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Biomedical subjects

J E Domer

Publications and source records attributed to J E Domer.

At least 37 records · Page 2Linked to original sources
PubMed1988

Intragastric colonization of infant mice with Candida albicans induces systemic immunity demonstrable upon challenge as adults.

A murine model of long-term colonization with Candida albicans, established by intubating infant CBA/J mice, was used to study the effects of colonization on the development of Candida-specific immune responses in mature animals. Two striking consequences were stimulation of protective immune responses, as evidenced by increased survival and decreased numbers of colony-forming units in mice challenged intravenously (iv), and priming of the T cell component responsible for delayed hypersensitivity (DH). Colonized mice, tested as adults by using a cell wall-derived antigen, had little or no demonstrable DH. If inoculated once cutaneously with viable Candida, however, they responded with significantly enhanced DH reactions that could not be correlated with the cutaneous inoculation. Inoculation of the same number of dead organisms into infant mice neither primed animals for enhanced DH nor stimulated protective immunity. Antibody to cytoplasmic antigens of Candida was demonstrable in colonized animals, and its production was increased significantly in animals challenged iv with the highest dose of blastoconidia.

Animals↗
PubMed1987

Enhanced immune responses in mice treated with penicillin-tetracycline or trimethoprim-sulfamethoxazole when colonized intragastrically with Candida albicans.

Immune consequences of gastrointestinal colonization of CD-1 and CBA/J mice with Candida albicans in the presence or absence of continuous antibiotic treatment with penicillin-tetracycline or trimethoprimsulfamethoxazole were investigated. Intubation with C. albicans in the absence of antibiotics resulted in the induction of low but detectable delayed-type hypersensitivity (DTH), demonstrable by footpad testing with a C. albicans wall glycoprotein (GP), and in the stimulation of a moderate level of protective immunity, demonstrable by intravenous (i.v.) challenge. DTH to a membrane extract, BEX, could not be detected in such animals. However, animals colonized in the presence of antibiotics and then inoculated cutaneously prior to being tested for DTH or protective immunity developed significantly enhanced levels of DTH to GP and BEX and were protected to an even greater extent than animals colonized in the absence of antibiotics who were not inoculated cutaneously. The priming effect of colonization, particularly with respect to the antigen GP, was also obvious from an enzyme-linked immunosorbent assay for GP-specific antibody with sera of mice surviving the i.v. challenge, in that GP-specific antibody was present in the highest titers in colonized animals that had been inoculated cutaneously prior to i.v. challenge. While the antibiotics promoted higher levels of colonization, as evidenced by stomach and fecal cultures of intubated mice, antibiotic administration was not necessary for the induction of C. albicans-specific responses. Moreover, contrary to reports in the literature, antibiotic administration had no adverse effect on the immune responses measured. Females were innately more resistant than males to i.v. challenge with C. albicans, but each sex was capable of developing protective immunity of equal intensity in response to colonization or immunization by cutaneous challenge.

Animals↗
PubMed1987

Enhancement of non-Candida antibody responses by Candida albicans cell wall glycoprotein.

Two cell wall glycoprotein extracts from Candida albicans (glycoprotein [GP] and peptidoglucomannan [PGM]) were tested for their influence on antibody responses to type III pneumococcal polysaccharide and sheep erythrocytes. GP was isolated from lipid-extracted cell walls with ethylenediamine, whereas PGM was extracted with dilute sodium hydroxide. Both glycoproteins increased the number of antibody-producing plaque-forming cells in the spleens of mice immunized with type III polysaccharide or sheep erythrocytes, although PGM appeared to be about 10 times more effective. PGM could be administered up to 3 days prior to immunization with sheep erythrocytes to elicit enhancement; it did not have to be administered by the same route as the immunogen to cause significant enhancement. Enhancement did not appear to be the result of a direct mitogenic effect of GP and PGM on lymphocytes, nor did these glycoproteins appear to stimulate the production of B-cell growth factors or interleukin 2.

Adjuvants, Immunologic↗
PubMed1986

Separation of immunomodulatory effects of mannan from Candida albicans into stimulatory and suppressive components.

