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Biomedical subjects

N F Pierce

Publications and source records attributed to N F Pierce.

At least 55 records · Page 3Linked to original sources
PubMed1980

Antitoxic immunity to cholera in dogs immunized orally with cholera toxin.

Colera toxin was evaluated as an oral immunogen against experimental canine cholera. Dogs were immunized orally with 100-microgram doses of purified cholera toxin or comparable doses of crude toxin. Both doses caused moderate diarrhea in most nonimmune dogs. Repeated oral doses (12 doses in 54 days) gave marked protection against the diarrheal effect of oral toxin, provoked a vigorous antitoxic response in jejunal mucosa, and gave nearly complete protection against subsequent oral challenge with living virulent Vibrio cholerae. Protection appeared to be due largely to the antitoxic response in intestinal mucosa. The effectiveness of cholera toxin as an oral vaccine contrasts with the previously described ineffectiveness of toxoid given orally. This study provides an example of mucosal immunity due to a nonreplicating vaccine given orally and suggests that cholera toxin may be useful as a component of an oral vaccine for cholera.

Administration, Oral↗
PubMed1980

Suppression of the intestinal immune response to cholera toxin by specific serum antibody.

The possibility that preexisting specific serum antibody could suppress a defined mucosal immune response to a topically applied antigen was studied in rats. Hyperimmune serum antibody induced by parenteral immunization of rats with cholera toxoid markedly suppressed the mucosal immune response to enterically applied cholera toxin. Such antibody was far more suppressive than antibody induced by primary parenteral immunization, apparently due to its greater avidity. Transfusion of small amounts (25 to 100 microliter) of hyperimmune serum suppressed the primary mucosal antitoxin response, the development of specific memory in the mucosal immune system, and, somewhat less effectively, the secondary mucosal antitoxin response. Suppression was due largely to a direct effect of serum antibody upon the interaction of absorbed enteric antigen with lymphoid tissue in Peyer's patches and, possible, mesenteric lymph nodes; interference with antigen absorption played little or no role in the observed suppression. These results do not explain the previously reported suppressive effect of primary parenteral immunization on the mucosal immune response to cholera toxin. However, they support the notions that repeated parenteral immunization can evoke avid serum antibody without necessarily stimulating mucosa-associated lymphoid tissue and that such antibody can markedly suppress primary and secondary phases of the local immune response to mucosally applied antigen. Thus, a mechanism is demonstrated by which repeated parenteral immunization may adversely affect efforts to initiate or sustain protective mucosal immune responses.

Animals↗
PubMed1980

Priming and suppression of the intestinal immune response to cholera toxoid/toxin by parenteral toxoid in rats.

Parenteral immunization of rats with cholera toxoid had both priming and suppressive effects upon the antitoxin response in jejunal lamina propria to locally applied toxoid/toxin. Priming was detected when parenteral toxoid was given i.p. but not i.v. or s.c., was enhanced by Freund's adjuvant, and appeared to reflect enhanced encounter of i.p. antigen with IgA-committed lymphocytes in extra-intestinal mucosa-associated lymphoid tissue. In contrast, suppression followed parenteral toxoid given i.p., i.v., or s.c.; suppression was antigen specific and lasted at least 16 weeks. Parenteral toxoid suppressed both primary and secondary types of mucosal antitoxin responses, ultimately preventing the generation of antitoxin-containing immunoblasts from Peyer's patches. Since suppression followed parenteral immunization by routes that did not provoke mucosal priming, it was, at least in those instances, not simply a regulatory consequence of mucosal priming. These results support the notion that priming and suppression of a specific mucosal immune response are independent effects of parenteral immunization that are probably determined by the distribution of antigen to mucosa-associated and systemic lymphoid tissue, respectively.

Animals↗
PubMed1979

Protein deprivation causes reversible impariment of mucosal immune response to cholera toxoid/toxin in rat gut.

Scretory antibodies may be the major defence against mucosal infections, especially those due to viruses and non-invasive pathogens such as Vibrio cholerae and toxinogenic Escherichia coli. The high incidence of mucosal infections in malnourished protein-deficient children may result from defective antibody production, but evidence for this is conflicting. We report here that protein deficiency markedly impairs the mucosal immune reponse to cholera toxiod/toxin (CT), a protein antigen, in rats and that this impairment is rapidly reversed by refeeding.

Animals↗
PubMed1978

The role of antigen form and function in the primary and secondary intestinal immune responses to cholera toxin and toxoid in rats.

