ovalbumin and Intestinal-Diseases--Parasitic

The impact of endemic parasitic infection on vaccine efficacy is an important consideration for vaccine development and deployment. We have examined whether intestinal infection with the natural murine helminth Heligmosomoides polygyrus bakeri alters Ag-specific Ab and cellular immune responses to oral and parenteral vaccination in mice. Oral vaccination of mice with a clinically relevant, live, attenuated, recombinant Salmonella vaccine expressing chicken egg OVA (Salmonella-OVA) induced the accumulation of activated, OVA-specific T effector cells rather than OVA-specific regulatory T cells in the GALT. Intestinal helminth infection significantly reduced Th1-skewed Ab responses to oral vaccination with Salmonella-OVA. Activated, adoptively transferred, OVA-specific CD4+ T cells accumulated in draining mesenteric lymph nodes of vaccinated mice, regardless of their helminth infection status. However, helminth infection increased the frequencies of adoptively transferred OVA-specific CD4+ T cells producing IL-4 and IL-10 in the mesenteric lymph node. Ab responses to the oral Salmonella-OVA vaccine were reduced in helminth-free mice adoptively transferred with OVA-specific CD4+ T cells harvested from mice with intestinal helminth infection. Intestinal helminth infection also significantly reduced Th2-skewed Ab responses to parenteral vaccination with OVA adsorbed to alum. These findings suggest that vaccine-specific CD4+ T cells induced in the context of helminth infection retain durable immunomodulatory properties and may promote blunted Ab responses to vaccination. They also underscore the potential need to treat parasitic infection before mass vaccination campaigns in helminth-endemic areas.

Topics: Animals; CD4-Positive T-Lymphocytes; Helminthiasis; Intestinal Diseases, Parasitic; Mice; Mice, Inbred BALB C; Ovalbumin; Vaccine Efficacy; Vaccines, Synthetic

The vitamin D receptor participates in the control of IgE class-switch recombination in B cells. The physiologic vitamin D receptor agonist, 1,25(OH)

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Animals; B-Lymphocytes; Bone Marrow; Calcitriol; Female; Helminthiasis, Animal; Immunoglobulin Class Switching; Immunoglobulin E; Immunoglobulin G; Intestinal Diseases, Parasitic; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Knockout; Nematospiroides dubius; Organ Specificity; Ovalbumin; Receptors, Calcitriol; Spleen; T-Lymphocytes; Vitamin D Deficiency

We have previously found that co-immunisation with ovalbumin (OVA) and the body fluid of the helminth Ascaris suum inhibited an OVA-specific delayed type hypersensitivity (DTH) response by reducing OVA-specific CD4+ T lymphocyte proliferation via an IL-4 independent mechanism. In the present study, we determined whether parasite infections themselves could induce similar changes to peripheral immunisation by examining the modulation of OVA-specific immune responses during acute and chronic helminth infections. Surprisingly, an acute infection with Trichinella spiralis, but not a chronic infection with Heligmosomoides polygyrus, inhibited the OVA-specific DTH reaction. Correspondingly, the T helper 1 (Th1) OVA-specific response was decreased in mice infected with T. spiralis, but not with H. polygyrus. Inhibition of the Th1 response may be a result of a shift in the Th1/Th2 balance as although both H. polygyrus and T. spiralis infected mice induced a Th2 OVA-specific response, that exhibited by T. spiralis was more potent. Furthermore, although IL-10 secretion upon OVA restimulation was similarly increased by both infections, production of this immunoregulatory cytokine may play a role in the suppression of immune responses observed with T. spiralis infection depending on the context of its release. Interestingly, analysis of the OVA-specific T lymphocyte division by carboxyfluorescein diacetate succinimidyl ester (CFSE) staining revealed that gastro-intestinal infection with the acute helminth T. spiralis, but not with chronic H. polygyrus, inhibited the systemic immune response by significantly inhibiting the antigen-specific T cell proliferation during the primary response, a mechanism similar to that observed when A. suum parasite extracts were directly mixed with the OVA during immunisation in our previous studies.

