TY - JOUR
T1 - Identification, immunomodulatory activity, and immunogenicity of the major helper T-cell epitope on the K blood group antigen
AU - Stephen, Jillian
AU - Cairns, Lindsay S.
AU - Pickford, Wendy J.
AU - Vickers, Mark A.
AU - Urbaniak, Stanislaw J.
AU - Barker, Robert N.
PY - 2012/6/7
Y1 - 2012/6/7
N2 - The K blood group remains an important target in hemolytic disease of the newborn (HDN), with no immune prophylaxis available. The aim was to characterize the T helper (Th) response to K as a key step in designing specific immunotherapy and understanding the immunogenicity of the antigen. Peripheral blood mononuclear cells from K-negative women who had anti-K antibodies following incompatible pregnancy, and from unimmunized controls, were screened for proliferative responses to peptide panels spanning the K or k single amino acid polymorphism. A dominant K peptide with the polymorphism at the C-terminus elicited proliferation in 90% of alloimmunized women, and it was confirmed that responding cells expressed helper CD3(+)CD4(+) and "memory" CD45RO(+) phenotypes, and were MHC class II restricted. A relatively high prevalence of background peptide responses independent of alloimmunization may contribute to K immunogenicity. First, cross-reactive environmental antigen(s) pre-prime Kell-reactive Th cells, and, secondly, the K substitution disrupts an N-glycosylation motif, allowing the exposed amino acid chain to stimulate a Th repertoire that is unconstrained by self-tolerance in K-negative individuals. The dominant K peptide was effective in inducing linked suppression in HLA-transgenic mice and can now be taken forward for immunotherapy to prevent HDN due to anti-K responses.
AB - The K blood group remains an important target in hemolytic disease of the newborn (HDN), with no immune prophylaxis available. The aim was to characterize the T helper (Th) response to K as a key step in designing specific immunotherapy and understanding the immunogenicity of the antigen. Peripheral blood mononuclear cells from K-negative women who had anti-K antibodies following incompatible pregnancy, and from unimmunized controls, were screened for proliferative responses to peptide panels spanning the K or k single amino acid polymorphism. A dominant K peptide with the polymorphism at the C-terminus elicited proliferation in 90% of alloimmunized women, and it was confirmed that responding cells expressed helper CD3(+)CD4(+) and "memory" CD45RO(+) phenotypes, and were MHC class II restricted. A relatively high prevalence of background peptide responses independent of alloimmunization may contribute to K immunogenicity. First, cross-reactive environmental antigen(s) pre-prime Kell-reactive Th cells, and, secondly, the K substitution disrupts an N-glycosylation motif, allowing the exposed amino acid chain to stimulate a Th repertoire that is unconstrained by self-tolerance in K-negative individuals. The dominant K peptide was effective in inducing linked suppression in HLA-transgenic mice and can now be taken forward for immunotherapy to prevent HDN due to anti-K responses.
U2 - 10.1182/blood-2012-02-410324
DO - 10.1182/blood-2012-02-410324
M3 - Article
C2 - 22490333
SN - 0006-4971
VL - 119
SP - 5563
EP - 5574
JO - Blood
JF - Blood
IS - 23
ER -