Reproductive immune microenvironment.

About 10 %-12 % of couples in the world suffer from infertility, and immunological factors are being paid more and more attention. Attempts to induce peripheral immune tolerance in pregnant women by injecting husband cells have been widely promoted, but ultimately proved unsuccessful. Over the past two decades, our understanding of how the immune system is involved in gametogenesis and embryonic development, especially in early pregnancy, has undergone a major shift, going from the periphery to the local area of reproductive tissue. However, a holistic overview of immune responses in reproductive organs and tissues is currently lacking. Here, we further highlight the importance of regional immunity research for understanding reproductive health by reviewing the research mileage of the testis, ovary, and uterine immune microenvironment. We propose the concept of "reproductive immune microenvironment (RIM)" by summarizing the common features and basic functions of the tissue microenvironment in which immune cells reside, including the interstitial space of the testis, the ovarian stroma and the endometrium. The establishment of the concept of RIM not only focuses on the comprehensive description of the immune response in reproductive tissues, but also provides a macroscopic perspective for a deeper understanding of the immune etiology of reproductive system-related diseases.

Establishment and Preclinical Therapy of Patient-derived Hepatocellular Carcinoma Xenograft Model.

Hepatocellular carcinoma (HCC) is a world-wide health problem. Poor and delayed diagnoses as well as high recurrence rate resulting in high mortality rate. In this study, we established a patient-derived xenograft (PDX) model from HCC patient, and continuously maintained with subcutaneous passage more than 20 times. This HCC PDX tumor exhibited the same histological characteristics with the HCC patient and could be used to verify therapeutic effect of liver cancer. We further evaluated this PDX model by experimental chemotherapy, demonstrating that this HCC PDX model was sensitive to sorafenib treatment. Further, the potential of natural killer cell-based immunotherapy for HCC was tested using this model. We found that NK92 cells effectively suppressed the tumor growth in vivo and prolonged the survival time of HCC-bearing PDX mice. This study indicates that HCC PDX model is a good platform to testify the efficacy of preclinical chemotherapy and immunotherapy.

Neuroprotective effect of combined therapy with hyperbaric oxygen and madopar on 6-hydroxydopamine-induced Parkinson's disease in rats.

Parkinson's disease (PD) is a common movement disorder in the elderly. In the present study, we examined whether the combination of hyperbaric oxygen (HBO) and madopar therapy provided a neuroprotective effect on dopaminergic neurons in the substantia nigra using a rat model of PD. Rotational assessments revealed that both HBO and combination therapy significantly attenuated apomorphine-induced turning in PD rats. Our results indicated that the combination therapy increased glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities and reduced the malondialdehyde (MDA) content in the SN. Furthermore, the combination therapy resulted in significant protection against the loss of neurons, and specifically tyrosine hydroxylase (TH)-positive neurons, in the SN and also alleviated the production of glial fibrillary acidic protein (GFAP). The levels of Bcl-2 were increased and Bax were decreased following the HBO or combination therapy. In brief, the neuroprotective effect of combined therapy with HBO and madopar against 6-OHDA-induced PD rats may rely on its ability to reduce oxidative stress and protect against Bax/Bcl-2-mediated apoptosis.

Nanoparticles encapsulating hepatitis B virus cytosine-phosphate-guanosine induce therapeutic immunity against HBV infection.

