Hiroshi Kiyono

Alternate Mucosal Immune System: Organized Peyer’s Patches Are Not Required for IgA Responses in the Gastrointestinal Tract

The progeny of mice treated with lymphotoxin (LT)-β receptor (LTβR) and Ig (LTβR-Ig) lack Peyer’s patches but not mesenteric lymph nodes (MLN). In this study, we used this approach to determine the importance of Peyer’s patches for induction of mucosal IgA Ab responses in the murine gastrointestinal tract. Immunohistochemical analysis revealed that LTβR-Ig-treated, Peyer’s patch null (PP null) mice possessed significant numbers of IgA-positive (IgA+) plasma cells in the intestinal lamina propria. Further, oral immunization of PP null mice with OVA plus cholera toxin as mucosal adjuvant resulted in Ag-specific mucosal IgA and serum IgG Ab responses. OVA-specific CD4+ T cells of the Th2 type were induced in MLN and spleen of PP null mice. In contrast, when TNF and LT-α double knockout (TNF/LT-α−/−) mice, which lack both Peyer’s patches and MLN, were orally immunized with OVA plus cholera toxin, neither mucosal IgA nor serum IgG anti-OVA Abs were induced. On the other hand, LTβR-Ig- and TNF receptor 55-Ig-treated normal adult mice elicited OVA- and cholera toxin B subunit-specific mucosal IgA responses, indicating that both LT-αβ and TNF/LT-α pathways do not contribute for class switching for IgA Ab responses. These results show that the MLN plays a more important role than had been appreciated until now for the induction of both mucosal and systemic Ab responses after oral immunization. Further, organized Peyer’s patches are not a strict requirement for induction of mucosal IgA Ab responses in the gastrointestinal tract.

Vaccines for Selective Induction of Th1- and Th2-Cell Responses and Their Roles in Mucosal Immunity

Publisher Summary The site of immunization and the choice of adjuvant and vehicles to deliver vaccines all play important roles in determining the degree of dissemination of secretory IgA (S-IgA) antibodies, the predominant immunoglobulin isotype present in mucosal secretions. T-cell-mediated immune (CMI) responses are also associated with mucosal immunity and the homing of sensitized T cells appears to be similar to that described for IgA plasma cell precursors. The differentiation pathways which T-helper (Th) cells undergo during mucosal and systemic immune responses is currently receiving extensive study, since it has been suggested that the function of mature Th cells is based upon the types of cytokines produced. In particular, Th1 cells, secreting IFNγ, IL-2, and tumor necrosis factor-β (TNFβ), are associated with delayed-type hypersensitivity and are less efficient than the Th2 subset (producing IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13) in providing help for antibody responses. The pattern of antibody isotypes secreted during an immune response is dependent upon the phenotype of the stimulating Th cells. Thus, in the murine system, Th1 cells through the secretion of IFNγ are more efficient in stimulating IgG2a production, whereas Th2 cells producing IL-4 induce IgGl and IgE antibodies. This chapter summarizes some of the recent findings on the role of Th1 and Th2 cells and derived cytokines for the induction and regulation of mucosal and systemic immune responses to well-defined vaccines and delivery systems. In addition it briefly discusses additional mucosal immunization approaches including mucosal delivery of soluble proteins, recombinant bacterial and viral vectors, and mucosal DNA (genetic) immunization.

Chapter 76 – Allergic Diseases in the Gastrointestinal Tract

This chapter reviews the role of mucosal effector cells, including eosinophils, mast cells, and Th2-type cells, in the development of allergic reactions in the gastrointestinal tract. Mucosal eosinophils, mast cells, and T cells play a critical role in the development of gastrointestinal allergic reactions. They have also elucidated the complex cell-to-cell interactions involved in the induction and regulation of mucosal cell-mediated allergic diseases. Eosinophils are multifunctional leukocytes involved in the pathogenesis of allergic disorders. Aberrant eosinophil accumulation in the gastrointestinal tissues is often associated with serious clinical symptoms such as—gastric dysmotility, malabsorption, cachexia, or diarrhea. Eosinophils can potentially initiate antigen-specific immune responses by mimicking antigen-presenting cells. In this regard, eosinophils express major histocompatibility (MHC) class II and costimulatory molecules, such as CD40, CD80, and CD86. Mast cells are the main effector cells in the development of IgE-mediated allergic responses. The pathologic processes of mucosal allergic reactions are known to be mediated by T helper (Th)2-type cells, which preferentially produce IgE-enhancing cytokines such as interleukin (IL)-4 and IL-13.