Combination peptide immunotherapy suppresses antibody and helper T-cell responses to the RhD protein in HLA-transgenic mice.
The offspring from pregnancies of women who have developed anti-D blood group antibodies are at risk of hemolytic disease of the newborn. We have previously mapped four peptides containing immunodominant T-helper cell epitopes from the RhD protein and the purpose of the work was to develop these into a product for suppression of established anti-D responses. A panel of each of the four immunodominant RhD peptides was synthesized with modifications to improve manufacturability and solubility, and screened for retention of recognition by human T-helper cells. A selected version of each sequence was combined in a mixture (RhDPmix), which was tested for suppressive ability in a humanized murine model of established immune responses to RhD protein. After HLA-DR15 transgenic mice had been immunized with RhD protein, a single dose of RhDPmix, given either intranasally (P=0.008, Mann-Whitney rank sum test) or subcutaneously (P=0.043), rapidly and significantly suppressed the ongoing antibody response. This was accompanied by reduced T-helper cell responsiveness, although this change was less marked for subcutaneous RhDPmix delivery, and by the recruitment of cells with a regulatory T-cell phenotype. The results support human trials of RhDPmix peptide immunotherapy in women with established antibody responses to the RhD blood group.
a.m.hall@abdn.ac.uk.
Lindsay S
LS
Hall
Andrew M
AM
Hall
Wendy
W
Pickford
Mark A
MA
Vickers
Stanislaw J
SJ
Urbaniak
Robert N
RN
Barker
D000328:Adult; D000818:Animals; D000917:Antibody Formation / Q000235:genetics* / Q000276:immunology*; D005260:Female; D006649:Histocompatibility Antigens / Q000235:genetics*; D006801:Humans; D016056:Immunodominant Epitopes / Q000008:administration & dosage / Q000276:immunology; D007167:Immunotherapy; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology*; D012204:Rh-Hr Blood-Group System / Q000737:chemistry / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D055815:Young Adult
D006649:Histocompatibility Antigens; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D012204:Rh-Hr Blood-Group System; C026410:Rho(D) antigen