CD4 T-Cell-mediated immune response to prostatic proteins in HLA-DRB1*1503 transgenic mice and identification of a novel HLA-DRB1*1503-restricted T-cell epitope from human prostatic acid phosphatase.
BACKGROUND
Transgenic mice engineered to express human leukocyte antigen (HLA) alleles are widely used for identification of immunogenic and naturally processed epitopes. Using HLA-DRB1*1501 (DR2b) transgenic mice, we have previously identified epitopes from two prostatic antigens, prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP). These antigens are implicated in the development of autoimmunity in the prostate and also are considered promising targets for prostate cancer immunotherapy. HLA-DRB1*1501 is the most common DR15 allele in Caucasians, while HLA-DRB1*1503 is the most common in African Americans. Hence characterization of peptide immunogenicity for these alleles is important for the development of prostate cancer immunotherapy in white and black patients.


METHODS
HLA-DRB1*1501 or HLA-DRB1*1503 transgenic mice were immunized with human PSA or PAP. Libraries of overlapping 20-mer peptides spanning the entire sequences of these proteins were screened by IFN-γ ELISPOT assay.


RESULTS
PSA and PAP peptides that were previously identified in HLA-DRB1*1501 tg mice were immunogenic in HLA-DR1503 tg mice and induced CD4 T-cell response against whole processed PSA or PAP respectively. However, the hierarchy of the immunodominance among the peptides differed significantly between strains. Using HLA-DRB1*1503 tg mice, a novel immunogenic and naturally processed 20-mer peptide, PAP (233-252) has been identified that showed no reactivity in HLA-DRB1*1501 tg mice.


CONCLUSIONS
Our data demonstrate a disparity in CD4 T-cell immune reactivity to PSA and PAP between HLA-DRB1*1501 and -DRB1*1503 alleles in HLA transgenic mouse models. It is possible that such immunological differences could contribute to racial disparity in prostate cancer outcome.
Klyushnenkova
Elena N
EN
VA Maryland Health Care System, Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. eklyushnenkova@smail.umaryland.edu
Alexander
Richard B
RB
D000135:Acid Phosphatase; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology*; D059811:HLA-DRB1 Chains; D016056:Immunodominant Epitopes / Q000276:immunology; D007371:Interferon-gamma / Q000032:analysis / Q000276:immunology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019151:Peptide Library; D011467:Prostate / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D017430:Prostate-Specific Antigen / Q000276:immunology*; D017027:Protein Tyrosine Phosphatases / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D016056:Immunodominant Epitopes; D019151:Peptide Library; D007371:Interferon-gamma; D000135:Acid Phosphatase; C428439:prostatic acid phosphatase; D017027:Protein Tyrosine Phosphatases; D017430:Prostate-Specific Antigen