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Some immunological aspects of opisthorchiasis.

Information regarding the development of acquired immunity in opisthorchiasis is particularly relevant if one is attempting eradication of the disease, e.g. by anthelmintic chemotherapy. Clinical observations in patients with opisthorchiasis suggest that if acquired immunity develops at all, it is of low degree. Using hamsters as experimental model, it was recently demonstrated that prior infection with Opisthorchis viverrini failed to confer protection against reinfection, regardless of the size of the challenging dose. These observations are not entirely unexpected because O. viverrini does not normally invade tissues during development in mammalian hosts. Therefore, the chance of stimulating the host immune system is minimal in this infection. In the present study, attempts were made to potentiate the immunity of hamsters with crude somatic extract of O. viverrini, with or without previous infection with 5 metacercariae. The animals were treated by an intraperitoneal injection of 200 micrograms of antigen in complete Freund's adjuvant (CFA) and were challenged with 25 metacercariae (Mc) 3 weeks later. As was to be expected, immunization of animals that had never been infected before did not provoke any immune response against a subsequent challenge infection. On the other hand, immunization of animals that had been infected previously with 5 Mc appeared to have developed some degree of immune response against a subsequent challenge with 25 Mc. Compared with unimmunized infected controls which received only CFA and the 25 Mc challenge, there was about 30% reduction in the worm burden in the group immunized with somatic extract. It is anticipated that with a better method of immunization, a higher degree of protection may be achieved.

Animals↗

A single DH gene segment creates its own unique CDR-H3 repertoire and is sufficient for B cell development and immune function.

To test the contribution of individual D gene segments to B cell development and function, we used gene targeting to create mice that contain only DFL16.1 in the DH locus. We term this D-limited IgH allele DeltaD-DFL. Although the absolute number of IgM+IgD- B cells in the bone marrow was decreased, homozygous DeltaD-DFL BALB/c mice contained normal numbers of IgM+IgD+ B cells in bone marrow and spleen and normal numbers of B1a, B1b, and B2 cells in the peritoneal cavity. Bone marrow IgM+IgD+ B cells express a CDR-H3 repertoire similar in length and amino acid composition to the DFL16.1 subset of the wild-type BALB/c repertoire but divergent from sequences that do not contain DFL16.1. This similarity in content is the product of both germline bias and somatic selection, especially in the transition to the mature IgM+IgD+ stage of development. Serum Ig concentrations and the humoral immune response to a T-dependent Ag ([4-hydroxy-3-nitrophenyl]acetyl hapten) were nearly identical to wild-type littermate controls. A greater variance in the immune response to the T-independent Ag (alpha(1-->3)-dextran) was observed in DeltaD-DFL homozygotes, with half of the mice exhibiting levels below the range exhibited by controls. Although limited to a repertoire specific to DFL16.1, the presence of a single DH gene segment of normal sequence was sufficient for development of normal numbers of mature B cells and for robust humoral immune function.

Amino Acid Sequence↗

Immune system development and function in prolactin receptor-deficient mice.

Prolactin (PRL) is the primary lactogenic pituitary hormone that plays an essential role in many aspects of reproduction, from fertilization to mammary gland development and maternal behavior. PRL has also been reported to play a role in immunoregulation. Because initial observations indicated that hypophysectomized rats present abnormalities of the immune system, including increased thymic atrophy and lymphopenia, a number of studies have focused on the potential immunomodulatory roles of PRL. This hormone exerts its biological activities following binding to specific cell surface PRL receptors (PRLRs). In this report, we have characterized the development and function of the immune system in PRLR-deficient mice. Compared with wild-type control mice, PRLR-/- mice demonstrate no alterations in thymic or splenic cellularity or in the composition of the lymphocyte subsets present in primary (bone marrow and thymus) or secondary (spleen and lymph nodes) lymphoid organs. Lymphocytes from PRLR-/- mice are functional in vitro, as they can proliferate normally to mitogens, cytokines, and allogeneic cells. PRLR-/- splenocytes display normal NK-mediated cytotoxicity to YAC-1 target cells. In vivo studies have revealed that PRLR-/- mice are able to 1) generate normal steady-state Ig levels, 2) mount a normal specific Ig response following immunization with a T-dependent Ag, 3) eliminate injected allogeneic tumor cells, and 4) effectively control Listeria monocytogenes infection. Taken together, these results show that immune system development and function proceed normally in the absence of PRL-mediated signaling and suggest that PRLR pathways are not essential for immunomodulation in vivo.