This report describes studies of the mucosal antitoxic response in rats after enteric administration of several forms of cholera toxin or toxoid, proteins which differ primarily in their ability to bind to cell membranes and activate cellular adenyl cyclase. These two characteristics appeared to markedly enhance the local primary response to these antigens. A single dose of toxoid lacking these features was ineffective in local priming even though it was absorbed and induced a systemic immune response. Single dose mucosal priming occurred only with preparations which bind to cell membranes and was enhanced by those which also activate cellular adenyl cyclase. In contrast, single-dose mucosal boosting was best accomplished by materials with these properties but was also seen with a toxoid lacking both of these functions. The property of membrane binding appears to be most advantageous in mucosal priming, perhaps by increasing effective trapping of absorbed antigen in unprimed mucosal lymphoid tissue, whereas the ability to activate adenyl cyclase appears to enhance primary and secondary type responses about equally. Combinations of crude toxoid and toxin were also more effective in mucosal priming than purified materials, a finding which is unexplained. A single dose of this combination induced mucosal priming which was fully developed in 2 wk, undiminished after 4 too, and only modestly diminished after 8 mo, thus demonstrating relatively prolonged memory in the IgA mucosal immune system. Effective two-dose local immunizing regimens were developed, and it was shown that there was no correlation between the mucosal and systemic secondary antitoxin responses provoked by these regimens.

Adenylyl Cyclases↗
PubMed1978

Induction of a mucosal antitoxin response and its role in immunity to experimental canine cholera.

The induction of a jejunal antitoxin response was studied in dogs immunized with cholera toxin or toxoid. Single doses of toxoid given subcutaneously (s.c.) or of toxin given intraluminally (i.l.) were each effective in priming the mucosal immune system, whereas toxoid given i.l. was much less effective. In contrast, toxin and toxoid given i.l. were each effective as booster antigens. The local secondary response was rapid and brief, the peak occurring at about 7 days after i.l. boosting and declining by 90% after 2 more weeks. After s.c. priming and i.l. boosting with toxoid, antitoxin-containing plasma cells appeared predominantly in the portion of jejunum exposed to the i.l. booster. The appearance of antitoxin-containing plasma cells in jejunal lamina propria correlated with the amount of antitoxin recovered in jejunal washings which, in turn, correlated with protection against challenge with cholera toxin. Thus, lamina propria antitoxin-containing plasma cells appeared to be the source of protective antitoxin. However, after sequential s.c.-oral immunization with toxoid, protection against challenge with Vibrio cholerae far outlasted the major systemic and local antitoxin responses and was not obviously explained by either. These studies reveal methods for induction of a mucosal antitoxin response, but leave in question the mechanism of prolonged protection induced by s.c.-oral immunization of dogs.

Animals↗
PubMed1977

Immunity to experimental cholera. III. Enhanced duration of protection after sequential parenteral-oral administration of toxoid to dogs.

Protection against experimental cholera after immunization with a purified glutaraldehyde toxoid given subcutaneously (sc), orally, or by a combined sc-oral sequence was compared in dogs. The protection induced by toxoid appeared to be entirely due to antitoxin. Repeated sc immunization with precipitated toxoid resulted in 77% protection at two weeks but no protection at four months. Protection after sc immunization correlated with titers of antitoxin in serum and appeared to result entirely from serum-derived antibody. In contrast, immunization by the sc-oral sequence resulted in prolonged protection (74% at two weeks, P=0.04; 100% after four months, P=0.004; and 57% after eight months, P=0.01) that was not related to the low serum antitoxin titers achieved. This sequence was effective only if the oral booster was given in divided doses. Immunization by oral priming and boosting was ineffective. These results suggest that the sc-oral sequence of immunization is an efficient means of stimulating the enteric immune response to nonreplicating protein antigens and may provide an improved approach to immunization against cholera.

Administration, Oral↗
PubMed1977

Immune response of the intestinal mucosa to cholera toxoid.

The intestinal immune response to cholera toxoid was studied in dogs and rats. Oral or intraperitoneal priming followed by duodenal boosting with toxoid reulted in antitoxin-containing plasma cells (ACC) in jejunal lamina propria of rats. Priming and boosting by the intraperitoneal route alone induced almost no jejunal response. Lamina propria ACC were derived largely from migrating immunoblasts, which appeared earlier among thoracic duct lymphocytes. Protection of dogs after repeated subcutaneous immunization with toxoid was mediated largely, or entirely, by serum-derived antibody. The sequence of subcutaneous priming and repeated oral boosting induced longer lasting protection mediated almost entirely by the local intestinal immune mechanism. The results suggest that cholera immunization should be specifically designed to stimulate the intestinal immune mechanism and that the subcutaneous oral immunizing sequence may be an efficient way to do this.

