Biomedical subjects

Hui Huang

Publications and source records attributed to Hui Huang.

60 records · Page 4Linked to original sources

PubMed2002

Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness.

Asthma is a common respiratory disorder characterized by recurrent episodes of coughing, wheezing and breathlessness. Although environmental factors such as allergen exposure are risk factors in the development of asthma, both twin and family studies point to a strong genetic component. To date, linkage studies have identified more than a dozen genomic regions linked to asthma. In this study, we performed a genome-wide scan on 460 Caucasian families and identified a locus on chromosome 20p13 that was linked to asthma (log(10) of the likelihood ratio (LOD), 2.94) and bronchial hyperresponsiveness (LOD, 3.93). A survey of 135 polymorphisms in 23 genes identified the ADAM33 gene as being significantly associated with asthma using case-control, transmission disequilibrium and haplotype analyses (P = 0.04 0.000003). ADAM proteins are membrane-anchored metalloproteases with diverse functions, which include the shedding of cell-surface proteins such as cytokines and cytokine receptors. The identification and characterization of ADAM33, a putative asthma susceptibility gene identified by positional cloning in an outbred population, should provide insights into the pathogenesis and natural history of this common disease.

ADAM Proteins↗

PubMed2002

Synergistic enhancement of antitumor immunity with adoptively transferred tumor-specific CD4+ and CD8+ T cells and intratumoral lymphotactin transgene expression.

The lack of efficient T-cell infiltration of tumors is a major obstacle to successful adoptive T-cell therapy. We have shown that transplanted SP2/0 myeloma tumors that have been engineered to express lymphotactin (Lptn) invariably regress under the influence of infiltrating XCR1+T cells and neutrophils. Herein, we characterize these T cells and investigate their therapeutic efficacy, either alone or with Lptn gene therapy. After stimulation with SP2/0 cells, these T cells were CD25+FasL+L-selectin-, expressed XCR-1, and were chemoattracted by Lptn in vitro. They comprised 66% CD4+ Th1 and 33% CD8+ Tc1 cells, both of which expressed significant amounts of IFN-gamma, perforin, and tumor necrosis factor-alpha, but not interleukin-4. The CD4+ Th1 and CD8+ Tc1 cells, which were inhibited and stimulated, respectively, for proliferation with Lptn signaling, displayed 38 and 84% specific killing, respectively, for Ia(d)/H-2K(d)-expressing SP2/0 tumor cells (E:T ratio, 100). In vivo, combined intratumoral Lptn gene transfer and adoptive immunotherapy with these CD4+ and CD8+ T cells eradicated well-established SP2/0 tumors in six of eight mice, and dramatically slowed tumor growth in the other two mice. Cell tracking using labeled T cells confirmed that these cells infiltrated better into the Lptn-expressing tumors than non-Lptn-expressing ones. Control or Lptn adenoviral treatments by themselves did not alter the lethal outcome for tumor-bearing mice, nor did T-cell therapy by itself, although the latter two treatments did slow its time frame. Combined Lptn gene transfer and adoptive CD4+ or CD8+ cell transfers were not nearly as efficacious as the combined Lptn gene and unfractionated T-cell transfers. Taken together, our data provide solid evidence of a potent synergy between adoptive CD4+ and CD8+ T-cell therapy and Lptn gene transfer into tumor tissues, which culminated in the eradication of well-established tumor masses.

Adenoviridae↗

PubMed2002

Intratumoral coinjection of two adenoviral vectors expressing functional interleukin-18 and inducible protein-10, respectively, synergizes to facilitate regression of established tumors.

We have constructed two recombinant adenoviral vectors AdVIP-10 and AdVIL-18 expressing the functional chemokine IFN-gamma inducible protein (IP)-10 and cytokine interleukin (IL)-18, respectively. Injection of either AdVIP-10 or AdVIL-18 subcutaneously into tumor nodules derived from the J558 murine myeloma cell line delayed some tumor growth but it was not curative in all cases. Coinjection of these two vectors at the same tumor nodule not only significantly suppressed the tumor growth, but also cured established tumors in 8 of 10 (80% tumor free) mice. The latter treatment stimulated T-cell infiltration into tumors in association with tumor necrosis formation, induced a type 1 immune response and induced the activation of J558 tumor-specific cytotoxic T lymphocytes. Moreover, the antitumor activity of IP-10 and IL-18 combined gene therapy was significantly diminished in mice with depletion of either CD4(+) (50% tumor free) or CD8(+) (40% tumor free) T cells, and completely lost (0% tumor free) in T cell-deficient nude and IFN-gamma knockout mice, indicating the critical roles of T cells and IFN-gamma in this therapeutical model. Taken together, the findings of this study demonstrate that the combined use of two adenoviral vectors expressing IP-10 and IL-18, respectively, synergize to facilitate regression of established tumors. These observations also suggest the potential use of double-recombinant adenoviral vectors expressing chemokines and immunomodulatory cytokines in cancer gene therapy.

Adenoviridae↗

PubMed2002

Enhanced HER-2/neu-specific antitumor immunity by cotransduction of mouse dendritic cells with two genes encoding HER-2/neu and alpha tumor necrosis factor.

