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Biomedical subjects

Steven J Czinn

Publications and source records attributed to Steven J Czinn.

At least 19 recordsLinked to original sources
PubMed2006

Induction of CTLA-4-mediated anergy contributes to persistent colonization in the murine model of gastric Helicobacter pylori infection.

Helicobacter pylori infection induces gastric inflammation but the host fails to generate protective immunity. Therefore, we evaluated the immunologic mechanisms that contribute to the failure of the T cells to promote active immunity to H. pylori in the mouse model of H. pylori infection. Spleen cells from infected C57BL/6 mice underwent significantly less proliferation and cytokine production than cells from immune mice upon in vitro stimulation with H. pylori lysate. Similar results were observed when stimulating with Ag-pulsed macrophages demonstrating that hyporesponsiveness was not due to a direct effect of H. pylori virulence factors on the T cells. Ag-specific hyporesponsiveness could be reversed by the addition of high-dose IL-2 but not by removal of CD4(+)CD25(+) T cells, indicating that hyporesponsiveness was due to anergy and not due to active suppression. Cells from infected mice lacked significant suppressor activity as shown by the failure to reduce the recall response of cells from immune mice in coculture at physiologic ratios. Direct blockade of CTLA-4 using anti-CTLA-4 Fabs or indirect blockade using CTLA-4 Ig plus anti-CD28 Ab resulted in significantly increased T cell activation in vitro. The importance of CTLA-4 in establishing anergy was confirmed in an in vivo model of H. pylori infection in which mice that received anti-CTLA-4 Fabs responded to H. pylori challenge with significantly greater inflammation and significantly reduced bacterial load. These results suggest that CTLA-4 engagement induces and maintains functional inactivation of H. pylori-specific T cells during H. pylori infection resulting in a reduced immune response.

Animals↗
PubMed2006

Challenges in pediatric inflammatory bowel disease.

It is estimated that of the >1 million individuals in the United States with inflammatory bowel disease (IBD), approximately 100,000 are children. IBD that begins in childhood affects the individual at a critical period of growth and development. Children with Crohn's disease and ulcerative colitis may experience complications such as growth failure, school absence, and depression. In addition, because children with IBD have fewer environmental confounders such as smoking, children may be an excellent population to study microbial and immune interactions. Despite these opportunities, the discipline of pediatric IBD investigation is still in its infancy. In September of 2005, a group of investigators with expertise in pediatric IBD met in Boston (Massachusetts) to review the current status of childhood IBD research and to develop research priorities that warranted funding from the Crohn's and Colitis Foundation of America. The group included pediatricians, internists, basic scientists, clinical investigators, and members of the administrative staff and board of the Crohn's and Colitis Foundation of America. The research needs in respective areas were outlined by the heads of 10 focus groups, each with expertise in their respective fields (genetics, psychosocial issues, epidemiology, microbiology, immunology, quality improvement, pharmacogenomics, nutrition, growth and skeletal health, and clinical trials). Before the conference, heads of the research focus groups developed their proposals with experts in the field. At the end of the conference, members of the focus groups and members of the steering committee rated the proposed areas of study in terms of feasibility and importance. It was recommended that the Crohn's and Colitis Foundation of America focus its initial efforts in pediatric IBD in 5 areas: the effects of inflammation on growth and skeletal development, the genetics of early-onset IBD, the development of quality improvement interventions to standardize and improve clinical care of children with IBD, the immunology of childhood IBD, and the diagnosis and treatment of psychosocial sequelae of childhood IBD. At the conclusion of the meeting, investigators discussed the formation of a multicenter collaborative network to advance clinical and basic research in the field.

Child↗
PubMed2006

Significant morbidity associated with RSV infection in immunosuppressed children following liver transplantation: case report and discussion regarding need of routine prophylaxis.

Respiratory syncytial virus (RSV) is an important cause of lower respiratory tract infection in infants and young children. In immunocompromised children, RSV infection poses a serious health threat with significantly increased and prolonged virus shedding and the development of severe respiratory disease. We report two patients, eight months and 20 months of age, who were admitted with severe RSV infection two months and 10 months post-transplant respectively. Major risk factors for severe infection is the degree of immunosuppression and the age of the patient (<24 months). Based on the significant morbidity associated with RSV infection in these patients, we recommend randomized trials in larger pediatric solid organ transplant centers to evaluate the use of palivizumab prophylaxis is efficacious to prevent morbidity in patients under the age of 24 months, while we emphasize good hygienic practices to prevent RSV nosocomial infection.

