authors.lastname: Bradley
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D007108:Immune Tolerance; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007518:Isoantibodies / Q000276:immunology*; D008297:Male; D010446:Peptide Fragments / Q000276:immunology*; D051381:Rats; D011994:Recombinant Proteins / Q000276:immunology; D014181:Transplantation Immunology / Q000276:immunology*
chemical_list: D015395:Histocompatibility Antigens Class I; D007140:Immunoglobulin Fab Fragments; D007518:Isoantibodies; D010446:Peptide Fragments; D011994:Recombinant Proteins