Striking the right immunological balance prevents progression of tuberculosis

Introduction

Tuberculosis (TB) caused by infection with Mycobacterium tuberculosis (Mtb) is a major burden for human health worldwide. Current standard treatments for TB require prolonged administration of antimycobacterial drugs leading to exaggerated inflammation and tissue damage. This can result in the reactivation of latent TB culminating in TB progression. Thus, there is an unmet need to develop therapies that would shorten the duration of anti-TB treatment and to induce optimal protective immune responses to control the spread of mycobacterial infection with minimal lung pathology.

Findings

Granulomata is the hallmark structure formed by the organized accumulation of immune cells including macrophages, natural killer cells, dendritic cells, neutrophils, T cells, and B cells to the site of Mtb infection. It safeguards the host by containing Mtb in latent form. However, granulomata can undergo caseation and contribute to the reactivation of latent TB, if the immune responses developed to fight mycobacterial infection are not properly controlled. Thus, an optimal balance between innate and adaptive immune cells might play a vital role in containing mycobacteria in latent form for prolonged periods and prevent the spread of Mtb infection from one individual to another.

Conclusion

Optimal and well-regulated immune responses against Mycobacterium tuberculosis may help to prevent the reactivation of latent TB. Moreover, therapies targeting balanced immune responses could help to improve treatment outcomes among latently infected TB patients and thereby limit the dissemination of mycobacterial infection.

     

Thalidomide prevents the progression of peritoneal fibrosis in mice

Thalidomide is clinically recognized as a therapeutic agent for multiple myeloma and has been known to exert anti-angiogenic actions. Recent studies have suggested the involvement of angiogenesis in the progression of peritoneal fibrosis. The present study investigated the effects of thalidomide on the development of peritoneal fibrosis induced by injection of chlorhexidine gluconate (CG) into the mouse peritoneal cavity every other day for 3 weeks. Thalidomide was given orally every day. Peritoneal tissues were dissected out 21 days after CG injection. Expression of CD31 (as a marker of endothelial cells), proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor (VEGF), α-smooth muscle actin (as a marker of myofibroblasts), type III collagen and transforming growth factor (TGF)-β was examined using immunohistochemistry. CG group showed thickening of the submesothelial zone and increased numbers of vessels and myofibroblasts. Large numbers of VEGF-, PCNA-, and TGF-β-positive cells were observed in the submesothelial area. Thalidomide treatment significantly ameliorated submesothelial thickening and angiogenesis, and decreased numbers of PCNA- and VEGF-expressing cells, myofibroblasts, and TGF-β-positive cells. Moreover, thalidomide attenuated peritoneal permeability for creatinine, compared to the CG group. Our results indicate the potential utility of thalidomide for preventing peritoneal fibrosis.     

Research on correlations of miR-585 expression with progression and prognosis of triple-negative breast cancer

Clinical and Experimental Medicine - Triple-negative breast cancer is a special type of breast cancer, characterized by younger onset age, shorter survival period, higher malignant degree, higher...     

Down-regulation of BRMS1 by DNA hypermethylation and its association with metastatic progression in triple-negative breast cancer

Breast cancer metastasis suppressor 1 (BRMS1) is a metastasis suppressor gene in several solid tumors. However, the expression and function of BRMS1 in triple-negative breast cancer (TNBC) have not been reported. In this study, we found that BRMS1 was down-regulation in breast cancer cell lines and primary TNBC, while decreased expression of BRMS1 mRNA was significantly associated with lymph node metastasis. And this down-regulation was found to be in accordance with aberrant methylation of the gene. Hypermethylation of the gene was observed in 53.4% (62/116) of the TNBC primary breast carcinomas, while it was found in only 24.1% (28/116) of the corresponding nonmalignant tissues. In addition, BRMS1 expression was restored in MDA-MB-231 after treatment with the demethylating agent, 5-aza-2-deoxycytidine (5-Aza-dC), and demethylation of the highly metastatic cells MDA-MB-231 induced invasion suppression of the cells. Furthermore, the suppression of BRMS1 by siRNA transfection enhanced cancer cells invasion. Collectively, our results suggest that the aberrant methylation of BRMS1 frequently occurs in the down-regulation of BRMS1 in TNBC and that it may play a role in the metastasis of breast cancer.     