Animals↗

Analysis of a previous smallpox vaccination study: estimation of the time period required to acquire vaccine-induced immunity as assessed by revaccination.

The time interval required to develop immunity after vaccination, in the event of a bioterrorist attack using variola virus, is yet to be clarified. In this article, a historical vaccination study conducted in Japan in 1929 was re-examined. Forty-four previously vaccinated and 44 unvaccinated children were involved. After successful first round primary (or re-) vaccination, all children underwent revaccination at variable intervals. Absence of a major reaction (vaccine 'take') after revaccination was taken as a sign of immunity conferred by first round primary (or re-) vaccination. Univariate analysis was employed to examine the relationship between vaccine 'take' and the exposure variables. Maximum likelihood estimates of the time period required to develop immunity were obtained using a simple logit model. The interval between vaccinations was significantly associated with vaccine 'take' in both the previously unvaccinated (p < 0.01) and vaccinated (p < 0.01) groups, and the median interval required for immunity after vaccination was estimated to be 6.4 [95% Confidence Interval (CI): 5.8, 7.1] and 4.3 days (95 % CI: 4.1, 4.7), respectively. Obtained estimates were consistent with previous observations, and the logistic fits reasonably explained the discrepancy among previous suggestions. The findings suggest that it is necessary to vaccinate exposed susceptible individuals within 3 days after exposure to ensure disease protection, and within at least 5 days (for those previously unvaccinated) to provide a certain level of protection; the probability shows a dramatic decline hereafter.

Child↗

Development of immunity to porcine rotavirus in piglets protected from disease by bovine colostrum.

Bovine colostrum with rotavirus-neutralizing activity was fed for 10 days to two groups of piglets, one of which was inoculated intranasally with a rotavirus of porcine origin. A third group, which did not receive colostrum, was also inoculated with the virus, and these piglets developed diarrhea, excreted rotavirus in the feces, and died 6 days after infection. In contrast, the infected piglets fed with bovine colostrum remained healthy, although they developed antibody to rotavirus. Twenty-seven days after the primary inoculation, piglets in the colostrum-fed groups were inoculated intranasally with virus. Those in the previously unexposed group became clinically ill and excreted rotavirus, whereas those which had experienced a previous subclinical infection (the colostrum-fed, virus-inoculated group) remained healthy. It was concluded that bovine colostrum protected piglets from the clinical effects of a porcine rotavirus and that these animals developed an immunity which prevented subsequent disease.

Animals↗

Maternal reactivity to fetal alloantigens is related to newborn immune responses and subsequent allergic disease.

BACKGROUND: Maternal allergy confers stronger allergy risk (than paternal allergy) suggesting that maternal patterns of immune response can directly influence immune development in offspring. Women prone to allergic immune responses to allergens may also have altered immune responses to other antigens including fetal antigens. OBJECTIVE: This exploratory study examines relationships between maternal immune responses to fetal antigens and the subsequent risk of allergy. METHODS: Mononuclear cells (MNC) were collected from 36 mother-infant pairs to compare maternal (and fetal) cellular immune responses to alloantigens (fetal, maternal or unrelated donor [URD]), and allergens in allergic (18 pairs) and non-allergic (18 pairs) mothers. Thirty children had documented allergic outcomes at 6 years of age. RESULTS: In this population, allergic outcomes in the offspring were associated more strongly with materno-fetal immune interactions than with a maternal family history of allergy. Specifically, allergic disease at 6 years of age was associated with significantly higher maternal responses to fetal alloantigens (lymphoproliferation, P=0.008; IL-13, P=0.02 and IFN-gamma, P=0.015), whereas associations with maternal allergy did not reach significance (P=0.07). Fetal IFN-gamma alloantigen responses were significantly correlated with the degree of human lymphocyte antigen (HLA) mismatch (maternal HLA class II antibodies) (tau=0.3, P=0.03). The capacity of the fetus to produce IL-13 (tau=0.4, P=0.001) and IL-10 (tau=0.3, P=0.029) was directly related to the level of these cytokines produced by the mother in response to fetal antigens. Allergic mothers showed a non-significant trend for stronger lymphoproliferation to fetal alloantigens. The number of previous pregnancies (gravidity) was associated with stronger maternal responses to fetal alloantigens, as shown by lymphoproliferation (Kendall tau=0.3, P=0.04) and IFN-gamma (tau=0.3, P=0.04) synthesis, but did not affect fetal responses to the various stimuli. CONCLUSIONS: Maternal responses to fetal antigens were related to fetal immune responses and subsequent allergy. This novel observation suggests that events at the materno-fetal interface have an important influence on early immune development and should be investigated further.