The present study uses an in vivo murine tumor model expressing the human HER-2/neu antigen to evaluate the potential vaccine using dendritic cells (DCs) infected with adenovirus AdVHER-2. We first investigated whether infected DCs (DC(HER-2)) engineered to express HER-2/neu could induce HER-2/neu-specific immune responses. Our data showed that (i) AdVHER2-infected DC(HER-2) expressed HER-2/neu by Western blot and flow cytometric analysis, and (ii) vaccination of mice with DC(HER-2) induced HER-2/neu-specific cytotoxic T-lymphocyte (CTL) responses, but protected only 25% of vaccinated mice from challenge of 3 x 10(5) MCA26/HER-2 tumor cells. Further, to enhance the efficacy of DC(HER-2) vaccine, we coinfected DCs with both AdVHER-2 and AdVTNF-alpha. The infected DCs (DC(HER-2/TNF-alpha)) displayed the expression of both HER-2/neu and TNF-alpha by flow cytometric and ELISA analysis. We next investigated whether DC(HER-2/TNF-alpha) could induce stronger HER-2/neu-specific immune responses. We found that DC(HER-2/TNF-alpha) displayed up-regulation of immunologically important CD40, CD86, and ICAM-I molecules compared with DC(HER-2), indicating that the former ones are more mature forms of DCs. Vaccination of DC(HER-2/TNF-alpha) induced stronger allogeneic T-cell proliferation and 36% enhanced HER-2/neu-specific T-cell responses in vitro than DC(HER-2) cells. More importantly, it stimulated the significant anti-HER-2/neu immunity in vivo, which protected 8/8 mice from challenge of 3 x 10(5) MCA26/HER-2 tumor cells. Therefore, DCs genetically engineered to express both the tumor antigen and cytokines such as TNF-alpha as an immunoadjuvant are likely to represent a new direction in DC vaccine of cancer.

Adenoviridae↗

PubMed2002

The orphan nuclear receptor, steroidogenic factor 1, regulates neuronal nitric oxide synthase gene expression in pituitary gonadotropes.

Steroidogenic factor 1 (SF-1), an essential nuclear receptor, plays key roles in steroidogenic cell function within the adrenal cortex and gonads. It also contributes to reproductive function at all three levels of the hypothalamic-pituitary-gonadal axis. SF-1 regulates genes in the steroidogenic pathway, such as LHbeta, FSHbeta, and steroid hydroxylase. Abundant evidence suggests that nitric oxide (NO) has an important role in the control of reproduction due to its ability to control GnRH secretion from the hypothalamus and the preovulatory LH surge in pituitary gonadotropes. Recently, we cloned and characterized the promoter of mouse neuronal NO synthase (nNOS). nNOS is localized at all three levels of the hypothalamic-pituitary-gonadal axis to generate NO. We find that its major promoter resides at exon 2 in the pituitary gonadotrope alphaT3-1 cell line and that there is a nuclear hormone receptor binding site in this region, to which SF-1 can bind and regulate nNOS transcription. Mutation of the nuclear hormone receptor binding site dramatically decreases basal promoter activity and abolishes SF-1 responsiveness. A dominant negative of SF-1, in which the transactivation (AF-2) domain of SF-1 was deleted, inhibits nNOS exon 2 promoter activity. Dosage-sensitive reversal- adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX-1), which colocalizes and interferes with SF-1 actions in multiple cell lineages, negatively modulates SF-1 regulation of nNOS transcription. These findings demonstrate that mouse nNOS gene expression is regulated by the SF-1 gene family in pituitary gonadotropes. nNOS, a member of the cytochrome p450 gene family, could be one of the downstream effector genes, which mediates SF-1's reproductive function and developmental patterning.

3T3 Cells↗

PubMedDate not supplied

Synergistic effect of adoptive T-cell therapy and intratumoral interferon gamma-inducible protein-10 transgene expression in treatment of established tumors.

The lack of efficient T-cell infiltration of tumors is a major obstacle to successful adoptive T-cell therapy. We have previously shown that transplanted SP2/0 myeloma tumors engineered to express lymphotactin invariably induced tumor regress mediated by SP2/0 tumor-specific T cells. Herein, we further systemically characterize these activated T cells and investigate their therapeutic efficacy, either alone or with the chemokine interferon gamma (IFN-gamma)-inducible protein-10 (IP-10) gene therapy. Following stimulation with SP2/0 cells, these activated T cells were CD25(+)FasL(+) L-selectin(low), expressed CXCR3 receptor and were chemoattracted by IP-10 in vitro. They comprised 64% CD4(+) Th1 and 36% CD8(+) Tc1 cells, both of which expressed IFN-gamma, perforin, and TNF-alpha, but not IL-4. The activated T cells were strongly cytotoxic for SP2/0 tumor cells (79% specific killing; E:T ratio, 50), mainly via perforin-mediated pathway. Cell tracking using labeled T cells confirmed that these T cells infiltrated better into the IP-10-expressing tumors than non-IP-10-expressing ones. In vivo, combined intratumoral IP-10 gene transfer and adoptive T-cell immunotherapy for well-established SP2/0 tumors eradicated the tumors in 7 of the 8 mice. Control or IP-10 adenoviral treatments by themselves neither alter the lethal outcome for tumor-bearing mice nor did T-cell therapy by itself, although the latter two treatments did slow its time-frame. Taken together, our data provide solid evidence of a potent synergy between adoptive T-cell therapy and IP-10 gene transfer into tumor tissues, which culminated in the eradication of well-established tumor masses.

Adenoviridae↗