Adult male and female B6C3F1 mice were exposed to perfluorooctane sulfonate (PFOS) daily via gavage for 28 days (0, 0.005, 0.05, 0.1, 0.5, 1, or 5 mg/kg total administered dose [TAD]). Following exposure, various immune parameters were assessed and serum PFOS concentrations were determined. Lymphocyte proliferation was not altered in either gender. Natural killer cell activity was increased compared with control at 0.5, 1, and 5 mg/kg TAD in male mice but was not altered in female mice. At these treatment levels, splenic T-cell immunophenotypes were minimally altered in females, but all T-cell subpopulations were significantly modulated in males beginning at 0.1 mg/kg TAD. The sheep red blood cell (SRBC) plaque-forming cell (PFC) response was suppressed in male mice beginning at 0.05 mg/kg TAD and in females at 0.5 mg/kg TAD. Serum trinitrophenyl (TNP)-specific IgM titers were also decreased by PFOS after TNP-LPS (TNP conjugated to lipopolysacharide) challenge suggesting that the humoral immune effects may be attributed to the B-cell rather than T-cell because both T-dependent (SRBC) and T-independent (TI) (TNP-LPS) antigens result in suppressed IgM production. Based on the PFC response, the low observed effect level (LOEL) for males was 0.05 mg/kg TAD (ED(50) = 0.021 mg/kg TAD) and for females was 0.5 mg/kg TAD (ED(50) = 0.59 mg/kg TAD). Measured PFOS serum concentrations at these dose levels were 91.5 +/- 22.2 ng/g and 666 +/- 108 ng/g (mean +/- SD), respectively. The male LOEL serum level was approximately 14-fold lower than reported mean blood levels from occupationally exposed humans and fell in the upper range of concentrations reported for the general population. Overall, this study provides a profile of PFOS immunotoxicity showing effects at levels reported in humans and identifies the B-cells as a potential target.

Methylation of the RAR-beta2 gene may be an initial step in breast carcinogenesis; treatment of cancer patients with demethylating agents followed by retinoic acid may offer a new therapeutic modality.

Gene silencing through de novo methylation of CpG island promoters contributes to cancer. We find that Mbd2, which recruits co-repressor complexes to methylated DNA, is essential for efficient tumorigenesis in the mouse intestine. As Mbd2-deficient mice are viable and fertile, their resistance to intestinal cancer may be of therapeutic relevance.

In the past, several authors described an association of vitiligo with autoimmune disorders and the presence of different tissue autoantibodies. A review of the literature showed large differences in the results. Therefore, 321 patients with vitiligo (male/female ratio 114/207) were examined to see whether the frequencies of associated diseases and phenomena (i.e. Koebner phenomenon, canities praecox, halo nevi, poliosis circumscripta), the number of pigmented lesions and the presence of autoantibodies are of significance in order to support (a) a subentity of childhood vitiligo and (b) whether there is a true predisposition or association of autoimmune or other diseases in this group of patients. The data confirm earlier results of a prevalence of thyroid disease and the presence of thyroid antibodies, whereas other diseases are a random event. 6.2% of the patients had congenital nevi compared with 2.8% in a normal healthy population. Based on the results of this study and the significant higher risk for development of melanomas in this patient group, an annual checkup is recommended.

High-risk human papillomaviruses (HPVs) are causally associated with multiple human cancers. Previous studies have shown that the HPV oncoprotein E7 induces immune suppression; however, the underlying mechanisms remain unknown. To understand the mechanisms by which HPV deregulates host immune responses in the tumor microenvironment, we analyzed gene expression changes of all known chemokines and their receptors using our global gene expression data sets from human HPV-positive and -negative head/neck cancer and cervical tissue specimens in different disease stages. We report that, while many proinflammatory chemokines increase expression throughout cancer progression, CXCL14 is dramatically downregulated in HPV-positive cancers. HPV suppression of CXCL14 is dependent on E7 and associated with DNA hypermethylation in the CXCL14 promoter. Using in vivo mouse models, we revealed that restoration of Cxcl14 expression in HPV-positive mouse oropharyngeal carcinoma cells clears tumors in immunocompetent syngeneic mice, but not in Rag1-deficient mice. Further, Cxcl14 reexpression significantly increases natural killer (NK), CD4+ T, and CD8+ T cell infiltration into the tumor-draining lymph nodes in vivo. In vitro transwell migration assays show that Cxcl14 reexpression induces chemotaxis of NK, CD4+ T, and CD8+ T cells. These results suggest that CXCL14 downregulation by HPV plays an important role in suppression of antitumor immune responses. Our findings provide a new mechanistic understanding of virus-induced immune evasion that contributes to cancer progression.