UNLABELLED: Infection with hepatitis B virus (HBV) is the most common cause of liver disease worldwide. However, because the current interferon (IFN)-based treatments have toxic side effects and marginal efficacy, improved antivirals are essential. Here we report that unmethylated cytosine-phosphate-guanosine oligodeoxynucleotides (CpG ODNs) from the HBV genome (HBV-CpG) induced robust expression of IFN-α by plasmacytoid dendritic cells (pDCs) in a Toll-like receptor 9 (TLR9)-dependent manner. We also identified inhibitory guanosine-rich ODNs in the HBV genome (HBV-ODN) that are capable of inhibiting HBV-CpG-induced IFN-α production. Furthermore, nanoparticles containing HBV-CpG, termed NP(HBV-CpG), reversed the HBV-ODN-mediated suppression of IFN-α production and also exerted a strong immunostimulatory effect on lymphocytes. Our results suggest that NP(HBV-CpG) can enhance the immune response to hepatitis B surface antigen (HBsAg) and skew this response toward the Th1 pathway in mice immunized with rHBsAg and NP(HBV-CpG). Moreover, NP(HBV-CpG)-based therapy led to the efficient clearance of HBV and induced an anti-HBsAg response in HBV carrier mice. CONCLUSION: Endogenous HBV-CpG ODNs from the HBV genome induce IFN-α production so that nanoparticle-encapsulated HBV-CpG may act as an HBsAg vaccine adjuvant and may also represent a potent therapeutic agent for the treatment of chronic HBV infection.

Trichosanthin induced Th2 polarization status.

Trichosanthin is extracted from the root tuber of Chinese medicinal herb Trichosanthes kirilowii maximowicz (Tian Hua Fen). TCS has abortifacient, anti-tumor, anti-HIV and immunoregulatory functions. It has been proved that it could inhibit immune response and arouse a T helper 2 response in the draining lymph node. In the current study the effect of TCS on mouse splenocytes was investigated. We stimulated C57BL/6 mice with TCS both in vivo and in vitro and analyzed the change of type 1 and type 2 cytokines in mouse splenocytes. The results showed that TCS could induce the expression of IL-4, one of the major T helper 2 (Th2) cytokines, and inhibit the expression of IFN-gamma, an important Th1 cytokine in spleen lymphocytes both in vivo and in vitro. It is also shown the kinetics of Th1-to-Th2 transition after TCS stimulation in vivo in C57BL/6 mice. We found that type 2 cytokines, such as IL-10, TGF-beta and IL-4 were increased regularly but IFN-gamma was decreased at day 3 and then increased. However the mechanism for cytokine change is not clear.

Protective effects of a Traditional Chinese Medicine, You-Gui-Wan, on steroid-induced inhibition of cytokine production in mice.

You-Gui-Wan (YGW), a classical yang-tonic prescription of Traditional Chinese Medicine (TCM), is thought to boost the body function against diseases. To determine the effects of YGW on the steroid-induced inhibition of cytokine production in mice, we established a murine model with hydrocoticoid (HC)-induced cytokine suppression. The results showed that oral administration of YGW protected mice against HC-induced inhibition of IFN-gamma, IL-2, IL-4 and IL-10 transcription, and the percentages of CD4+ and CD8+ T cells containing intracellular cytokines including IFN-gamma, IL-4 and IL-10 were significantly increased in murine spleen. The protection of YGW against HC-induced inhibition of cytokine production was further confirmed by the elevated serum level of IFN-gamma in YGW-treated mice. The results suggest that YGW improve the immune function even in the serious immunosuppressive condition.

Type two cytokines predominance of human lung cancer and its reverse by traditional Chinese medicine TTMP.

Type 2 cytokines are usually predominant in tumor patients and associated with tumor progression. To explore whether reversing of type 2 predominance could be a promising strategy in tumor immunotherapy, PBMC of 35 lung cancer patients and 19 healthy subjects were prepared and subjected to be examined for cytokine secretion and gene expression. Tetra-Methylpyrazine (TTMP), extracted from a traditional Chinese medicinal herb which has been used in clinic to reverse the Th2 status of cancer patients in China, was added to PBMC culture. Determined by RT-PCR, the positive percentages of mRNA expression of type 1 cytokines (8.6% for IFN-gamma and 11.4% for IL-2) were lower than those of type 2 cytokines (71.4% for IL-4, 60% for IL-6 and 80% for IL-10) in patients' PBMCs. The potential of gene expressing (measured as relative intensity to the ratio of beta-actin) in the patients for type 1 cytokines was also in a low level (0.111 for IFN-gamma, 0.119 for IL-2) in comparison with a relative high level for type 2 cytokines (0.319 for IL-4, 0.303 for IL-6 and 0.377 for IL-10). Meanwhile, both positive percentage and relative intensity of gene expression were lower for a type 1 cytokine-related transcription factor T-bet (31.4% and 0.142, respectively) than those for type 2 cytokine-related GATA3 (85.7% and 0.378, respectively). The blood serum levels of IFN-gamma and IL-2 in the patients were slightly lower but not significantly when compared with healthy control. In contrast, the levels IL-4 and IL-6 in patients were significantly higher than those in healthy subjects by ELISA analysis. TTMP could enhance supernatant concentration and gene expression levels of IFN-gamma, IL-2 and T-bet, but reduce those of type 2 cytokines. These results demonstrate that the lung cancer patients had a predominant expression of type 2 cytokines and TTMP could reverse the type 2 dominant status, which might offer an alternative therapeutic regime for lung cancer patients.