Mannan extracted from Candida albicans was studied for its immunomodulatory activity on in vivo antibody responses to type III pneumococcal polysaccharide (SSS-III), a helper-T-cell-independent antigen, and to sheep erythrocytes (SRBC), a helper-T-cell-dependent antigen. In some studies, the antibody response to SSS-III was converted to a helper-T-cell-dependent response by attaching it to a carrier (horse erythrocytes, HRBC); this complex then was used to immunize mice primed with a subimmunogenic dose of HRBC. Mannan enhanced the antibody response to both SSS-III and SRBC when administered at the same time or 1 or 2 days after immunogen. However, when both mannan and SSS-III were coated onto HRBC for immunization, either enhancement or suppression was noted; the effect depended upon the amount of mannan used. Larger amounts stimulated, whereas smaller amounts suppressed, the antibody response to SSS-III. The enhancing and suppressive components of mannan could be separated by molecular size or charge by chromatography on Sepharose 4B or on DEAE-Sephadex A-50 columns, indicating that mannan extracts contain individual components having opposing immunomodulatory properties. These components can be separated on the basis of molecular size and charge.

Animals↗
PubMed1986

Innate and acquired immune responses against Candida albicans in congenic B10.D2 mice with deficiency of the C5 complement component.

Congenic mice, sufficient or deficient with respect to the C5 component of complement, were evaluated for their innate and acquired immune responses to Candida albicans. When unimmunized mice were challenged intravenously and sacrificed at intervals for cultural analyses of kidneys, it was clear that C5-sufficient mice were able to deal more effectively with C. albicans during the first week after challenge than C5-deficient mice. When immunized mice were challenged intravenously to assess the development of protective responses, an intact complement cascade appeared to contribute to the more rapid clearance of fungi during the first few weeks following challenge, but by the fourth week after challenge, the numbers of fungi had decreased significantly in both types of mice and were at levels which were not significantly different. No significant differences were detected in the development of delayed hypersensitivity or Candida-specific antibody between C5-sufficient and C5-deficient mice either. C5-deficient mice did have slightly elevated levels over the C5+ mice, but this may simply reflect the prolonged antigenic load during the first 3 weeks following intravenous challenge in both immune and nonimmune animals. The later-acting complement components, while appearing to contribute to the early inhibition of the growth of C. albicans in the nonimmune animal, had no adverse effect on the development of specific immune responses, in that delayed hypersensitive responses were equivalent between the two groups, antibody response was not significantly altered and the ultimate outcome of challenge in immunized animals was not affected.

Animals↗
PubMed1985

Immunoregulation in experimental murine candidiasis: specific suppression induced by Candida albicans cell wall glycoprotein.

Immune regulation in candidiasis is inferred from studies of both human and animal infection, with a suppressive role suggested for cell wall polysaccharide. To study the immunosuppressive potential of Candida albicans in a murine model, whole blastoconidia or purified cell wall components of C. albicans were tested for their effects on the development of acquired immune responses by superimposing a pretreatment regimen upon an established immunization protocol. CBA/J or BALB/cByJ mice were pretreated twice intravenously with 100 micrograms of mannan (MAN), 100 or 200 micrograms of glycoprotein (GP), or 5 X 10(7) heat-killed C. albicans blastoconidia, followed 1 week later by an immunization protocol of two cutaneous inoculations of viable C. albicans blastoconidia given 2 weeks apart. Delayed hypersensitivity (DTH) to GP or to a membrane-derived antigen, B-HEX, was tested 7 days after the second inoculation, and lymphocyte stimulation was tested with mitogens and Candida antigens after 12 days. To assess protection, mice were challenged intravenously with viable C. albicans blastoconidia 14 days after the second cutaneous inoculation and sacrificed 28 days later for quantitative culture of kidneys and brains. Sera were obtained for enzyme-linked immunosorbent assays at selected intervals. Pretreatment with GP resulted in specific in vivo suppression of DTH to GP but not to B-HEX antigen and specific in vitro suppression of lymphocyte stimulation to GP but not to other Candida antigens or mitogens. MAN and heat-killed C. albicans blastoconidia had no such effects. GP pretreatment also diminished the protective effect of immunization against challenge, demonstrable in the brain, while not altering significantly the production of antibody in response to infection. Contrary to clinical evidence, MAN was not immunosuppressive in this model, and in fact, the immunosuppressive potential of GP, which is composed largely of MAN, was found to be dependent upon the presence of its heat-labile protein moiety.

