To identify HLA markers that may contribute to the genetic susceptibility of Koreans to psoriasis, we studied 84 psoriasis patients, with serologic HLA types of A, B, and genotypes of HLA-Cw, DRB1, DQA1, DQB1, DPB1 alleles. The distribution of HLA markers and the associated haplotypes were analyzed according to age and sex. HLA-Cw*0602 showed the strongest association with psoriasis (relative risk = 36.0, p < 10-8, Pc < 8 x 10-7). The frequencies of A1 (relative risk = 17.0, p < 9 x 10-7, Pc < 7 x 10-5), A30 (relative risk = 5.5, p < 2 x 10-5, Pc < 0.001), B13 (relative risk = 5.6, p < 4 x 10-6, Pc < 3 x 10-4), B37 (relative risk = 30.3, p < 7 x 10-7, Pc < 6 x 10-5), DRB1*07 (relative risk = 5.9, p < 2 x 10-6, Pc < 8 x 10-5), DRB1*10 (relative risk = 26.4, p < 4 x 10-6, Pc < 3 x 10-4), DQA1*02 (relative risk = 6.2, p < 5 x 10-7, Pc < 4 x 10-4), DQB1*02 (relative risk = 2.5, p < 0.005, Pc = ns) and DPB1*1701 (relative risk = 24.6, p < 9 x 10-6, Pc < 7 x 10-4) were also significantly increased in Korean psoriasis patients. Type I and type II psoriasis were subdivided into groups of below and above 30 y of age, because of the significant difference found in HLA-Cw*0602 phenotype frequency between the two groups (83.9% vs. 54.5%, p < 0. 009). In addition to HLA-Cw*0602, the frequencies of B37 and DPB1*1701 were significantly higher in type I as opposed to type II psoriasis. HLA-A30-B13-Cw*0602-DRB1*07-DQA1* 02-DQB1*02 was identified as a high risk haplotype. This was particularly true at an early age in the female. HLA-A33-B44-Cw*1401-DRB1*13-DQA1* 01-DQB1*06-DPB1*0401 was defined as a protective haplotype for psoriasis. The extended haplotype HLA-A1-B37-Cw*0602-DRB1*10-DQA1*01-DQB1*05 was discovered to be a high-risk factor in Koreans. To summarize, this study demonstrates the differential association of HLA according to sex, and identifies a newly found high-risk haplotype and a protective haplotype in Korean psoriasis patients.
To define whether individual human leukocyte antigen (HLA) class I allotypes are used preferentially in human cytomegalovirus (CMV)-specific cytotoxic T lymphocyte responses, CD8+ T cell responses restricted by up to six HLA class I allotypes in an individual were measured in parallel using K562-based artificial antigen-presenting cells expressing both CMV pp65 antigen and one of 32 HLA class I allotypes (7 HLA-A, 14 HLA-B, and 11 HLA-C) present in 50 healthy Korean donors. The CD8+ T cell responses to pp65 in the HLA-C allotypes were lower than responses to those in HLA-A and -B allotypes and there was no difference between the HLA-A and HLA-B loci. HLA-A*02:01, -B*07:02, and -C*08:01 showed the highest magnitude and frequency of immune responses to pp65 at each HLA class I locus. However, HLA-A*02:07, -B*59:01, -B*58:01, -B*15:11, -C*03:02, and -C*02:02 did not show any immune responses. Although each individual has up to six different HLA allotypes, 46% of the donors showed one allotype, 24% showed two allotypes, and 2% showed three allotypes that responded to pp65. Interestingly, the frequencies of HLA-A alleles were significantly correlated with the positivity of specific allotypes. Our results demonstrate that specific HLA class I allotypes are preferentially used in the CD8+ T cell immune response to pp65 and that a hierarchy among HLA class I allotypes is present in an individual.
Most tumors express an array of antigens that act as targets for their immune-mediated destruction, and a number of potential therapies have emerged to exploit this (22). The immunotherapeutic strategy used to induce an immune response against tumors is quite attractive because it offers the potential for a high level of tumor-specific cytotoxicity, minimal side effects, and a durable effect.Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs) in the induction of primary immune responses (29, 33). Because of their central role in controlling cell-mediated immunity, DCs hold much promise as cellular adjuvants in therapeutic cancer vaccines. DC-based immunotherapy has been reported to induce strong antitumor immune responses in animal experiments and in selected clinical trials involving malignant gliomas (2, 11, 36). However, its clinical effects on patients with malignancies have not been up to the expectations because of immune tolerance, the sheer physical burden of tumor antigens, and the mechanisms of tumor escape from the immune surveillance system, among others (10,20).Calreticulin (CRT) acts as a danger signal for DCs, allowing them to phagocytose tumor cells and to prime tumor antigenspecific cytotoxic T cells (CTLs) (12). It was recently reported that CRT exposure on the surfaces of dying tumor cells may determine whether chemotherapy is immunogenic (26). The capacity of chemotherapies to induce immunogenic tumor cell death is associated with the expression of CRT on the tumor cell surface. Furthermore, it was shown with an animal tumor model that the provision of CRT from an exogenous CRT exposure source as enforcement for endogenous CRT exposure could improve the efficacy of chemotherapy by stimulating antitumor immunity (27). Thus, whether chemotherapy triggers such an immunogenic effect depends on the exposure of CRT on the cell surface. The use of multimodality treatments that combine conventional antitumor therapies with immunotherapy, such as vaccination with DC-based vaccines, has emerged as a potentially plausible approach to the treatment of tumors (3, 5). We previously reported that the use of a multimodality treatment regimen with a DC-based vaccine in combination with the chemotherapeutic agent temozolomide (TMZ) leads to enhanced tumor-specific CTL responses and enhanced antitumor effects, resulting in a cure rate higher than that achieved with either a DC-based vaccine or TMZ alone (17,28). However, the immunological factors relating to the antitumor effect of TMZ chemoimmunotherapy in a murine glioma model are still unclear.
Interleukin (IL)-12 has been reported to induce cellular immune responses for protection against tumor formation. Here we investigate the utility of adenoviral delivery of IL-12 as an adjuvant for a human papillomavirus E7 subunit vaccine in a mouse tumor challenge model. Direct intratumoral injection of AdIL-12 resulted in a significant suppression of tumor growth compared to the control group. Injection of E7 protein into either a tumor site or the distance site along with AdIL-12 further enhanced antitumor effects significantly higher than either AdIL-12 or E7 injection alone. This combined injection resulted in complete regression of 9-mm-sized tumor in 40% of animals as well as lasting antitumor immunity against tumor recurrence. We also evaluated immune responses induced by these injections. AdIL-12 plus E7 enhanced E7-specific antibody responses significantly higher than AdIL-12 or E7 injection. In particular, the production level of interferon (IFN)-gamma from E7-specific CD4(+) T cells was similar between AdIL-12 group and AdIL-12 + E7 group. However, IFN-gamma production from E7-specific CD8(+) T cells was the most significant when injected with AdIL-12 + E7. This was consistent with intracellular IFN-gamma staining levels of CD8(+) T cells, suggesting that AdIL-12 + E7 injection enhances antitumor immunity in the human papillomavirus (HPV) 16 tumor model through increased expansion of the cytotoxic T-lymphocyte (CTL) subset. This enhanced protection appeared to be mediated by CD8(+) T cells, as determined by in vivo T-cell subset deletion. Thus, these studies demonstrate that E7 vaccines can induce CTL responses responsible for antitumor effects in the presence of IL-12 delivered via adenovirus vectors. This likely provides one additional approach for immune therapy against cervical cancers.
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