IgA Isotype Restriction in the Mucosal but Not in the Extramucosal Immune Response after Oral Immunizations with Cholera Toxin or Cholera B Subunit

Lycke, Nils; Lindholm, Leif; Holmgren, Jan

doi:10.1159/000234853

Cited by 36 publications

(19 citation statements)

References 8 publications

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“…This isotype restriction is in accord with the 80-90% predomi nance of IgA-producing cells in the lamina propria [18] including specific antitoxin-containing cells [18,24], It also agrees with the isotype pattern for cholera antibodies in intestinal fluid [17]. Secretory IgA de rived from milk from mothers in cholera-endemic areas has been found to neutralize CT and afford pro tection to the breast-fed child [5,8].…”

Section: Discussionsupporting

confidence: 75%

“…Cholera antitoxin antibodies were determined by means of an isotype-specific, enzyme-linked immunosorbent assay (ELISA) as previously described [17], Supernatants from the cultured cells were analyzed at an initial dilution of 1:3 and in serial triple dilutions. Antibody titers were defined as the interpolated dilutions of the samples which in 10 min gave rise to an absorbance of 0.2 above the background.…”

Section: Antibody Production In Cell Culturesmentioning

confidence: 99%

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Role of Local IgA Antitoxin-Producing Cells for Intestinal Protection against Cholera Toxin Challenge

Lycke

Bromander²,

Holmgren³

1989

Int Arch Allergy Immunol

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We examined in mice, perorally immunized with cholera toxin (CT) or cholera B subunit (CTB), the association between protection against intestinal toxin challenge and frequency and function of gut mucosal IgA antitoxin-forming cells. The in vitro production of IgA antitoxin by isolated cells and the toxin-neutralizing ability of culture supernatants were determined. Repeated oral immunizations with CT gave rise to high numbers of IgA antitoxin ‘spot-forming’ cells (SFC) in the lamina propria as well as to protection against challenge with CT in ligated intestinal loops. In contrast, mice immunized with purified CTB, gave poor IgA antitoxin SFC responses in the lamina propria and little or no protection. When a small amount of CT was used to adjuvant the response to CTB, many IgA antitoxin SFC were found; however, protection in intestinal loops remained poor. This discrepancy was explained by the predominant localization of antitoxin SFC in the proximal small intestine following oral CTB/CT-adjuvant immunization, whereas relatively few SFC were found further down in the intestine where the loop-protection test was performed. Thus, when lamina propria plasma cells were isolated from challenged loops and cultured in vitro, they released only low titers of IgA antitoxin and CT-neutralizing antibodies in culture supernatants; this was in contrast to cells from optimally immunized mice which gave supernatants with high IgA antitoxin and toxin-neutralizing antibody titers. Increasing the dose of CT, added as adjuvant to the CTB, resulted in better protection and higher numbers of IgA antitoxin SFC in more distal parts of the intestine. We also found that the build-up of strong local immunity in the gut was more dependent on repeated exposures to antigen than on immune maturation over time after oral immunizations. Our findings confirm that intestinal IgA antitoxin formation and protection against toxin challenge after oral immunization with CT are closely correlated, and that this correlation also holds true for CT-adjuvanted CTB administered by the oral route.

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Section: Discussionsupporting

confidence: 75%

Section: Antibody Production In Cell Culturesmentioning

confidence: 99%

Role of Local IgA Antitoxin-Producing Cells for Intestinal Protection against Cholera Toxin Challenge

Lycke

Bromander²,

Holmgren³

1989

Int Arch Allergy Immunol

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“…The presence of circulating anti-toxin-specific AFC in mice and humans after oral immunization with CT-B has been demonstrated using a similar ELISPOT technique by Lyke et al [13] but interestingly they were only able to demonstrate such cells using the ELISPOT technique after several days of in vitro culture. It might be that the use of the antibody amplification and the choice of solid media in the present study made the ELISPOT assay more sensitive, as we had no difficulty in demonstrating spontaneously secret- manifest a response but this was highly variable.…”