Traditional Chinese medicine Astragalus reverses predominance of Th2 cytokines and their up-stream transcript factors in lung cancer patients.

Th2 cytokine is predominant in tumor patients and was found to be associated with tumor progression. Reversing of Th2 dominant status is thought to be a promising strategy. In the present study, peripheral blood mononuclear cells (PBMNC) of 37 lung cancer patients and 19 healthy subjects were prepared and used for examination of cytokine secretion and gene expression. The positive percentage of mRNA transcripts of Th1 cytokines (8.1% for IFNgamma and 13.5% for IL-2) in patients' PBMNC were lower than those of Th2 cytokines (70.3% for IL-4, 64.9% for IL-6 and 83.8% for IL-10). The gene expression capacity (measured as relative intensity to ratio of beta-actin) of patients for Th1 cytokines was low, but constitutively relatively high for Th2 cytokines. Both positive percentage and relative intensity were lower in transcript factor for Th1 cytokine, T-bet (40.5% and 0.139, respectively) than those for Th2 cytokine, GATA3 (89.2% and 0.364, respectively). Traditional Chinese medicine, Astragalus (AG) was observed to reverse Th2 status of lung cancer. AG enhanced culture supernatant and gene expression levels of Th1 cytokine (IFNgamma and IL-2) and its transcript factor (T-bet), and reduced those of Th2 cytokines in cultured PBMNC of lung cancer patients. These results demonstrated that traditional Chinese medicine AG might reverse the Th2 predominant status in lung cancer patients, which is a probable alternative therapeutic regime in future.

[Expression of transcription factor T-bet/GATA3 in lung cancer patients and its interference by the traditional Chinese herbal medicine].

OBJECTIVE: To study the relation between the expression of transcription factor T-bet/GATA3 and Th1/Th2 type cytokines in peripheral blood mononuclear cells (PBMC) from lung cancer patients and their interference by the traditional Chinese herbal medicine. METHODS: The gene expression of Th1/Th2 type cytokine IFN gamma, IL-2, IL-4, IL-6, IL-10, transcription factor T-bet/GATA3 and tumor tissue specific mRNA CEA, CK19 in PBMC from lung cancer patients were detected by reverse transcription-polymerase chain reaction RT-PCR. Meanwhile, the change of IFN gamma, IL-4, T-bet and GATA3 in PBMC before and after being cultured with the traditional Chinese herbal medicine-Astragulus and Tetramethylpyrazine was also observed. RESULTS: Predominant expression of Th2 type cytokines was detected in 42 lung cancer patients. The positive rates of IL-4, IL-6, IL-10, IFN gamma and IL-2 were 27/42, 24/42, 31/42, 4/42 and 5/42, respectively. But, the positive rates of transcription factor T-bet and GATA3 were 16/42 and 34/42. Moreover, the expression intensity of T-bet was lower in the CEA and CK19 positive patients than the negative ones. On the contrary, the expression intensity of GATA3 was significantly higher in the same patients. CONCLUSION: Predominant expression of Th2 type cytokines may be related to lower expression of T-bet or higher expression of GATA3. This condition can be interfered by the traditional Chinese herbal medicine-Astragulus and Tetramethylpyrazine.