Administration, Oral↗
PubMed1976

Intestinal immunization with soluble bacterial antigens: the example of cholera toxoid.

The studies described are aimed at a better understanding of the intestinal immunological system and its role in protection against enteric infection. The cellular kinetics of the intestinal immune response to cholera toxoid were studied in rats and the protection afforded by toxoid immunization was studied in dogs. Memory was demonstrated in the gut immune system. Plasma cells containing IgA antitoxin appeared in large numbers in gut lamina propria when intraduodenal boosting followed either intraperitoneal priming or prolonged oral priming, intraperitoneal priming being the most efficient. Immunization by the intraperitoneal route alone produced no response in small bowel lamina propria. Lamina propria plasma cells were derived from precursors in Peyer's patches or mesenteric lymph nodes which migrated through the thoracic duct and systemic circulation before homing to the gut. Dogs were immunized parenterally with cholera toxin or toxoid and challenged orally with Vibrio cholerae. Protection correlated closely with serum antitoxin titres and was usually brief. Passive intravenous immunization with IgG antitoxin was also protective. In contrast, subcutaneous priming followed by oral boosting yielded longer protection without elevated serum antitoxin titres. Antitoxin was detected in jejunal washings only briefly after local boosting. The mechanism by which protection is prolonged is unclear but its greater duration after parenteral priming and oral boosting emphasizes the importance of stimulating the gut immune mechanism in attempts to immunize against enteric bacterial infections. The parenteral-oral squence may be an effective means of immunizing the intestine with non-replicating protein antigens.

Administration, Oral↗
PubMed1976

Challenge of dogs with live enterotoxigenic Escherichia coli and effects of repeated challenges on fluid secretion in jejunal Thiry-Vella loops.

Dogs were evaluated as experimental models for the study of diarrheal disease produced by enterotoxigenic Escherichia coli. Although a suitable whole model for orogastric bacterial challenge could not be developed, chronic jejunal Thiry-Vella loops were used to study the secretory effects of multiple jejunal challenges with enterotoxin of either Vibrio cholerae or E. coli. The heat-stable and heat-labile E. coli enterotoxins could be differentiated clearly in this model. Sequential weekly challenges over a four-week period showed a significant decrease in loop secretory response to homologous enterotoxin, although levels of antitoxin in serum remained unchanged, a finding suggesting a local immune response. Dogs challenged with E. coli enterotoxin were markedly protected against subsequent challenge with V. cholerae enterotoxin; the converse was not true. Histologic studies of the loops showed only minimal atrophy, and results of absorption studies in the loops were normal. These studies suggest that mongrel dogs are resistant to colonization by enterotoxigenic E. coli and partially resistant to challenge with enterotoxin, perhaps on an immune basis due to prior antigenic exposure. Multiple challenges with enterotoxin effect a decreased secretory response; this finding also suggests a local immune mechanism.

Animals↗
PubMed1975

Cellular kinetics of the intestinal immune response to cholera toxoid in rats.

The aims of this study were (a) to find a regime of immunization with cholera toxoid in rats which would establish a high density of antitoxin containing cells (ACC) in the lamina propria of the intestine and (b) to determine the origin of the ACC. The best cellular response was achieved by a single i.p. dose of toxoid in FCA followed by an intraintestinal boost 2 wk later. ACC appeared in the thoracic duct lymph 2 days after boosting, reaching a peak of about 200,000 ACC/h at 3--4 days. This was followed by the appearance of large numbers of ACC in the intestine. The i.p. dose of toxoid by itself gave rise to very few ACC in the gut or thoracic duct lymph, but it had clearly primed the gut immune system for a secondary response. Priming was also achieved by the prolonged oral intake of toxoid. The importance of the intestinal route for boosting was shown by the failure of i.p. challenge to give an ACC response in the intestine after i.p. priming and the small response it provoked after oral priming. ACC among thoracic duct lymphocytes (TDL) and in the lamina propria contained predominantly IgA. Two observations indicated that the major source of the lamina propria ACC was from cells that emerged in the thoracic duct lymph after intraintestinal challenge. Firstly, the establishment of a thoracic duct fistula immediately before challenge prevented the appearance of ACC in the intestine. Secondly, many ACC appeared in the intestine of normal rats after the injection of TDL rich in ACC. Although homing of ACC precursors to the gut was not antigen-dependent, the distribution of ACC in the lamina propria was considerably influenced by the site of the intestinal challenge, the density of ACC being greatest at or distal to the site of injection of toxoid into the lumen of the gut.

Animals↗