Showing papers by "Harry B. Greenberg published in 2000"

Lymphocyte CC chemokine receptor 9 and epithelial thymus-expressed chemokine (TECK) expression distinguish the small intestinal immune compartment: Epithelial expression of tissue-specific chemokines as an organizing principle in regional immunity.

Abstract: The immune system has evolved specialized cellular and molecular mechanisms for targeting and regulating immune responses at epithelial surfaces. Here we show that small intestinal intraepithelial lymphocytes and lamina propria lymphocytes migrate to thymus-expressed chemokine (TECK). This attraction is mediated by CC chemokine receptor (CCR)9, a chemoattractant receptor expressed at high levels by essentially all CD4+ and CD8+ T lymphocytes in the small intestine. Only a small subset of lymphocytes in the colon are CCR9+, and lymphocytes from other tissues including tonsils, lung, inflamed liver, normal or inflamed skin, inflamed synovium and synovial fluid, breast milk, and seminal fluid are universally CCR9−. TECK expression is also restricted to the small intestine: immunohistochemistry reveals that intense anti-TECK reactivity characterizes crypt epithelium in the jejunum and ileum, but not in other epithelia of the digestive tract (including stomach and colon), skin, lung, or salivary gland. These results imply a restricted role for lymphocyte CCR9 and its ligand TECK in the small intestine, and provide the first evidence for distinctive mechanisms of lymphocyte recruitment that may permit functional specialization of immune responses in different segments of the gastrointestinal tract. Selective expression of chemokines by differentiated epithelium may represent an important mechanism for targeting and specialization of immune responses.

Sustained survival of human hepatocytes in mice: A model for in vivo infection with human hepatitis B and hepatitis delta viruses

Abstract: Sustained survival of human hepatocytes in mice: A model for in vivo infection with human hepatitis B and hepatitis delta viruses

Immunity to Calicivirus Infection

Abstract: The evolution of our understanding of immunity to calicivirus infection, using Norwalk virus as the prototype, is discussed in three stages: (1) "ancient times (1972-1978), when human volunteer studies prevailed, (2) the "middle ages (1978-1990), which were characterized by the development and implementation of solid-phase immunoassays based on native viral antigens, and (3) "modern times (1990 to present), which began with the cloning of the genome of the noncultivatable 8FIIa strain of Norwalk virus and resulted in a readily available source of recombinant virus-like particles that have revolutionized the study of caliciviruses. Throughout these stages, it has been shown repeatedly that short-term immunity develops to homologous virus. However, the search for determinants of long-term immunity continues. These studies will likely be facilitated by the newest reagents-the noninfectious recombinant virus-like particles-used in the setting of human volunteer studies and large epidemiologic studies.

Protective immunity to rotavirus shedding in the absence of interleukin-6: Th1 cells and immunoglobulin A develop normally.

Abstract: We investigated whether interleukin-6 (IL-6) was required for the development of immunoglobulin A (IgA)- and T-helper 1 (Th1)-associated protective immune responses to rotavirus by using adult IL-6-deficient mice [BALB/c and (C57BL/6 x O1a)F(2) backgrounds]. Naive IL-6(-) mice had normal frequencies of IgA plasma cells in the gastrointestinal tract. Consistent with this, total levels of IgA in fecal extracts, saliva, and sera were unaltered. In specific response to oral infection with rhesus rotavirus, IL-6(-) and IL-6(+) mice exhibited efficient Th1-type gamma interferon responses in Peyer's patches with high levels of serum IgG2a and intestinal IgA. Although there was an increase in Th2-type IL-4 in CD4(+) T cells from IL-6(-) mice following restimulation with rotavirus antigen in the presence of irradiated antigen-presenting cells, unfractionated Peyer's patch cells failed to produce a significant increase in IL-4. Moreover, virus-specific IgG1 in serum was not significantly increased in IL-6(-) mice in comparison with IL-6(+) mice. Following oral inoculation with murine rotavirus, IL-6(-) and IL-6(+) mice mediated clearance of rotavirus and mounted a strong IgA response. When IL-6(-) and IL-6(+) mice [(C57BL/6 x O1a)F(2) background] were orally inoculated with rhesus rotavirus and later challenged with murine rotavirus, all of the mice maintained high levels of IgA in feces and were protected against reinfection. Thus, IL-6 failed to provide unique functions in the development of IgA-secreting B cells and in the establishment of Th1-associated protective immunity against rotavirus infection in adult mice.

Rotavirus Entry into Tissue Culture Cells

Abstract: Rotavirus (RV) is a triple-protein-layered icosahedral virus, for which studies have established that the two outer-layer proteins, viral protein 4 (VP4) and viral protein 7 (VP7), are required for viral infectivity (1,2). VP7, a glycoprotein, is the major component of the outer-layer, but its role in viral entry is unclear. VP4 forms dimers extending out from the VP7-coated viral surface (3,4) and have been shown to be a determinant of host range and virulence, and is directly involved in cell attachment and RV entry into cells (5-8). Proteolytic cleavage of VP4 into two noncovalently associated subunits, VP8* and VP5* (2,9,10), significantly enhances viral infectivity (11-13).

In Vivo Study of Immunity to Rotaviruses

Abstract: Rotaviruses (RVs) are important human pathogens. The murine model of RV infection has been very useful in clarifying the mechanisms that mediate clearance of primary RV infection, and the mechanisms that mediate immunity to reinfection. The use of immunodeficient strains of mice, immunodepletion studies with specific monoclonal antibodies (MAbs), and passive transfer of purified cells are three basic, complementary experimental approaches that have been used for this purpose, and are the subject of this chapter. These experimental approaches analyze the outcome of RV infection under artificial conditions; thus, the relevance of the results obtained, to the physiological immune response of immunocompetent mice or humans, is at times difficult to establish. For example, immunodeficient strains of mice frequently develop compensatory immune mechanisms that are potentially absent or nonfunctional in immunocompetent mice. Immunodepletion experiments introduce into the experimental animal high (nonphysiological) levels of antibodies (Abs) that potentially have other immunomodulatory effects different from the desired one, and, many times, depletion strategies fail to completely eliminate the target cell population. Passive cell transfer experiments analyze the antiviral capacity of a specific cell population (many times abnormal in number), independent of other cells with which it may normally interact, and in an environment to which it is at least partially alien. Because of these and other limitations of such experimental approaches, one should be very careful in selecting adequate controls, and cautious in the interpretation of the results, by taking into account results obtained with two or three of the approaches and analysis of the characteristics of the immune response in normal animals. The combination of two or three strategies (for example, passive cell transfer into immunodeficient hosts and immunodepletion of selected cell populations in immunocompetent hosts) have proven particularly useful in the study of immunity to RV.