Animals↗
PubMed1985

Chemical and enzymatic variation in the cell walls of pathogenic Candida species.

Cell walls, isolated from seven pathogenic species of Candida, were lipid extracted and fractionated by treatment with ethylenediamine or enzymatically hydrolyzed using chitinase and laminarinase. Two different chitinase preparations were used, one from Streptomyces sp. which had some beta-1,3-glucanase activity, and another from Serratia marcescens which did not have glucanase activity. Laminarinase was a commercial preparation. The monosaccharide constituents of whole cell walls and the fractions derived from them were determined qualitatively and quantitatively by gas-liquid chromatography of the products of a mild acid hydrolysis and by the phenol - sulfuric acid assay of the products of a stronger acid hydrolysis. The monomeric constituents of the enzymatic hydrolyses were analyzed using gas-liquid chromatography. Approximately 50% of all walls was soluble in ethylenediamine. Glucose and mannose were the only monosaccharides found in all of the fractions derived from ethylenediamine extraction examined. Similarities among the strains, based upon relative amounts of glucose and mannose, were more apparent than differences, but statistical analyses of the data revealed a general trend of decreasing similarity in the following order, C. albicans and C. stellatoidea, C. tropicalis and C. parapsilosis, and C. pseudotropicalis, C. guilliermondii, and C. krusei. In the enzymatic assays, mannose and glucose were released by laminarinase, whereas glucose and N-acetyl-D-glucosamine or N-acetyl-D-glucosamine alone were released by the chitinases. These assays supported the trend in relationships cited above, with the data being somewhat more definitive.

Acetylglucosamine↗
PubMed1984

Immunodeficient CBA/N mice respond effectively to Candida albicans.

An immune defect in CBA/N mice diminishes their ability to respond adequately to certain well-defined antigens. Since the contribution of T and B cells to immunity in candidiasis has not been clearly defined, it was hoped that CBA/N mice might prove a useful model for the study of specific responses to Candida albicans. Therefore, immunodeficient CBA/N and immunocompetent CBA/J mice were immunized by two cutaneous inoculations of viable C. albicans B311 given 2 weeks apart and challenged iv 14 days after the second inoculation. Delayed-type hypersensitivity (DTH) was tested with a membrane-derived antigen (B-HEX) 7 days following the second inoculation, and lymphocyte stimulation with B-HEX, a cytoplasmic antigen (SCS), and mitogens was done at 12 days. Antibody to SCS was determined by ELISA 2 days after DTH testing and 28 days after iv challenge, at which time the animals were sacrificed for quantitative culture of kidneys and brains. Naive CBA/N mice were no more susceptible to challenge than CBA/J mice in that the mean log colony-forming units (CFU) were 3.79 and 5.48, respectively. Both strains responded to immunization by a similar reduction in CFU, a marked DTH response (e.g., reactions at 24 hr were 1.12 mm for CBA/N and 1.34 mm for CBA/J), and significant and similar quantities of antibody. The immune defect in CBA/N mice had no demonstrable effect on the development of immune responses to infection with C. albicans.

Animals↗
PubMed1983

Control of systemic spread of Candida albicans with ketoconazole in the stomachs of mice treated with cytarabine.