Antibodies, Monoclonal↗
PubMed2006

Regulation of murine dendritic cell immune responses by Helicobacter felis antigen.

Helicobacter infections are present in approximately 50% of humans, causing severe illnesses such as gastritis and malignancies. Dendritic cells (DC) are critical antigen-presenting cells which link innate and adaptive immune responses. The mechanism of dendritic cell regulation in Helicobacter-induced gastritis is poorly understood. These studies characterized DC isolated from the lamina propria of Helicobacter-infected mice and analyzed innate and adaptive immune responses elicited by Helicobacter antigen (Ag)-pulsed DC. The presence of DC was elevated in the gastric lamina propria infiltrate of infected mice in comparison with controls. After treatment with Helicobacter felis Ag, DC were polarized to secrete interleukin-6 as the dominant cytokine. In the presence of DC and Helicobacter Ag, responder allogeneic T cells in culture exhibited limited cell division. We suggest that the response of DC and T cells to Helicobacter Ag is critical to the chronic persistence of Helicobacter-induced gastritis.

Animals↗
PubMed2005

Colon lamina propria dendritic cells induce a proinflammatory cytokine response in lamina propria T cells in the SCID mouse model of colitis.

Intestinal immune responses are normally regulated to maintain a state of immune balance. Dendritic cells (DC) are antigen-presenting cells, which induce immune responses against microbes and other stimuli and are key players in the regulation of tolerance in the gut. These cells influence the differentiation of cytokine responses in T cells, and in the gut, in particular, such interactions may be critical to the course of inflammatory bowel disease (IBD). Using the CD45RBhi CD4+ T cell-reconstituted severe combined immunodeficient mouse model of colitis, we investigated the ability of isolated colon DC to stimulate immune responses in syngeneic and allogeneic spleen CD4+ T cells, as well as in colon T cells isolated from the same tissue as DC in IBD mice. We found that the frequency of DC in IBD mice colons and spleens was elevated in comparison with control mice, but colon and spleen DC exhibited different phenotypic and functional properties. Colon DC stimulated significantly higher levels of interferon-gamma and interleukin-6 when cocultured with autologous colon T cells than in cocultures with syngeneic or allogeneic spleen T cells. These data suggest that in the IBD colon, DC-T cell interactions may create conditions with an abundance of proinflammatory cytokines, which favor the inflammatory state.

Animals↗
PubMed2005

Helicobacter pylori infection: detection, investigation, and management.

Helicobacter pylori infection causes gastritis and peptic ulcers and is associated with the development of gastric cancer. Approximately 50% of the world population is infected with H pylori , with the highest prevalence rates in developing countries. In the vast majority of individuals, infection is acquired during childhood with those of low socioeconomic means and having infected family members being at highest risk for early childhood acquisition. Definitive routes of transmission of the infection are unclear, with evidence suggesting oral-oral, gastric-oral, and fecal-oral routes. If untreated, H pylori infection is lifelong. Although clinical disease typically occurs decades after initial infection acquisition, children infected with H pylori may have gastritis, ulcers, mucosal-associated lymphoid type lymphoma, and, rarely, gastric atrophy with/without intestinal metaplasia (ie, both precursor lesions for gastric cancer). Controversy persists regarding testing for and treating H pylori , if found, in the large number of children who present with recurrent abdominal pain. Because young children (ie, younger than 5 years of age) who are treated and cured of their H pylori infection may be at risk for reinfection, the current recommendations do not recommend treatment unless an ulcer or gastric atrophy is present. However, despite the lack of clinical evidence, the trend is to more aggressively screen children for the presence of H pylori and to treat those children who are found to have the infection. H pylori infection can be eradicated by antimicrobial therapy plus a proton pump inhibitor, but no treatment regimen is 100% effective. Multiple drugs, frequent dosing, and length of treatment often contribute to poor patient compliance, and antibiotic eradication therapy is associated with increasing drug resistance.

Anti-Bacterial Agents↗
PubMed2005

Eradication of Helicobacter pylori and resolution of gastritis in the gastric mucosa of IL-10-deficient mice.