Child↗

[The intensity and dynamics of the development of immunity in the administration of experimental corpuscular ozena vaccines].

Experiments on the active protection of mice from ozenous infection in its two forms, generalized (acute sepsis) and local (plantar infiltration), have demonstrated that immunity, induced by experimental heat-killed ozena vaccine (Klebsiella ozaenae strain 2211, antigens 02B:K4) introduced in a single injection, is characterized by sufficiently high intensity (the degree of protection increases up to 10,000-fold) and duration (at least 30 days). In both forms the development of immunity is characterized by a rapid rise of its intensity to the maximum level (achieved by the end of week 1), subsequent decrease by weeks 3-4 and disappearance by days 50-60 after immunization. Immunity becomes more intense with the increase of the number of injections if these injections are separated by sufficient intervals (up to 14 days). The optimum schedule used in the study of postvaccinal immunity to experimental generalized and local ozenous infection consists of the subcutaneous injection of K. ozaenae strain 2211 in a dose of 250-500 million microbial bodies per mouse with the subsequent challenge with the virulent strain on week 2 from the date of immunization.

Animals↗

Costimulation in resistance to infection and development of immune pathology: lessons from toxoplasma.

Parasitic infections remain an important cause of disease worldwide, and it is important to understand how the immune system protects against these organisms. In addition, the study of how the immune system deals with different types of pathogens provides the opportunity to discern how innate and adaptive arms of the immune system interact to provide an integrated protective response. Costimulatory signals are an important element involved in the control of lymphocyte response, and this laboratory studies the role of the costimulatory molecules CD28 and ICOS in the events that lead to resistance to the opportunistic pathogen Toxoplasma gondii as well as the development of immune pathology associated with this infection.

Animals↗

Comparative evaluation of intranasal and subcutaneous route of immunization for development of mucosal vaccine against experimental tuberculosis.

Activation of mucosal immunity in the respiratory tract is crucial for protection against respiratory infections. Whether the intranasal route of vaccination imparts better protection against pulmonary tuberculosis than that of subcutaneous vaccination remains a debatable issue. In this study, we have investigated the effect of the routes of immunization on the induction of immunoprotection against experimental tuberculosis employing mycobacterial culture filtrate proteins complexed with dimethyldioctadecylammonium bromide. Vaccination via intranasal and subcutaneous routes triggered immune activation in the spleen and cervical lymph node, while the former route of vaccination lead to higher antigen-specific lymphocyte proliferation, interferon-gamma, interleukin-12 and interleukin-4 responses in cervical lymph node and induction of antigen-specific IgA responses at mucosal level of the respiratory tract. Mice vaccinated via the intranasal route were found to be better protected against experimental tuberculosis particularly in lung compared to subcutaneous-immunized mice. These results emphasize the importance of the intranasal route vaccination in tuberculosis.

Adjuvants, Immunologic↗

Influences of microbiota on intestinal immune system development.

The normal colonization of the mammalian intestine with commensal microbes is hypothesized to drive the development of the humoral and cellular mucosal immune systems during neonatal life and to maintain the physiologically normal steady state of inflammation in the gut throughout life. Neonatal conventionally reared mice and germ-free, deliberately colonized adult mice (gnotobiotic mice) were used to examine the efficacy of certain intestinal microbes.

Animals↗

[Effects of Bacillus Calmette-Guerin vaccination on immune functional development of splenic T cell in neonatal mice].