The immunosuppressant FK-506 prevents progression of diabetes in nonobese diabetic mice.

A novel immunosuppressive compound, FK-506, isolated from Streptomyces has potent immunosuppressive activities. To investigate the effect of FK-506 on the course of diabetes in nonobese diabetic (NOD) mice, we gave this drug to these animals, from the age of 8 weeks, intraperitoneally, in doses of 0.1 mg (2.5 mg/kg/day) or 0.01 mg (0.25 mg/kg/day) three times a week. Overt diabetes were observed in 75.5% of control mice by the age of 20 weeks. In contrast, no diabetes occurred in mice given 0.1 mg of FK-506. Sixteen percent of mice treated with 0.01 mg of the drug became diabetic. Administration of this drug prevented the progression of insulitis in NOD mice. The mice given 0.1 mg of FK-506 lost weight, but this was reversible.     

Dipyridamole is an interferon inducer

2,6-Bis(diethanolamino)-4,8-dipiperidinopyrimido-[5,4-d]-pyrimidine (dipyridamole) induced interferon production in vitro in explanted mouse peritoneal leukocytes and to a lower degree in non-lymphoidal cell cultures of mouse (L cells primary embryo fibroblasts) and human (diploid embryo lung fibroblasts) origin. Dipyridamole induced interferon also in mice after intravenous administration. Peak interferon levels in the blood (128 IU/ml) were attained at 49 hr after injection of 0.1 mg dipyridamole per kg body weight and at 24 and 12 hr after injection of 0.6-1.8 and 16.7 mg/kg respectively. By its pH stability, thermostability and antigenic properties the interferon induced in mice, mouse peritoneal leukocytes and L cells corresponded to IFN-alpha and IFN-beta. This interferon-inducing capacity of dipyridamole may account for its broad-spectrum antiviral effect.     

Anti-alpha beta T cell receptor antibody prevents the progression of experimental autoimmune myocarditis.

We investigated the effects of anti-alpha beta T cell receptor antibody in rat experimental autoimmune myocarditis (EAM), using a new animal model of autoimmune myocarditis characterized by the appearance of multinucleated giant cells. EAM was induced by injecting Lewis rats subcutaneously in the footpads with 1.0 mg of human cardiac myosin in an equal volume of Freund's complete adjuvant (FCA) on days 0 and 7. In experiment 1, we evaluated the effect of long-term anti-alpha beta TCR antibody therapy on prevention of progression of EAM. Long-term administration of anti-alpha beta TCR antibody prevented progression of EAM in a dose-dependent manner. Flow cytometry performed at the time of sacrifice showed that the percentage of alpha beta T cells in lymph nodes and spleen was similar in the control group and the group in which almost no histologic evidence of myocarditis was found. In experiment 2, we examined the effects of short-term therapy. Rats were killed at different stages and pathologic specimens were examined. Short-term therapy delayed the onset of myocarditis. Results of flow cytometry suggested that impairment of antigen recognition or T cell function by occupancy of the TCR rather than depletion of TCR was the mechanism responsible for suppression of EAM.     

An immunosuppressant compound, FK-506, prevents the progression of autoimmune myocarditis in rats.

