Identification of HLA-DRB1*1501-restricted T-cell epitopes from prostate-specific antigen.
The development of immunotherapy for prostate cancer based on the induction of autoimmunity to prostate tissue is very attractive because prostate is not a vital organ beyond the reproductive years. CD4 T cells play an important role in the development of antitumor immune responses, yet the identification of naturally processed MHC Class II-restricted epitopes derived from prostate differentiation antigens has not been described. To facilitate the search for prostate-specific antigen (PSA)-derived MHC class II-restricted peptides, we immunized mice transgenic for HLA-DRB1*1501 with human PSA and showed a robust dose-dependent immune response to the antigen. Screening a library of overlapping 20-mer peptides that span the entire PSA sequence identified two 20-mer peptides, PSA(171-190) and PSA(221-240), which were responsible for this reactivity. Immunization of DR2b transgenic mice with these peptides induced specific responses to the peptide and whole PSA. Identified peptides were used to stimulate CD4 T cells from HLA-DRB1*1501+ patients with a rare condition, granulomatous prostatitis, and who seem to have a preexisting immune response directed against the prostate gland. We previously showed a linkage of granulomatous prostatitis to HLA-DRB1*1501, suggesting that this disease may have an autoimmune etiology. Peptide-specific CD4 T-cell lines were generated from the peripheral blood of these patients as well as one patient with prostate cancer. These lines also recognized whole, processed PSA in the context of HLA-DRB1*1501. This study will be instrumental in understanding the interaction between circulating self-reactive T cells, organ-specific autoimmunity, and antitumor immune response. The use of these peptides for the immunotherapy of prostate cancer is under investigation.
Klyushnenkova
Elena N
EN
Urology Section, VA Maryland Health Care System, and Division of Urology, University of Maryland School of Medicine, Baltimore, Maryland 21202, USA. eklyushnenkova@smail.umaryland.edu
Link
Jason
J
Oberle
Warren T
WT
Kodak
James
J
Rich
Cathleen
C
Vandenbark
Arthur A
AA
Alexander
Richard B
RB
D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006684:HLA-DR Antigens / Q000276:immunology*; D015802:HLA-DR2 Antigen / Q000235:genetics / Q000276:immunology; D059811:HLA-DRB1 Chains; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000276:immunology*
D000939:Epitopes; D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D015802:HLA-DR2 Antigen; D059811:HLA-DRB1 Chains; C489631:HLA-DRB1*15:01 antigen; D009842:Oligopeptides; D007371:Interferon-gamma; D017430:Prostate-Specific Antigen