Section: Discussionmentioning

confidence: 97%

“…Lycke et al [13] found that after a second oral immunization with CT-B in mice, the peak circulating AFC response occurred after 4 to 8 days, which was in agreement with Kantele et al [18] who studied the AFC response after three immunizations of live Salmonella typi Ty2la given orally to humans who found a peak response at 8 days after the third immunization, and Forrest [17] who found a peak at 6 days after a third immunization of live Salmonella typhi Ty2la in humans. In contrast Czerkinsky et al [14] found a mean peak AFC response 10 to 12 days after oral immunization with killed S. rnutans in humans.…”

Section: Discussionmentioning

confidence: 99%

The early cellular and humoral immune response to primary and booster oral immunization with cholera toxin B subunit

et al. 1991

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The immune response to cholera toxin B subunit given orally was studied in 13 human volunteers. A serum IgG and IgA antitoxin response was observed, which was boosted by a second immunization. Using an immunospot assay, cells spontaneously secreting anti-toxin IgG and IgA, but not IgM appeared transiently in the blood after immunization. There were 105 IgG- and 87 IgA-secreting cells per 2 x 10(6) mononuclear cells 7 days after the first immunization, and 282 IgG- and 413 IgA-secreting cells 5 days after the second immunization. A polyclonal increase in total IgM-secreting cells was observed. Few anti-toxin-secreting cells were observed in the bone marrow at the peak of the circulating cell response, which could be accounted for by contamination of the sample with peripheral blood, suggesting that the bone marrow is not a significant site of anti-toxin-secreting cells after oral immunization.

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“…It should be noted that circulating IgG antibodies are also effectively stimulated by these approaches, thereby expanding the range of infections that can potentially be addressed by mucosal immunization (Lycke et al, 1983;Jackson et al, 1993). Cell-mediated immunity, including the generation of cytotoxic T lymphocytes (CTL), has been less frequently studied in this context; however, it is noteworthy that CTL with activity against HIV-infected cells can be induced by mucosal immunization with HIV peptides administered together with CT or LT(R192G) (Porgador et al, 1997;Belyakov et al, 2000).…”

Section: Applications and Significance With Respect To Oral Diseasementioning

confidence: 99%

Immunomodulation with Enterotoxins for the Generation of Secretory Immunity or Tolerance: Applications for Oral Infections

et al. 2005

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The heat-labile enterotoxins, such as cholera toxin (CT), and the labile toxins types I and II (LT-I and LT-II) of Escherichia coli have been extensively studied for their immunomodulatory properties, which result in the enhancement of immune responses. Despite superficial similarity in structure, in which a toxic A subunit is coupled to a pentameric binding B subunit, different toxins have different immunological properties. Administration of appropriate antigens admixed with or coupled to these toxins by oral, intranasal, or other routes in experimental animals induces mucosal IgA and circulating IgG antibodies that have protective potential against a variety of enteric, respiratory, or genital infections. These include the generation of salivary antibodies that may protect against colonization with mutans streptococci and the development of dental caries. However, exploitation of these adjuvants for human use requires an understanding of their mode of action and the separation of their desirable immunomodulatory properties from their toxicity. Recent findings have revealed that adjuvant action is not critically dependent upon the enzymic activity of the A subunits, and that the isolated B subunits may exert different effects on cells of the immune system than do the intact toxins. Interaction of the toxins with immunocompetent cells is not exclusively dependent upon their conventional ganglioside receptors. Immunomodulatory effects have been observed on dendritic cells, macrophages, CD4(+) and CD8(+) T-cells, and B-cells. Numerous factors-including the precise form of the toxin adjuvant, properties of the antigen, whether and how they are coupled, route of administration, and species of animal model-affect the outcome, whether this is enhanced humoral and cellular immunity, or specific induced tolerance toward the antigen.

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IgA Isotype Restriction in the Mucosal but Not in the Extramucosal Immune Response after Oral Immunizations with Cholera Toxin or Cholera B Subunit

Cited by 36 publications

References 8 publications

Role of Local IgA Antitoxin-Producing Cells for Intestinal Protection against Cholera Toxin Challenge

Role of Local IgA Antitoxin-Producing Cells for Intestinal Protection against Cholera Toxin Challenge

The early cellular and humoral immune response to primary and booster oral immunization with cholera toxin B subunit

Immunomodulation with Enterotoxins for the Generation of Secretory Immunity or Tolerance: Applications for Oral Infections

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