Emerging Technologies for Nutrition Research Potential for Assessing Military Performance Capability (1997) / Chapter Skim
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Emerging Technologies for Nutrition Research, 1997 Pp.
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Promising new technologies from recombinant DNA and biodegradable polymer research will change the way vaccines are produced and will simplify how immunity is induced and maintained (Michalek et al., 1995; Walker, 1994)
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numerous opportunities for interdisciplinary collaboration and leveraging of the tasks. CURRENT CONCEPTS AND ISSUES IN IMMUNITY It may be useful to digress from the primary objective (i.e., that of describing the exciting new technologies)
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The concept of anatomic compartmentalization of immunity is supported by observations from several disciplines (Kroemer et al., 1993)
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Figure 22-1 A simplified drawing of the structures and connections of secondary lymphatic tissues where antigen may most efficiently direct immune responses. Multiple known and unknown factors intrinsic to the microenvironments of lymph node, spleen, and mucosa-associated lymphatic tissue (here, M.A.L.T is represented by Peyer's patch)
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Compartmentalized Humoral Immunity All immunoglobulins, whether peripheral or mucosal, function by binding antigen in a pocket formed by the complementarity-determining regions (CDRs) encoded by the immunoglobulin heavy (VH)
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Figure 22-2 Diagram of an immunoglobulin molecule. The heavy and light chains of an immunoglobulin molecule are displayed linearly in Panel A, and the antigen-combining site is displayed in native configuration in Panel B
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blood microvasculature. These antibodies maximize cellular uptake and internalization of antigens.
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Figure 22-3 Diagram of small intestinal mucosa. Panel A shows the synthesis of secretory IgA by plasma cells and transport to the intestinal lumen by epithelial cells (dots and interrupted arrows)
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The profile of cytokines secreted by T-cells dictates immunoreactive cell commitment to either peripheral or mucosal immune functions. Gamma interferon from T-helper 1 (Th1)
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CD8 Homing and Cross-Regulation. When mice with severe combined immunodeficiency (SCID)
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Immune Assessment by T-Cell Phenotypes. Monoclonal antibodies are now available that enable phenotypic distinction of the class and potential function of T-cells, including their commitment to being peripheral or mucosal cells.
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luminal surfaces of endothelial cells. These recognition events may happen in skin, mucosa, or specific secondary lymphatic tissues, such as Peyer's patch or peripheral lymph node.
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Recirculation Is the Integrating Principle. Recirculation of a precursor pool of uncommitted lymphocytes, from the blood into lymph nodes or mucosal lymphatic tissues and then back to the blood again, forms the basis of immuno-surveillance and integration of immune functions across the segregated systems.
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are activated in lymphatic tissues sampling antigens from the gastrointestinal (GI) tract, they become specialized to migrate preferentially into the GI tract and serve its immunologic needs (Abernethy et al., 1991; Kimpton et al., 1989)
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αeβ7 integrin in T-cells destined to enter the intraepithelial compartment, where it anchors T-cells to E-cadherin on epithelial cells (Cepek et al., 1994)
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via the blood into mucosal lamina propria. This process takes 5 to 7 days, at least 4 trips in the blood, and 2 to 3 cell generations (Cebra et al., 1977)
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ISSUES FOR CONVENTIONAL MODES OF VACCINATION Complicated Diseases Require Peripheral and Mucosal Protective Immunity Protection from diseases that threaten military personnel requires complex forms of immunity (Mobley, 1995)
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often delayed or prevented induction of peripheral immunity and vice versa (Chase, 1946; MacDonald, 1982; Mattingly and Waksman, 1978)
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elicited an immune response that protected mice from challenge by parenteral route but not from challenge by aerosol. This asymmetric immunity also was found for the C84 Venezuelan equine encephalitis virus vaccine (Jahrling and Stephenson, 1984)
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(classical and nonclassical MHC20) that target antigens for induction of immunity (Agace et al., 1993; Eckmann et al., 1993; McCormick et al., 1993)
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Figure 22-6 This diagram, resembling the oriental symbol for yin and yang, represents microenvironmental factors that stimulate T-cells to express either T-helper 1 (Th1) or T-helper 2 (Th2)
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of T-helper types in lymph nodes or Peyer's patches influences selective expression of IgG or IgA immunoglobulin isotypes, respectively (Stavnezer, 1995)
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response is initiated (Weinstein and Cebra, 1991; Weinstein et al., 1991)
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Solutions from Microencapsulation Technology The first technology to be highlighted is microencapsulation of vaccines with biodegradable polymers for immunization of the peripheral and mucosal immune systems. There are a number of recent reviews (in new journals committed to the field)
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Microencapsulated Vaccines Overcome Cross-Regulation When vaccine antigen in poly(lactide/glycolide) copolymer was administered orally in various size ranges between 1 and greater than 10 µm, particles of over 10-µm diameter were not absorbed in the gut.