Topics: Acute Disease; Adoptive Transfer; Animals; Antigens, Helminth; CD4 Lymphocyte Count; Chronic Disease; Female; Helminthiasis; Hypersensitivity, Delayed; Immune Tolerance; Intestinal Diseases, Parasitic; Mice; Mice, Transgenic; Models, Animal; Nematospiroides dubius; Ovalbumin; Strongylida Infections; Th1 Cells; Th2 Cells; Trichinella spiralis; Trichinellosis

In these studies, we examined the effects of OX40 ligand (OX40L) deficiency on the development of Th2 cells during the Th2 immune response to the intestinal nematode parasite Heligmosomoides polygyrus. Elevations in IL-4 production and total and Ag-specific serum IgE levels were partially inhibited during both the primary and memory immune responses to H. polygyrus in OX40L(-/-) mice. The host-protective memory response was compromised in OX40L(-/-) mice, as decreased worm expulsion and increased egg production were observed compared with H. polygyrus-inoculated OX40L(+/+) mice. To further examine the nature of the IL-4 defect during priming, adoptively transferred DO11.10 T cells were analyzed in the context of the H. polygyrus response. Although Ag-specific T cell IL-4 production was reduced in the OX40L(-/-) mice following immunization with OVA peptide plus H. polygyrus, Ag-specific T cell expansion, cell cycle progression, CXCR5 expression, and migration were comparable between OX40L(+/+) and OX40L(-/-) mice inoculated with OVA and H. polygyrus. These studies suggest an important role for OX40/OX40L interactions in specifically promoting IL-4 production, as well as associated IgE elevations, in Th2 responses to H. polygyrus. However, OX40L interactions were not required for serum IgG1 elevations, increases in germinal center formation, and Ag-specific Th2 cell expansion and migration to the B cell zone.

Topics: Amino Acid Sequence; Animals; Antigens, Helminth; B-Lymphocyte Subsets; Cell Cycle; Cell Movement; Chemokines, CXC; Epitopes, T-Lymphocyte; Germinal Center; Host-Parasite Interactions; Immunity, Innate; Immunization, Secondary; Immunoglobulin E; Immunoglobulin G; Injections, Subcutaneous; Interleukin-4; Intestinal Diseases, Parasitic; Ligands; Lymph Nodes; Lymphocyte Activation; Membrane Glycoproteins; Mice; Mice, Inbred BALB C; Mice, Knockout; Mice, Transgenic; Molecular Sequence Data; Neck; Nematospiroides dubius; Ovalbumin; OX40 Ligand; Peptide Fragments; Receptors, Chemokine; Receptors, CXCR5; Receptors, Cytokine; Receptors, OX40; Receptors, Tumor Necrosis Factor; Strongylida Infections; Th2 Cells; Tumor Necrosis Factor Receptor Superfamily, Member 7; Tumor Necrosis Factors; Up-Regulation

Although in vitro development of a Th2 response from naive CD4+ T cells is Stat6 dependent, mice immunized with a goat Ab to mouse IgD have been reported to produce a normal primary IL-4 response in Stat6-deficient mice. Experiments have now been performed with mice immunized with more conventional Ags or inoculated with nematode parasites to account for this apparent discrepancy. The ability of an immunogen to induce a primary in vivo IL-4 response in Stat6-deficient mice was found to vary directly with its ability to induce a strong type 2 cytokine-biased response in normal mice. Even immunogens, however, that induce strong primary IL-4 responses in Stat6-deficient mice induce poor memory IL-4 responses in these mice. Consistent with this, Stat6-deficient CD4+ T cells make relatively normal IL-4 responses when stimulated in vitro for 3 days with anti-CD3 and anti-CD28, but poor IL-4 responses if they are later restimulated with anti-CD3. Thus, Stat6 signaling enhances primary IL-4 responses that are made as part of a type 0 cytokine response (mixed type 1 and type 2) and is required for normal development or survival of Th2 memory cells.

Topics: Animals; Antibodies; Antibodies, Monoclonal; CD3 Complex; CD4-Positive T-Lymphocytes; Chickens; Female; Goats; Immunoglobulin D; Immunologic Memory; Injections, Intravenous; Interleukin-4; Intestinal Diseases, Parasitic; Male; Mast Cells; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Nematospiroides dubius; Nippostrongylus; Ovalbumin; Receptors, Interleukin-4; Signal Transduction; STAT6 Transcription Factor; Strongylida Infections; Th2 Cells; Trans-Activators; Trichinella spiralis; Trichinellosis

Oral administration of soluble protein Ags typically induces Ag-specific systemic nonresponsiveness. However, we have found that feeding a model food protein, OVA, to helminth-infected mice primes for a systemic OVA-specific Th2 response. In this report we show that, in addition to creating a Th2-priming cytokine environment, helminth infection up-regulates costimulatory molecule expression on mucosal, but not peripheral, APCs. To examine the consequences of mucosal infection for the T cell response to orally administered Ag, we adoptively transferred transgenic, OVA-specific, T cells into normal mice. We found that helminth infection enhances the expansion and survival of transgenic T cells induced by Ag feeding. Transfer of 5,6-carboxyfluorescein diacetate succinimidyl ester-labeled donor cells showed that T cell proliferation in response to Ag feeding takes place primarily in the mesenteric lymph nodes. Upon subsequent peripheral exposure to Ag in adjuvant, the proliferative capacity of the transferred transgenic T cells was reduced in noninfected mice that had been fed OVA. Helminth infection abrogated this reduction in proliferative capacity. Our data suggests that enteric infection can act as an adjuvant for the response to dietary Ags and has implications for allergic responses to food and the efficacy of oral vaccination.