One-hundred and two patients from the area of Hamburg, Germany, with vitiligo (photo-skin types II and III, Fitzpatrick classification, 1979), were examined for a possible association of the human lymphocyte antigen (HLA) complex with this disease. Antisera panels for the detection of 75 HLA antigens were utilized for this HLA typing (WHO Bulletin, 1988). The results were compared with 400 unrelated age- and sex-matched controls with photo-skin types II and III from the same geographical area. Nine of 76 vitiligo patients showed a significantly increased expression of the rare antigen HLA DRW 12 (p_c = 0.000708), and 65/102 patients showed a marginally significant increased frequency of HLA A2 (p_c = 0.04850) compared with controls. For HLA BW60 (40), a significant increase in frequency was shown only in the adult vitiligo group (p_c = 0.0126). A ‘preventive’ antigen for the manifestation of vitiligo has not been identified in this study. A comparative analysis of all published data on the possible association of HLA with vitiligo does not support a definitive linkage to the MHC so far.

Study design: Open label study to determine drug dose for a randomized double-blind placebocontrolled parallel study. Objectives: To assess the efficacy and side effects of oral D 9 -tetrahydrocannabinol (THC) and rectal THC-hemisuccinate (THC-HS) in SCI patients. Setting: REHAB Basel, Switzerland. Method: Twenty-five patients with SCI were included in this three-phase study with individual dose adjustment, each consisting of 6 weeks. Twenty-two participants received oral THC open label starting with a single dose of 10 mg (Phase 1, completed by 15 patients). Eight subjects received rectal THC-HS (Phase 2, completed by seven patients). In Phase 3, six patients were treated with oral THC and seven with placebo. Major outcome parameters were the spasticity sum score (SSS) using the Modified Ashworth Scale (MAS) and self-ratings of spasticity. Results: Mean daily doses were 31 mg with THC and 43 mg with THC-HS. Mean SSS for THC decreased significantly from 16.72 (77.60) at baseline to 8.92 (77.14) on day 43. Similar improvement was seen with THC-HS. We observed a significant improvement of SSS with active drug (P ¼ 0.001) in the seven subjects who received oral THC in Phase 1 and placebo in Phase 3. Major reasons for drop out were increase of pain and psychological side effects. Conclusion: THC is an effective and safe drug in the treatment of spasticity. At least 15-20 mg per day were needed to achieve a therapeutic effect.

Evasion of the host immune responses is critical for both persistent human papillomavirus (HPV) infection and associated cancer progression. We have previously shown that expression of the homeostatic chemokine CXCL14 is significantly downregulated by the HPV oncoprotein E7 during cancer progression. Restoration of CXCL14 expression in HPV-positive head and neck cancer (HNC) cells dramatically suppresses tumor growth and increases survival through an immunedependent mechanism in mice. Although CXCL14 recruits natural killer (NK) and T cells to the tumor microenvironment, the mechanism by which CXCL14 mediates tumor suppression through NK and/or T cells remained undefined. Here we report that CD8 + T cells are required for CXCL14-mediated tumor suppression. Using a CD8 + T-cell receptor transgenic model, we show that the CXCL14-mediated antitumor CD8 + T-cell responses require antigen specificity. Interestingly, CXCL14 expression restores major histocompatibility complex class I (MHC-I) expression on HPV-positive HNC cells downregulated by HPV, and knockdown of MHC-I expression in HNC cells results in loss of tumor suppression even with CXCL14 expression. These results suggest that CXCL14 enacts antitumor immunity through restoration of MHC-I expression on tumor cells and promoting antigen-specific CD8 + T-cell responses to suppress HPV-positive HNC.