A new immunosuppressive compound, FK-506, is a macrolide produced by Streptomyces tsukubaensis. It is reported that FK-506 prolongs the viability of allogenic grafts of the heart and kidney in vivo and inhibits the development of autoimmune diseases. Furthermore, immunosuppressive therapy of myocarditis in humans has been given special attention by various observers; however, it is controversial. This study investigates the effects of FK-506 on experimental autoimmune myocarditis in rats. We performed two experiments. In Experiment 1, FK-506 was given intramuscularly on Days 11-20 after the first immunization. The rats were immunized twice (on Day 0 and Day 7). They were injected subcutaneously in the footpads with 1.0 mg of human cardiac myosin in equal volumes of complete Freund's adjuvant supplemented with Mycobacterium tuberculosis. They were divided into four groups: Control (six rats, saline), group 1 (six rats, FK-506: 0.1 mg/kg/day), group 2 (seven rats, FK-506: 0.32 mg/kg/day), and group 3 (six rats, FK-506: 1.0 mg/kg/day). To investigate the histologic extent of myocarditis, we formulated a histologic score (0-3). Histologic scores were: Control, 1.90 +/- 0.14; group 1, 0.97 +/- 0.46; group 2, 0.03 +/- 0.05; and group 3, 0 +/- 0. The indices of heart weight/body weight were: Control, 0.74 +/- 0.10%; group 1, 0.45 +/- 0.05%; group 2, 0.35 +/- 0.03%; and group 3, 0.35 +/- 0.03%. In Experiment 2, FK-506 was given on Days 1-10 after the first immunization, earlier than in Experiment 1. The rats were similarly divided into four groups. Each group was given the same dose of FK-506 as in Experiment 1. Histologic scores were: Control 1.49 +/- 0.24; group 1, 1.60 +/- 0.22; group 2, 0.29 +/- 0.41; and group 3, 0.03 +/- 0.03. The indices of heart weight/body weight were: Control, 0.69 +/- 0.15%; group 1, 0.76 +/- 0.09%; group 2, 0.42 +/- 0.08%; and group 3, 0.37 +/- 0.03%. Accordingly, in Experiments 1 and 2, the effects of FK-506 on autoimmune myocarditis were dose-dependent. On the other hand, in Experiments 1 and 2, not only in the control group but also in all treated groups, the titers of anti-myosin IgG were high. In conclusion, even if it is administered just before the onset of myocarditis, FK-506 is extremely effective at suppressing autoimmune myocarditis, despite a high titer of anti-myosin IgG.     

Dedifferentiation-like progression of breast carcinoma: report of a case showing transition from luminal-type carcinoma to triple-negative carcinoma with myoepithelial features

Certain genetic events that occur at various stages of carcinogenesis can result in phenotypic changes. In breast carcinoma, these changes may occur either in situ, at the primary invasive site, or at a distant metastatic site. This report presents a case of dedifferentiation-like progression of breast carcinoma showing transition from luminal-type carcinoma to triple-negative carcinoma (i.e. negative for estrogen receptor, progesterone receptor, and HER2) with myoepithelial features. An 87-year-old woman was referred to us from another hospital for surgery. Preoperative ultrasonography revealed a mass measuring 16 × 12 × 8 mm. Following partial mastectomy, gross examination revealed a whitish tumor on the cut surface measuring 15 × 10 × 8 mm. Histopathological investigation revealed a predominant high-grade carcinoma containing some short spindle-shaped cells and expressing p63, muscle-specific actin, and alpha smooth muscle actin. The tumor also showed decreased expression of pan-cytokeratin and increased expression of vimentin on immunohistochemistry. Estrogen receptor was not detected by immunostaining. A high Ki-67 labeling index and diffuse nuclear accumulation of p53 were observed in the high-grade carcinoma. In the peripheral area, low-grade carcinoma with estrogen receptor expression was observed, but appeared displaced by the high-grade carcinoma. The high-grade carcinoma exhibiting myoepithelial carcinoma-like morphology and molecular phenotype was deemed to be carcinoma showing dedifferentiation-like changes arising from the peripherally situated pre-existing low-grade carcinoma. Thus, follow-up ought to be mandatory, considering the presumably aggressive nature of the predominant carcinoma showing dedifferentiation-like changes in this case.