Attempts were made to colonize the gastrointestinal tract of outbred CD-1 mice with Candida albicans or Candida tropicalis before assessing the effects of cytarabine and ketoconazole on colonization. Stable populations of C. albicans but not C. tropicalis could be maintained in the stomachs of mice infected as adults if they were maintained on penicillin and tetracycline, or in untreated mice if the fungus was administered while they were infants. Treatment with cytarabine of mice colonized with C. albicans resulted in increased levels of yeast in the stomach, and small numbers of yeasts were recovered from the livers, kidneys, and spleens. Ketoconazole limited the multiplication of the yeast in the stomachs of colonized mice, although the effect was somewhat variable. Systemic spread of the fungus was essentially eliminated in animals receiving both ketoconazole and cytarabine, suggesting that ketoconazole may be an appropriate prophylactic agent for individuals undergoing therapy with cytarabine.

Animals↗
PubMed1983

Cellular immunity in a cutaneous model of cryptococcosis.

The temporal development of cellular immune responses in mice inoculated cutaneously with viable Cryptococcus neoformans 145 was determined in vivo and in vitro by comparing several antigen preparations for their efficacy in the assays selected. Three antigens derived from C. neoformans 145, viz., a culture filtrate preparation (CneF-145), a membrane extract (B-HEX), and soluble cytoplasmic substances (SCS), were compared for their ability to detect delayed hypersensitivity (DH) in vivo in a footpad assay or to stimulate lymphocytes in vitro in a thymidine incorporation assay. DH to B-HEX could be demonstrated as early as 1 week after infection, whereas significant responses to SCS and CneF-145 were not regularly detected until 3 weeks after infection. Substantial reactions were observed to all three antigens up to 12 weeks, although they peaked at 2 to 3 weeks. Reactions to B-HEX and SCS were somewhat better than those to CneF. Differences in the efficacies of the three antigens were not obvious after the sixth week of infection, however. In vitro, lymph node cells from infected animals were stimulated significantly with all three antigens beginning at week 1. As with DH, however, responses to CneF-145 were usually less than those to SCS and B-HEX. In vitro lymphocyte responses waned after approximately 6 weeks, whereas DH responses were clearly positive through 12 weeks. In addition to the studies in infected animals, animals immunized with heat-killed cells of C. neoformans 145 or 184 were tested 6 to 8 days later for DH with CneF-145, CneF-184, or B-HEX derived from C. neoformans 145. The CneF-145 and CneF-184 were equally effective for detecting DH, regardless of the cryptococcal strain used for immunization. Likewise, the B-HEX detected equivalent responses in mice sensitized with each cryptococcal strain. Since all three antigens were soluble and easily extracted and since each elicited significant cellular immune responses in infected animals, further studies involving their specificity and the nature of their reactive components seems warranted as they may help evaluate immune responses in humans infected with this fungus.

Animals↗
PubMed1982

Immunization of mice by intracutaneous inoculation with viable virulent Cryptococcus neoformans: immunological and histopathological parameters.

Immune responses, including protection and delayed hypersensitivity, were evaluated in experimental murine cryptococcosis. Mice were immunized by the intracutaneous inoculation of viable virulent Cryptococcus neoformans yeasts. Response to the cutaneous infection was evaluated histologically and by cultural assays of the internal organs, as well as by intravenous challenge with the same strain. Protection was assessed by survival, histopathology, and quantitative organ culture. The intracutaneous inoculation of cryptococci resulted in a local inflammatory response that effectively limited dissemination of the organisms systemically and induced the development of delayed hypersensitivity demonstrable with a membrane extract of C. neoformans and with soluble cytoplasmic substances. A protective response was induced by the cutaneous inoculation of cryptococci as well, in that immunized animals survived longer, with about 25% of the challenged group ridding themselves completely of the cryptococci. Protection could be demonstrated by cultural analyses, but all animals, whether control or immunized, allowed considerable multiplication of the inoculum during the first 4 weeks after intravenous challenge. It would appear, therefore, that the protective mechanism(s) required additional antigenic stimulation before it could eventually function to eliminate all cryptococci from tissues. Histologically, there were no differences in pathology of the internal organs between immunized and unimmunized animals. Although the model described herein for the induction of immune responses in murine cryptococcosis has at least one drawback, viz., the presence of cryptococci in the skin lesion of many animals throughout the duration of the experiment, it does have the advantage that the immune responses were stimulated by a virulent strain and only minimal dissemination occurred. Therefore, lymphocytes could be removed from animals that were not contaminated with cryptococci for in vitro and in vivo transfer.

