The long-term objective of this proposal is the elucidation of immunological and other mechanisms leading to helminth rejection of killing in the gut. Intestinal helminths cause significant disease in man and domestic animals and are informative probes of intestinal immune function. In T. spiralis infected rats, we have demonstrated that the intestine is the site of development and expression of three distinct immune responses-rapid expulsion (RE), adult worm rejection and anti- newborn larvae activity. Furthermore we have also shown that a unique population (or subpopulations) of thoracic duct lymphocytes present at day 3/4 post infection can adoptively transfer both adult worm rejection, and, in conjunction with antibody, RE (RE initiators). In a separate system, we have demonstrated passive transfer of intestinal anti-newborn larvae immunity with immune serum. The fact that protective cells are present at day 3/4 and migrate preferentially to the gut in large numbers is persuasive evidence that these cells are the natural mediators of rejection. Thus, for the first time a detailed analysis of the phenotype, migration pattern and ultimate effects of the natural cellular effectors of helminth rejection can be performed. Analysis of cell migration will be done by radiolabelling 0X-8-OX-22-and RE(in) cells using 125 lododeoxyuridine. We will determine whether each protective function is a property of the same cell subset by phenotypic analysis using a panel of mAbs cell affinity chromatography and panning for functional testing of isolated T cell subsets. Function will be assessed by a combination of allogeneic cell transfers, bone marrow transplants to irradiated T cell recipients and in vitro studies. Changes will be monitored by histopathological and histochemical analysis of the gut and by worm burden. Serum effectors of RE and NBL larvae immunity will be defined by fractionation of serum into lgG (and its subclasses) IgM and IgE fractions. In addition, experiments with RE-functional (in neonates) monoclonal IgG1 and IgG2c antibody are planned. Purified functional immunoglobulin will be radiolabelled (1251) and examined for its adherence to cells in the gut prior to challenge (to help define reactive cells) and to infectious muscle larvae collected from the gut lumen 20-30' after challenge. These procedures are expected to provide new insight into functional mechanisms of protection in the gut against the nematode T. spiralis.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Bacteriology and Mycology Subcommittee 2 (BM)
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Cornell University
Schools of Veterinary Medicine
United States
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Bell, R G (1998) The generation and expression of immunity to Trichinella spiralis in laboratory rodents. Adv Parasitol 41:149-217
Negrao-Correa, D; Adams, L S; Bell, R G (1996) Intestinal transport and catabolism of IgE: a major blood-independent pathway of IgE dissemination during a Trichinella spiralis infection of rats. J Immunol 157:4037-44
Ramaswamy, K; Negrao-Correa, D; Bell, R (1996) Local intestinal immune responses to infections with Trichinella spiralis. Real-time, continuous assay of cytokines in the intestinal (afferent) and efferent thoracic duct lymph of rats. J Immunol 156:4328-37
Ramaswamy, K; Goodman, R E; Bell, R G (1994) Cytokine profile of protective anti-Trichinella spiralis CD4+ OX22- and non-protective CD4+ OX22+ thoracic duct cells in rats: secretion of IL-4 alone does not determine protective capacity. Parasite Immunol 16:435-45
Bell, R G; Issekutz, T (1993) Expression of a protective intestinal immune response can be inhibited at three distinct sites by treatment with anti-alpha 4 integrin. J Immunol 151:4790-802
Llana, T; Bell, R G (1993) Characterization of an inhibitory factor derived from epithelial cells of the small intestine. Reg Immunol 5:18-27
Goodman, R E; Oblak, J; Bell, R G (1992) Synthesis and characterization of rat interleukin-10 (IL-10) cDNA clones from the RNA of cultured OX8- OX22- thoracic duct T cells. Biochem Biophys Res Commun 189:1-7
Bell, R G (1992) Trichinella spiralis: evidence that mice do not express rapid expulsion. Exp Parasitol 74:417-30
Wang, C H; Bell, R G (1992) Characterization of cellular and molecular immune effectors against Trichinella spiralis newborn larvae in vivo. Cell Mol Biol 38:311-25
Bell, R G; Appleton, J A; Negrao-Correa, D A et al. (1992) Rapid expulsion of Trichinella spiralis in adult rats mediated by monoclonal antibodies of distinct IgG isotypes. Immunology 75:520-7

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