T-cell recognition of prostatic peptides in men with chronic prostatitis/chronic pelvic pain syndrome.

PURPOSE: A potential etiology of chronic prostatitis/chronic pelvic pain syndrome is autoimmunity. We determined whether T cells from men with chronic prostatitis/chronic pelvic pain syndrome would recognize peptides derived from the normal self-prostatic proteins prostate specific antigen and prostatic acid phosphatase. MATERIALS AND METHODS: CD4 T cells purified from peripheral blood of 31 patients with chronic prostatitis/chronic pelvic pain syndrome and from the buffy coat preparation of 27 normal male blood donors were stimulated in vitro with a panel of immunogenic peptides from prostate specific antigen and prostatic acid phosphatase, and assayed for reactivity with the peptides by interferon-gamma enzyme-linked immunosorbent spot assay. Intermediate resolution HLA typing was done by polymerase chain reaction. Peptides were also tested by binding assay against different class II alleles. RESULTS: Peptide PAP(173-192) was recognized more frequently by CD4 T cells from patients with chronic prostatitis/chronic pelvic pain syndrome than from healthy donors. The recognition of prostate specific antigen peptides was not statistically different when comparing cases to normal male blood donors individually. Peptide reactivity was more common in patients than in normal male blood donors for any prostate specific antigen peptide or any tested peptide. All peptides showed high promiscuity on binding assays. There was no association of cases with any specific HLA class II phenotype at intermediate resolution. CONCLUSIONS: CD4 T cells from patients with chronic prostatitis/chronic pelvic pain syndrome have a higher rate of recognizing the self-prostatic proteins prostatic acid phosphatase and prostate specific antigen compared to those from normal male blood donors. Data provide further evidence to support the role of autoimmunity in some men with chronic prostatitis/chronic pelvic pain syndrome.

Vaccination with agonist peptide PSA: 154-163 (155L) derived from prostate specific antigen induced CD8 T-cell response to the native peptide PSA: 154-163 but failed to induce the reactivity against tumor targets expressing PSA: a phase 2 study in patients with recurrent prostate cancer.

We conducted a clinical trial of peptide prostate specific antigen (PSA): 154-163 (155L) vaccination in human leukocyte antigen (HLA)-A2 patients with detectable and rising serum PSA after radical prostatectomy for prostate cancer (Clinicaltrials.gov identifier NCT00109811). The trial was a single dose-level, phase 2 pilot trial of 1 mg of PSA: 154-163 (155L) emulsified with adjuvant (Montanide ISA-51). The primary endpoint was the determination of immunogenicity of the vaccine; secondary outcomes were determination of toxicity and effect on serum PSA. The vaccine was given subcutaneously 7 times on weeks 0, 2, 4, 6, 10, 14, and 18. Peptide-specific CD8 T-cell responses in the peripheral blood mononuclear cells (PBMC) of patients were measured by interferon (IFN)-gamma enzyme-linked immunosorbent spot assay. CD8 T-cell cultures were also established by in vitro stimulation with the peptide presented by autologous dendritic cells. Five patients were enrolled and completed all vaccinations. No IFN-gamma response to PSA: 154-163 (155L) was detected in unfractioned PBMC in any patient either before or after vaccination. Three of 5 patients demonstrated strong IFN-gamma responses to PSA: 154-163 (155L) and native PSA: 154-163 peptides in CD8 T-cell cultures derived from postvaccination PBMC. However, peptide-specific T cells failed to recognize HLA-A2 positive targets expressing endogenous PSA. There were no significant changes in serum PSA level in any subject. No serious adverse events were observed. PSA: 154-163 (155L) is not an effective immunogen when given with Montanide ISA-51. The PSA: 154-163 peptide is poorly processed from endogenous PSA and therefore represents a cryptic epitope of PSA in HLA-A2 antigen-presenting cells.

Cutting edge: permissive MHC class II allele changes the pattern of antitumor immune response resulting in failure of tumor rejection.

We studied the growth of transgenic adenocarcinoma of mouse prostate (TRAMP)-C1 tumor cells expressing human prostate-specific Ag (PSA) in HLA-DRB1*1501 (DR2b) transgenic mice. TRAMP-PSA tumors were frequently rejected by HLA-DR2b(-) mice but had increased incidence in HLA-DR2b(+) littermates. The levels of PSA-specific CD8 T cell responses were significantly higher in the HLA-DR2b(-) mice that rejected TRAMP-PSA tumors compared with HLA-DR2b(+) tumor-bearing littermates. In contrast, Ab responses to PSA were strong in HLA-DR2b(+) mice bearing TRAMP-PSA tumors and were virtually undetectable in HLA-DR2b(-) littermates. The analysis of CD4 T cell responses to PSA revealed the presence of several CD4 T cell epitopes in HLA-DR2b(+) mice but failed to identify strong I-A(b)-restricted epitopes in HLA-DR2b(-) mice. Our data demonstrate that the expression of a permissive HLA class II allele can change the pattern of the immune response to a tumor Ag, resulting in the failure of tumor rejection.