Animals↗
PubMed1982

Mammary gland contamination as a means of establishing long-term gastrointestinal colonization of infant mice with Candida albicans.

Infant outbred CD-1 mice were infected intragastrically with Candida albicans by inoculating the mammary glands of the lactating mothers with viable blastospores and allowing the infants to suckle. Levels of colonization were determined by quantitative cultures of stomachs and selected organs at various intervals up to 6 weeks after infection. The results demonstrate that a high percentage of infant mice can be colonized in this manner and that the colonization is of long duration. Although systemic spread of the yeast to other visceral organs did occur, the numbers of yeasts recovered were minimal.

Animals↗
PubMed1982

Immune responses to Candida albicans in genetically distinct mice.

Mice from six genetically distinct strains were examined for their immune responses to Candida albicans in in vitro and in vivo assays, and naive mice and mice immunized with the fungus were challenged intravenously with three different doses of C. albicans to determine differences in susceptibility. Naive mice from the six groups showed substantial differences in resistance to challenge based on mortalities and quantitative cultures of kidneys, with mice from strains C57BL/6J and BALB/cByJ showing the most resistance; mice from strains A/J, C3H/HeJ, and CBA/J showing moderate susceptibility; and mice from strain DBA/2J showing the highest degree of susceptibility to challenge. Unimmunized mice from strains C57BL/6J and BALB/cByJ did not produce detectable levels of Candida-specific antibody by the end of the 28-day observation period when challenged intravenously, but the other strains did. Immunized mice showed a degree of protection to challenge, with all groups except mice from strain BALB/cByJ showing a reduction of two to three log units in the level of colonization in their kidneys and all strains producing significant levels of antibody. Additionally, the immunized mice of all strains developed substantial levels of delayed-type hypersensitivity and demonstrated nearly identical lymphocyte proliferative responses to Candida antigens. The results indicate that resistance to systemic candidiasis is dependent upon a combination of innate factors, predominately an intact complement system, and the acquisition of an immune response, most likely of a cell-mediated type. Additionally, the findings suggest that genetic control of acquired resistance to C. albicans may not be associated with the H-2 complex.

Animals↗
PubMed1981

Immunological relatedness among Candida albicans and other pathogenic Candida species.

Membrane-mitochondrial (butanol-hot phosphate-buffered saline) and cytosol (soluble cytoplasmic substances) extracts from seven pathogenic species of Candida were used in in vivo and in vitro immunological assays to study antigenic similarities among the strains with respect to C. albicans. Mice were sensitized with C. albicans serotype A for footpad testing or to provide cells for lymphocyte stimulation assays, and guinea pigs were immunized with whole cells or butanol-hot phosphate-buffered saline extracts of C. albicans to obtain antisera for immunodiffusion assays. When extracts from each of the seven species were used in the assays, they consistently segregated, as determined by statistical or subjective analyses, into three groups. Extracts of C. albicans serotype A or B and C. stellatoidea were the most immunologically reactive in all assays, indicating close similarities between those two species, whereas extracts of C. tropicalis and C. parapsilosis elicited only moderate responses. Extracts from C. krusei, C. guilliermondii, and C. pseudotropicalis were hypo- or nonreactive in the assays, indicating a low level of antigenic relatedness to C. albicans.

Animals↗
PubMed1980

Experimental murine candidiasis: cell-mediated immunity after cutaneous challenge.