Topics: Adjuvants, Immunologic; Adoptive Transfer; Animals; Antigen-Presenting Cells; Antigens; Antigens, CD; B7-1 Antigen; B7-2 Antigen; CD4-Positive T-Lymphocytes; Chickens; Down-Regulation; Eating; Epitopes, T-Lymphocyte; Freund's Adjuvant; Intestinal Diseases, Parasitic; Intestinal Mucosa; Lipids; Lymph Nodes; Lymphocyte Activation; Lymphoid Tissue; Membrane Glycoproteins; Mesentery; Mice; Mice, Inbred BALB C; Mice, Transgenic; Models, Immunological; Nematospiroides dubius; Ovalbumin; Receptors, Antigen, T-Cell; Strongylida Infections; T-Lymphocyte Subsets; Up-Regulation

Lambs weaned at eight weeks old were compared with control lambs which remained with their dams; both groups grazed the same pasture. Weaning significantly reduced the growth rate, control lambs being, on average, 6 kg heavier than weaned lambs at 15 weeks old. When contamination of pasture with larval parasites was light, both groups of lambs suffered only modest parasitic infections. When lambs were experimentally infected with 5000 Haemonchus contortus and 10,000 Trichostrongylus colubriformis larvae at eight weeks old, the mean faecal egg count for weaned lambs was twice that for controls at 12 weeks old (P less than 0.001) and weaned lambs suffered a significantly greater decline in packed cell volume than controls over the next four weeks. Antibody responses following immunisation with either ovalbumin or Brucella abortus at four and at eight weeks old, did not differ significantly between control and weaned lambs. In contrast serum antibody responses to H contortus and T colubriformis differed significantly between the two groups, with controls responding earlier and more strongly than weaned lambs. The practical significance of these findings is that up to three months old, suckled lambs, when faced with a substantial parasite challenge, have much better prospects than weaned lambs.

Topics: Animals; Antibodies, Helminth; Antibody Formation; Body Weight; Brucella abortus; Feces; Haemonchiasis; Haemonchus; Intestinal Diseases, Parasitic; Ovalbumin; Parasite Egg Count; Sheep; Sheep Diseases; Trichostrongylosis; Trichostrongylus; Weaning

In these studies we compared jejunal permeability to two probes--chromium 51-labeled ethylenediaminetetraacetic acid (51Cr-EDTA) (mol wt, 360) and ovalbumin (mol wt, 45,000)--under control conditions, during acute intestinal inflammation, and in response to systemic anaphylaxis. Acute inflammation was produced after infection with Nippostrongylus brasiliensis and rats were studied at day 0 (control), day 4 (early), day 10 (acute), and day 35 (postinfection). At the latter stage, immune rats were also studied during anaphylaxis induced by i.v. N. brasiliensis antigen. In each study, blood and urine were sampled over 5 h after the probes were simultaneously injected into ligated loops in anesthetized rats. In controls, small quantities (less than 0.04% and 0.002% of the administered dose for 51Cr-EDTA and ovalbumin, respectively) appeared in the circulation and plateaued at 1 h. During acute inflammation, the appearance of both probes continued to increase with time. Compared with controls, 5-h values for 51Cr-EDTA and ovalbumin were (a) significantly elevated at day 4 (p less than 0.005), (b) increased approximately 20-fold at day 10 (p less than 0.005 and less than 0.01, respectively), and (c) normal at day 35. Urinary recovery of 51Cr-EDTA followed the same pattern. During anaphylaxis, appearance of the probes in the circulation increased at 1 h to values approximately 10-fold those in controls (p less than 0.001 and less than 0.01, for 51Cr-EDTA and ovalbumin, respectively), and then declined. Urinary recovery of 51Cr-EDTA over 5 h was also significantly increased. We conclude that epithelial barrier function becomes impaired during both acute inflammation and anaphylaxis. In this rat model, gut permeability changes to 51Cr-EDTA reflect gut permeability changes to macromolecular antigens. If similar conditions exist in humans, urinary recovery of 51Cr-EDTA may be useful in monitoring intestinal abnormalities associated with inflammation.

Topics: Acute Disease; Anaphylaxis; Animals; Antigens, Helminth; Chromium Radioisotopes; Edetic Acid; Intestinal Diseases, Parasitic; Jejunal Diseases; Jejunum; Male; Nematode Infections; Nippostrongylus; Ovalbumin; Permeability; Rats; Rats, Inbred Strains