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Adjuvant Activity of Cholera Toxin CT is a potent immunogen regardless of route of administration (Fuhrman and Cebra, 1981; Pierce and Gowans, 1975)
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Cholera Toxin and E Coli Heat-Labile Enterotoxin CT and heat-labile enterotoxins (LTs)
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Effect of Cholera Toxin or Cholera Toxin B-Subunit on Lymphoid Tissue Compartments When T-and B-cell compartments in lymphatic tissues from mice that had received CT or CTB orally were examined by immunohistochemistry, there were no glaring changes in T-and B-cell populations in lymph nodes, spleen, or Peyer's patches. However, CT and CTB very quickly depleted the CD8+ cells in the intraepithelial compartment, cells that are normally very prevalent.
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threats that are endemic in countries whose financial resources preclude any chance of buying the product. The next section will show how both of these issues may be resolved by producing antigens or antibodies in plants.
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of plant-made protein to the amounts needed for a commercial vaccine is to add acreage. Cheaper vaccines that are available in large quantities make vaccination of an entire expeditionary force feasible in contingency situations.
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Preselection of "High Affinity-Ig" B-Cells for ComplementarityDetermining Region Isolation and Expression in Transgenic Plants After in vivo antigenic stimulation in mammals, B-cells undergo molecular and cellular changes within germinal centers of lymphoid follicles. An important change that B-cells undergo is "affinity maturation," whereby B-cells expressing specific antibodies for a given antigen undergo progressive changes that result in selection of cells capable of making antibodies with higher binding affinity (Eisen and Siskind, 1964; Gearhart, 1993)
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Making Recombinant Human Antibodies in Transgenic Plants Expression of the selected CDRs on conserved framework structures of human immunoglobulins in transgenic plants should allow production of large amounts of protective antibodies (Ma et al., 1995)
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Figure 22-7 This schematic diagram illustrates the process for generating transgenic plants expressing assembled immunoglobulins. Individual plants were first transformed with one of four genes encoding kappa-light chain, alpha-heavy chain, J-chain, or secretory component.
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intestinal tract and other mucosa that provide for optimal nutrition. An added benefit of support for this discipline has been a better understanding of how vaccines can be used more effectively.
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Anderson, A.O. 1985 Multiple effects of immunological adjuvants on lymphatic microenvironments.
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Bendelac, A 1995 CD1: Presenting unusual antigens to unusual T lymphocytes.
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Cryz, S.J., Jr., ed. 1991 Vaccines and Immunotherapy.
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1984b Generalized systemic and mucosal immunity in mice after mucosal stimulation with cholera toxin.
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Haq, T.A., H.S. Mason, J.D.
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Kagnoff, M.F. 1996 Mucosal immunology: New frontiers.
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Lyons, A.B., and C.R. Parish 1995 Are murine marginal-zone macrophages the splenic white pulp analog of high endothelial venules?
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Mobley, J.A. 1995 Biological warfare in the twentieth century: Lessons from the past, challenges for the future.
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Quiding-Jarbrink, M., M Lakew, I
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Stavnezer, J 1995 Regulation of antibody production and class switching by TGF-beta.
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Wong, Y.W., P.H. Kussie, B
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were given crude tobacco leaf extract. In later experiments, they ate raw potato tubers.
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On the other hand, there is a great deal of interest in using enterotoxinderived carriers in stimulating immunity via intranasal route, which accesses the tonsils and adenoids as antigen-reactive mucosal lymphatic tissues. DOUGLAS WILMORE: There is another route by which antigens can enter the gut, and that is by paracellular channels -- gaps that form when the gut is under-perfused and as a result of the effects of acidosis on mucosal integrity.
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What you referred to is a phenomenon which only occurs in infants. It is called the phenomenon of gut closure.
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DAVID SCHNAKENBERG: What is the lag time from dosage to effective protection? If you are using this only to a point of deployment, is this something you start 2 weeks ahead of time?
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