BACKGROUND: Helicobacter pylori has been shown to induce pronounced gastric inflammation in the absence of interleukin-10 (IL-10) by 6 weeks post inoculation. The ability of IL-10(-/-) mice to eradicate H. pylori has not been demonstrated, possibly due to early sacrifice. Therefore, the long-term effect of enhanced gastritis on H. pylori colonization was determined in IL-10(-/-) mice. METHODS: C57BL/6 and IL-10(-/-) mice were infected with H. pylori and assessed for the degree of gastritis, bacterial load, and in vitro T-cell recall response at 4 and 16 weeks of infection. RESULTS: Infection of IL-10(-/-) mice resulted in significantly more severe gastritis than wild-type control mice and eradication of H. pylori by 4 weeks post inoculation. By 16 weeks, the level of gastritis in IL-10(-/-) was reduced to the levels observed in wild-type mice. Splenocytes from IL-10(-/-) mice were prone to produce significantly greater amounts of IFN-gamma than wild-type mice when stimulated with bacterial antigens. CONCLUSIONS: These results indicate that the host is capable of spontaneously eradicating H. pylori from the gastric mucosa when inflammation is elevated beyond the chronic inflammation induced in wild-type mice, and that the gastritis dissipates following bacterial eradication. Additionally, these data provide support for a model of gastrointestinal immunity in which naturally occurring IL-10-producing regulatory T cells modulate the host response to gastrointestinal bacteria.

Animals↗
PubMed2004

Helicobacter pylori in children and adolescents.

There is now considerable evidence that suggests that the H. pylori organism isa human pathogen. The strong association between H. pylori and gastroduodenal disease is well documented. A number of hypotheses have been suggested for the pathogenic mechanisms of H. pylori-induced gastroduodenal disease, including the presence of bacterial virulence factors, the production of inflammatory mediators, disregulation of acid secretion, and the host immune response. At the present time, treatment with a combination of a proton pump inhibitor and antimicrobial agents continues to be recommended for the treatment of H. pylori-associated peptic ulcer disease.

Adolescent↗
PubMed2004

Helicobacter infection: pathogenesis.

PURPOSE OF REVIEW: Helicobacter pylori remains one of the world's most prevalent bacterial pathogens, often causing gastritis, peptic ulcer disease, gastric mucosa-associated lymphatic tissue lymphoma, or gastric adenocarcinoma. Elucidation of H. pylori virulence mechanisms and characteristics of the host that contribute to pathogenesis will facilitate the development of both pharmacologic and immunologic therapies. RECENT FINDINGS: The functional status of the outer inflammatory protein A may have predictive value for duodenal ulcer, and host alleles for interleukin-1beta, interleukin-1R, tumor necrosis factor-alpha, and interleukin-10 correlate with increased risk for gastric cancer. H. pylori vacuolating cytotoxin A and cytotoxin-associated gene A protein interact with multiple host proteins, although downstream signaling events need further characterization. It does appear however, that CagA may participate in a negative feedback loop on Src family kinases to prevent further phosphorylation of CagA. Several models, including delayed type hypersensitivity in immune mice, and spontaneous clearance of H. pylori from interleukin-10 and phagocyte oxidase mice, provide evidence that severe inflammation may be sufficient to eradicate H. pylori. The strategies used by H. pylori to avoid the inflammatory response are also becoming clearer. H. pylori remains viable when internalized by epithelial cells, and it remains viable in macrophage phagosomes by inhibiting phagosome maturation. Additionally, H. pylori may regulate the host immune response through activation of dendritic cells and CD25 regulatory T cells, and it may direct immunosuppression of T cells. SUMMARY: Helicobacter pylori virulence is accomplished through many mechanisms, including vacuolating cytotoxin A and CagA activities, and may be predicted based on bacterial and host genotypes. Ultimately, H. pylori persistence may depend on its success in downregulating the inflammatory response.

Journal Article↗
PubMed2004

Absence of catalase reduces long-term survival of Helicobacter pylori in macrophage phagosomes.

BACKGROUND: Some Helicobacter pylori strains can survive within macrophage phagosomes for up to 24 hours. The factors that play a role in this survival remain ill-defined. Therefore, the contribution of catalase in mediating the survival of H. pylori following phagocytosis was investigated in vitro. METHODS: An isogenic, catalase-deficient strain of H. pylori was generated and tested for sensitivity to hydrogen peroxide and susceptibility to macrophage-mediated killing. RESULTS: The isogenic, catalase-deficient strain of H. pylori was effectively killed by hydrogen peroxide within 3 minutes compared to wild-type H. pylori which maintained 100% survival up to 21 minutes. The catalase-deficient mutant was also significantly more susceptible to macrophage-mediated killing than the parent strain, even when the ratio of bacteria to macrophage was increased. CONCLUSION: These results indicate that although some strains of H. pylori are capable of survival within the macrophage phagosome, survival is dependent on virulence factors such as catalase for evasion of innate host defense.

Animals↗
PubMed2003

Vaccine-induced reduction of Helicobacter pylori colonization in mice is interleukin-12 dependent but gamma interferon and inducible nitric oxide synthase independent.

