CD4+ T cell responses are critical for the pathogenesis of Helicobacter pylori infection. The present study evaluated the role of the Th17 subset in H. pylori infection. H. pylori infection induced significant expression of IL-17 and IFN-g in mouse gastric tissue. IL-23 and IL-12 were increased in the gastric tissue and in H. pylori-stimulated macrophages. Cell responses were examined by intracellular staining for IFN-g, IL-4, and IL-17. Mice infected with H. pylori developed a mixed Th17/Th1 response; Th17 responses preceded Th1 responses. Treatment of mice with an anti-IL-17 Ab but not a control Ab significantly reduced the H. pylori burden and inflammation in the stomach. H. pylori colonization and gastric inflammation were also lower in IL-17 2/2 mice. Furthermore, administration of recombinant adenovirus encoding mouse IL-17 increased both H. pylori load and inflammation. Further analysis showed that the Th1 cell responses to H. pylori were downregulated when IL-17 is deficient. These results together suggest that H. pylori infection induces a mixed Th17/Th1 cell response and the Th17/IL-17 pathway modulates Th1 cell responses and contributes to pathology. The Journal of Immunology, 2010, 184: 5121-5129. H elicobacter pylori is a Gram-negative, microaerophilic bacterium that resides extracellularly in the gastric mucosa and infects .50% of the population worldwide. H. pyloriinduced chronic inflammation is the cause of gastritis and peptic ulcers and a risk factor for gastric cancer (1, 2). H. pylori infection causes severe local inflammation in the gastric mucosa. CD3 + CD4 + T cells are increased in infected gastric lamina propria and play important roles in the pathogenesis of persistent H. pylori infection (3). Traditionally, CD4 + T cells are classified into two main classes: Th1 and Th2, on the basis of their cytokine secretion and immune regulatory function. Th1 cells secrete IFN-g, IL-2, and IL-12 and regulate cellular immunity, whereas Th2 cells produce IL-4, IL-5, and IL-13 and mediate humoral responses. To date, studies of immune responses to H. pylori have largely focused on Th1 and Th2 cells, and it is generally accepted that H. pylori infection results in a Th1-dominant response and that gastric inflammation largely depends on Th1 cell responses (3-6); however, IFN-g secretion alone is insufficient to induce gastritis (3). Thus, the detailed mechanism of pathogenesis is not clear. A novel subset of effector T cells, identified by secretion of IL-17, has been defined as Th17 cells. Th17 cells are distinct from Th1 and Th2 cells in their differentiation and function (7,8). TGF-b and IL-6 from activated macrophages/dendritic cells are required for Th17 cell differentiation in murine systems (9), whereas IL-12 and IFN-g promote Th1 cell development and IL-4 primes Th2 cell differentiation. The expansion and survival of Th17 cells are promoted by IL-23 (9), a heterodimeric cytokine composed of a unique p19 subunit and a p40 subunit shared with IL-12 (10). The identification of Th17 cells necessit...

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Purpose. The purpose of the current study were to assess the safety and feasibility of repetitive intratumoral administration of E10A, an adenoviral vector encoding the wild-type endostatin gene, to patients with solid tumors, and to evaluate its biologic effect and the pharmacokinetics of endostatin.Methods. Patients were treated with escalating doses from 1 × 10 10 VP to 1 × 10 12 VP of E10A intratumorally on days 1 and 8. Patients were assessed for toxicity and viral shedding, and antitumor response was evaluated by imaging techniques and tumor biopsy. Circulating levels of endostatin were examined.Results. Fifteen patients received 29 injections of E10A. No dose-limiting toxicity was developed, and the maximum tolerated dose had not yet been reached. Fever and local reaction of injection site were common, but rarely severe. Mild and transient hepatotoxicity was observed in one patient. Minor response of injected tumor was achieved and improvement of the control tumor was observed in one patient with nasopharyngeal carcinoma, and tumor necrosis was occurred in two patients. Sustained elevation of serum endostatin levels was detected.Conclusion. Weekly intratumoral injection of up to 1 × 10 12 VP of E10A to patients with solid tumor is a feasible and well-tolerated procedure that exerts mild antitumor effects. A small and sustained elevation of endogenous endostatin in blood possibly has antitumor activity.

CD30 ligand (CD30L, CD153), a member of the tumor necrosis factor (TNF) superfamily, and its receptor CD30 are important for differentiation and activation of CD4(+) T helper type 17 (Th17) cells. In this report, we demonstrate that the interleukin 17A (IL-17A)-producing γδ T cells normally developed in the fetal thymus, whereas Vγ1(-)Vγ4(-) γδ T cells expressed Vγ6/Vδ1 gene transcript selectively decreased in mucosa-associated tissues in naive CD30KO or CD30LKO mice. Moreover, CD30 and CD30L were expressed preferentially by Vγ1(-)Vγ4(-) γδ T cells in naive mice. The bacteria clearance was attenuated by the impaired response of the IL-17A-producing γδ T cells and decreased infiltration of neutrophils in CD30KO or CD30LKO mice. In vivo administration of agonistic anti-CD30 monoclonal antibody restored the ability of protection against Listeria monocytogenes by enhancing Vγ1(-)Vγ4(-) γδ T cells producing IL-17A not only in wild-type but also CD30LKO mice. Taken together, it appears that CD30L/CD30 signaling plays an important role in the maintenance and activation of IL-17A-producing γδ T cells presumably bearing Vγ6 in the mucosa-associated tissues of mice.