Control of HIV-1 by an HLA-B*52:01-C*12:02 Protective Haplotype.

HLA-B*52:01-C*12:02, which is found in approximately 20% of all Japanese persons, is well known to be associated with ulcerative colitis and Takayasu arteritis. This haplotype is also known to be protective in individuals infected with human immunodeficiency virus (HIV) type 1. Recent studies showed that HLA-B*52:01-restricted HIV-1-specific T cells suppress HIV-1 and that HLA-C*12:02 together with KIR2DL2 play an important role in natural killer cell-mediated control of HIV-1. However, the role of HLA-C*12:02-restricted cytotoxic T lymphocytes (CTLs) in suppressing HIV-1 replication remains unknown. In the present study, we demonstrated that HLA-C*12:02-restricted CTLs specific for 2 immunodominant epitopes, Pol IY11 and Nef MY9, contributed to the suppression of HIV-1 replication in HIV-1-infected individuals. Further analysis demonstrated that these 2 HLA-C*12:02-restricted CTLs together with 4 HLA-B*52:01-restricted ones effectively suppressed HIV-1 in individuals with the HLA-B*52:01-C*12:02 haplotype. Thus, both HLA-C*12:02 and HLA-B*52:01 alleles contribute to HIV-1 suppression via both HIV-1-specific CTLs and natural killer cells in individuals with this haplotype.

Rhabdomyosarcomas are potential target of MAGE-specific immunotherapies.

The search for alternative strategies of therapy remains a major issue for most neoplastic diseases. The expression of several tumor antigens makes human rhabdomyosarcomas, which are the most frequent form of soft tissue tumor in children, a good candidate for tumor-specific immunotherapy. To assess the feasibility of this approach, we evaluated the ability of rhabdomyosarcoma cell lines to process and present the MAGE-A tumor antigens to effectors of the immune system. To this end, we investigated recognition of MAGE-A-positive rhabdomyosarcoma cells by HLA-B*3701-restricted T cells specific for a MAGE-A-derived peptide. Low level of HLA expression impaired recognition of the tumor cells. Therefore, to obtain HLA expression avoiding the use of IFN-gamma and TNF-alpha, which could affect the proteasome activity, a rhabdomyosarcoma line was transduced by a retroviral vector encoding the HLA-B*3701 allele. Recognition of the infected cells was then observed also in the absence of IFN-gamma and TNF-alpha treatment, thus demonstrating that rhabdomyosarcoma cells were indeed able to naturally process and present the MAGE-A antigens. These results demonstrate that rhabdomyosarcoma cells expressing MAGE-A can be targets of tumor-specific effectors, suggesting the feasibility of clinical protocols of specific immunotherapy also for the treatment of rhabdomyosarcoma.

Treatment with an HLA-peptide and cyclosporine A prolongs rat small bowel allograft survival.

BACKGROUND: The ultimate treatment for severe short bowel syndrome is small bowel transplantation (SBT). Current immunosuppression for SBT is relatively ineffective and toxic. Peptides derived from residues 75-84 of the HLA-B7 molecule are immunomodulatory in vitro, and in rodents, when combined with subtherapeutic doses of cyclosporine (CsA), prolong cardiac and skin allograft survival without altering the recipient's rejection kinetics to third party allografts. We investigated the effects of HLA-B7 peptide fragment in a rat model of SBT. METHODS: Heterotopic allogeneic SBT was performed in Dagouti (RT1a) to Lewis (RT1l) high-responder rat strain combination. B7.75-84 (40 mg/kg/d) and subtherapeutic CsA (10 mg/kg/d) were administered alone, or in combination, by gavage to allograft recipients on days 0 to 4 after SBT. Recipient pretreatment with B7.75-84 on days -14, -12, -10, and -7 followed by subtherapeutic CsA on days 0 to 4 after SBT was also carried out. Graft rejection was determined by the presence of a palpable abdominal mass on daily examination or by loss of more than 10% initial body weight. RESULTS: Without immunosuppression allografts rejected at a median time of 6 days (range, 5 to 7; n = 7). This was not significantly altered with either CsA therapy alone (median 6 days; range, 6 to 7; n = 6) or B7.75-84 alone (median, 5 days; range, 5 to 6; n = 6). Recipient combination therapy with B7.75-84 and CsA after allografting significantly prolonged allograft survival (median, 11 days; range, 9 to 13; n = 9), as did recipient B7.75-84 pretransplant therapy (median, 10 days; range, 9 to 12; n = 6), when administered over a 2-week period before allografting. CONCLUSION: Post-SBT recipient treatment with B7.75-84 produced statistically significant improvement in allograft survival only after combination with subtherapeutic CsA. Recipient pre-SBT treatment with B7.75-84 alone however, resulted in statistically significant improvement in allograft survival in combination with post-SBT subtherapeutic CsA. These synergistic effects may be valuable in achieving improved SBT survival clinically and warrant further exploration.

T cell sensitivity to HLA class I-mediated apoptosis is dependent on interleukin-2 and interleukin-4.

Antibody interaction with a specific epitope of the HLA class I alpha1 domain triggers apoptosis of activated but not resting T and B cells by a pathway which involves neither Fas ligand nor tumor necrosis factor-alpha. We have investigated at which stage of activation and proliferation T cells become sensitive to HLA class I-mediated apoptosis, using two monoclonal antibodies (mAb) which recognize the same monomorphic epitope of the HLA class I alpha1 domain (mAb9O, mouse IgG1, and YTH862, rat IgG2b) and can induce apoptosis of phytohemagglutinin (PHA)-activated peripheral blood lymphocytes. Sensitivity to apoptosis develops after the expression of G1 markers (CD69 expression) but it is accelerated by addition of recombinant interleukin-2 (rIL-2). Blocking the IL-2 pathway by cyclosporin A, FK506, rapamycin, anti-IL-2 or CD25 antibodies, prevented the development of sensitivity to apoptosis. Addition of IL-2 and, to a lesser extent, IL-4, reversed the inhibitory effect of cyclosporin A. Conversely, rIL-7 and recombinant interferon-gamma restored proliferation of peripheral blood lymphocytes stimulated by PHA in the presence of cyclosporin A but did not restore sensitivity to class I-mediated apoptosis. Finally cells stimulated in the presence of the DNA polymerase inhibitor aphidicolin did not enter into S phase of the cell cycle but secreted IL-2 and underwent apoptosis when exposed to mAb90 or YTH862. Together, the data indicate that sensitivity of peripheral T cells to HLA class I-mediated apoptosis depends on both activation signals and IL-2 or IL-4, but does not require cell proliferation. These data suggest that YTH862 and mAb90 might be used for achieving clonal deletion of antigen-activated peripheral T cells in vivo, provided that the IL-2 pathway is not blocked by other immunosuppressive agents.