Previous studies with mice have shown that major histocompatibility complex class II (MHC-II) is required for protection from Helicobacter pylori, while MHC-I and antibodies are not. Thus, CD4(+) T cells are presumed to play an essential role in protective immunity via secretion of cytokines. To determine which cytokines are associated with a reduction of bacterial load in immunized mice, gastric cytokine expression was examined by semiquantitative reverse transcription-PCR in protected (defined as > or =2-log-unit decrease in bacterial load) and unprotected mice 4 weeks after challenge. Elevated levels of mRNA for interleukin-12p40 (IL-12p40), gamma interferon (IFN-gamma), tumor necrosis factor alpha, and inducible nitric oxide synthase (iNOS) were associated with protection in immunized-challenged (I/C) mice, but Th2 cytokine (IL-4, IL-5, IL-10, and IL-13) and chemokine (KC, MIP-2, and MCP-1) expression was not associated with protection. Despite the association of IFN-gamma and iNOS message with protection, I/C mice genetically lacking either of these products were able to reduce the bacterial load as well as the wild-type I/C controls. The I/C mice lacking IL-12p40 were not protected compared to unimmunized-challenged mice. All I/C groups developed gastritis. We conclude that neither IFN-gamma nor iNOS is essential for vaccine-induced protection from H. pylori infection. The p40 subunit of IL-12, which is a component of both IL-12 and IL-23, is necessary for protection in immunized mice. These findings suggest a novel IFN-gamma-independent function of IL-12p40 in effective mucosal immunization against H. pylori.

Administration, Intranasal↗
PubMed2003

Protective efficacy of anti-Helicobacter pylori immunity following systemic immunization of neonatal mice.

Helicobacter pylori infection of the gastric mucosa is a significant cause of morbidity and mortality because of its etiologic role in symptomatic gastritis, peptic ulcer disease, and gastric adenocarcinoma. Infection occurs in young children; therefore, a prophylactic vaccine would have to be administered within the first year of life, a period thought to be immunologically privileged. We investigated vaccine formulations administered by different routes to confer protective anti-H. pylori immunity in neonatal mice. Neonatal mice immunized with a single dose of vaccine in complete Freund's adjuvant (CFA) generated antigen-specific gamma interferon-, interleukin-2 (IL-2)-, IL-4-, and IL-5-secreting T cells in numbers similar to those in immunized adult mice, while vaccine administered to neonates in incomplete Freund's adjuvant (IFA) induced such cells in reduced numbers compared to those in adult mice. Both IFA and CFA, however, provided partial protection from a challenge with infectious H. pylori when the vaccine was administered subcutaneously. Neonatal immunized mice also had reduced bacterial loads when immunized intraperitoneally with CFA. In all cases, protection was equivalent to that achieved when adult counterparts were immunized. These studies suggest that an efficacious vaccine might be successfully administered to very young children to prevent perinatal infection of H. pylori.

Aluminum Hydroxide↗
PubMed2003

Vaccine-induced protection against Helicobacter pylori in mice lacking both antibodies and interleukin-4.

To test the hypothesis that a Th2 response to Helicobacter pylori is necessary for protection and to address the possibility that humoral and Th2 cellular responses may compensate for each other, we generated mice deficient in both interleukin-4 (IL-4) and antibodies. The immunized double-knockout mice were protected from H. pylori challenge, as were the parental strains and wild-type C57BL/6 mice. Neutralization of IL-4 in B-cell-deficient mice did not prevent protection. Immunized IL-5-deficient mice were also protected. Thus, IL-4 and IL-5 are not essential for protection.

Animals↗
PubMed2002

Helicobacter pylori inflammation and immunity.

Gastric inflammation is a significant contributor to the disease process associated with Helicobacter pylori infection. It appears that both bacterial genes and differential host responses make interrelated contributions to gastritis and disease outcome after H. pylori infection. While the cag pathogenicity island (PAI) continues to be a focus for much of this investigation on the bacterial side, other bacterial genes/proteins are certainly important as well. On the host cell side, significant progress is being made defining the eucaryotic signaling cascades induced after host cells interact with H. pylori. The role of host cell cytokines, gastric acid, and mast cells is also being actively studied. Prospects for control of H. pylori associated disease continue to include vaccination. The mechanism(s) for vaccine-mediated control of H. pylori infection and disease remain ill-defined but recent evidence from animal models suggests that the inflammatory response may be involved. Manipulating the host response to H. pylori infection in humans to take advantage of the possible beneficial effects of inflammation, while minimizing its detrimental effects is a significant challenge for the future.

Animals↗