Male CBA/J mice, sensitized by cutaneous inoculation with viable Candida albicans blastospores, were used to study in vivo and in vitro cellular immune responses. Three antigens of C. albicans, viz., a cell wall glycoprotein (GP), a membrane extract (ppt-HEX), and soluble cytoplasmic substances (SCS), were used in vitro in a lymphocyte stimulation assay, whereas the GP and ppt-HEX were used in vivo to detect delayed hypersensitivity by the footpad assay. Delayed hypersensitivity to GP and ppt-HEX was transferred from sensitized donors to naive recipients with peritoneal exudate cells and not with serum. Moreover, the transfer of the reactivity to ppt-HEX was abrogated by the prior treatment of the transfer suspension with anti-theta 1.2 serum and complement. The in vitro lymphocyte response to GP and ppt-HEX correlated qualitatively with the in vivo responses. SCS, a preparation shown to be ineffective in vivo previously, did stimulate lymphocytes from sensitized animals in vitro. The in vitro response to Candida antigens, as well as phytohemagglutinin, was abolished by treatment of the lymphocyte suspension with anti-thymocyte 1.2 serum before assay, whereas anti-immunoglobulin serum had less effect on these responses. The in vivo and in vitro reactivity to the Candida antigens, therefore, was dependent upon viable T-lymphocytes. Preliminary specificity studies were carried out in the lymphocyte stimulation assay, using lymphocytes from mice infected with C. albicans tested against ppt-HEX preparations extracted from two other species of Candida, C. tropicalis and C. guillermondii, and from two other pathogenic yeast forms, Histoplasma capsulatum and Blastomyces dermatitidis. Significant cross-reactivity was observed with C. tropicalis only, a species which is known to be serologically related to C. albicans.

Animals↗
PubMed1980

Effects of cyclophosphamide on murine candidiasis.

Male CBA/J mice were given a single dose of 200 mg of cyclophosphamide (CY) per kg 3 days before a first or second cutaneous inoculation with viable Candida albicans in an attempt to suppress antibody formation and determine the effects of such suppression on the development of acquired immunity. After cutaneous inoculation, mice not treated with CY developed acquired immunity to intravenous challenge, which was accompanied by the development of circulating antibodies, delayed hypersensitivity, and in vitro responsiveness of lymph node cells to Candida antigens. CY treatment resulted in an immediate depression of peripheral blood leukocytes, with polymorphonuclear leukocytes and monocytes rebounding quickly to normal or above normal levels while lymphocyte remained depressed throughout the 4-week observation period. In vitro stimulation of lymph node cells from CY-treated mice was depressed shortly after treatment; however, responses to phytohemagglutinin and three Candida antigens (a cell wall preparation, a membrane preparation, and soluble cytoplasmic substances) recovered, whereas the responses to lipopolysaccharide did not. CY effects on the cutaneous lesion were twofold; first, the number of viable Candida cells in the lesions was much higher in animals receiving CY 3 days before Candida inoculation, and second, the size of the dermal lesion was either greatly enhanced or reduced depending upon the time of CY treatment relative to the number of cutaneous Candida inoculations. CY-treated animals developed higher levels of delayed hypersensitivity to the membrane preparation when infected once cutaneously than did corresponding untreated animals. The number of mice responding with circulating antibodies to soluble cytoplasmic substances after cutaneous inoculation was greatly reduced in CY-treated groups, and this impaired ability to produce antibodies correlated with the poor survival of these mice after intravenous challenge. Our results suggest that the ability to produce antibody at the time of challenge is crucial to successful defense against systemic candidiasis in this murine model.

Animals↗
PubMed1978

Experimental murine candidiasis: pathological and immune responses to cutaneous inoculation with Candida albicans.

Cutaneous infection of mice with Candida albicans elicited a predominantly acute inflammatory response, stimulated the production of precipitating antibodies, and conferred protection against subsequent intravenous challenge with the same organism. The acute inflammatory skin reaction seen after cutaneous infection suggested a predominantly humoral response to Candida. Animals infected cutaneously a second time with viable C. albicans developed larger skin lesions than animals infected only once, and the twice-infected animals were more resistant to an intravenous challenge as well. The cutaneous inoculation of mice with heat-killed C. albicans was less effective in stimulating antibody production, in eliciting the inflammatory response, and in inducing a protective response demonstrable by intravenous challenge with viable Candida. This model of experimental candidiasis represents a reproducible means of studying a protective immune response to the organism.

Animals↗