OBJECTIVE: Almost every neonate receives Bacillus Calmette-Guerin (BCG) vaccination in China. The authors' previous study showed that BCG promoted cord blood monocyte-derived dendritic cells maturation and induced high level of interleukin (IL)-10, medium level of interferon (IFN)-gamma, but low level of IL-4 production by cord naive T cells. The experiments in the present study were designed to explore the effects of neonatal BCG vaccination on immune functional development of splenic T cells in mice in vivo. METHODS: Neonatal BALB/c mice were inoculated with BCG intraperiotoneally. Four weeks later, spleen cells of mice were isolated and surface molecular markers of CD4, CD25 and CD44 and intracellular IFN-gamma, IL-10, and IL-4 in CD3(+) T cells were detected by flow cytometry. Furthermore, mRNA expression of transcription factor T-bet, Foxp3 and GATA-3 were analyzed by RT-PCR. RESULTS: The percentage of total CD4(+) T cells decreased [(23.50 +/- 2.59)% vs. (47.38 +/- 10.41)%, P < 0.01] but the percentage of CD25(+) [(24.92 +/- 2.74)% vs. (20.27 +/- 2.85)%, P < 0.05] and CD44(+) [(89.29 +/- 2.56)% vs. (82.98 +/- 5.51)%, P < 0.05] T cells in CD4(+) T cells was higher in BCG-vaccinated mice than that in controls. Meanwhile, the percentage of IFN-gamma positive [(6.52 +/- 2.40)% vs. (3.13 +/- 2.03)%, P < 0.05] and IL-10 positive [(14.81 +/- 3.65)% vs. (10.90 +/- 1.61)%, P < 0.05] but not IL-4 positive [(1.17 +/- 0.46)% vs (1.51 +/- 0.75)%, P > 0.05] cells in CD3(+) T cells of BCG-vaccinated mice was significantly higher than that of non-BCG-vaccinated mice. In comparison with BCG-naive mice, T-bet was significantly high in BCG-vaccinated mice [T-bet/beta-actin 0.44 +/- 0.11 vs. 0.28 +/- 0.06, P < 0.05], but there was no significant difference in GATA-3 [GATA-3/beta-actin 0.46 +/- 0.08 vs. 0.50 +/- 0.10,P > 0.05] and Foxp3 [Foxp3/beta-actin vs. 0.27 +/- 0.11 and 0.30 +/- 0.16, P > 0.05] mRNA expression between the two groups. CONCLUSION: Neonatal BCG vaccination could induce strong Th1 but weak Th2 response as reported previously. Though neonatal BCG vaccination was not capable of inducing CD4(+)CD25(+) regulatory T cell response with Foxp3 expression, it caused increase of IL-10(+) CD3(+) cells which might represent some regulatory T cells producing IL-10.

Animals↗

Responses by murine macrophages infected with Listeria monocytogenes crucial for the development of immunity to this pathogen.

Macrophages and other mammalian cells respond to infection with Listeria monocytogenes (L. monocytogenes) by the transient or persistent activation of host cell signal transduction pathways. In addition, L. monocytogenes infection influences expression of various host cell genes, such as stress genes, genes from the MHC I and II complex, cytokine genes, and cytokine receptor genes. The possible influences of the different host cell responses on the outcome of an L. monocytogenes infection in vitro as well as for the development of immunity are discussed.

Animals↗

Regulatory effects of macrophage inflammatory protein 1alpha/CCL3 on the development of immunity to Cryptococcus neoformans depend on expression of early inflammatory cytokines.

Macrophage inflammatory protein 1alpha (MIP-1alpha)/CCL3 prevents the development of eosinophilic pneumonia (EP) driven by a nonprotective T2-type immunity during infection with a highly virulent strain of Cryptococcus neoformans. The present study evaluated the interaction of MIP-1alpha with other innate immune system cytokines by comparing the immune responses that followed pulmonary infections with high- (C. neoformans 145A) and low (C. neoformans 52D)-virulence strains. In contrast to what was found for C. neoformans 145A infection, lack of MIP-1alpha in C. neoformans 52D infection did not cause the development of EP. C. neoformans 52D induced tumor necrosis factor alpha (TNF-alpha), gamma interferon (IFN-gamma), and MCP-1 in the lungs of infected wild-type (WT) and MIP-1alpha knockout (KO) mice by day 7 postinfection. Both WT and MIP-1alpha KO mice subsequently cleared this infection. Thus, the robust expression of early inflammatory cytokines in C. neoformans 52D-infected mice promoted the development of protective immunity even in the absence of MIP-1alpha. Alternatively, C. neoformans 145A-infected WT and MIP-1alpha KO mice had diminished TNF-alpha, IFN-gamma, and macrophage chemoattractant protein 1 (MCP-1) responses, indicating that virulent C. neoformans 145A evaded early innate host defenses. However C. neoformans 145A-infected WT mice had an early induction of MIP-1alpha and subsequently did not develop EP. In contrast, C. neoformans 145A-infected MIP-1alpha KO mice developed EP and had increased C. neoformans dissemination into the brain by day 35. We conclude that, in the absence of other innate immune response effector molecules, MIP-1alpha is crucial to prevent the development of EP and to control C. neoformans dissemination to the brain.

Animals↗

Observations on crystals found in the intestine of Nematodirus battus during the development of immunity to this nematode in lambs.

Lambs which were given 60000 infective larvae of Nematodirus battus progressively threw off adult nematodes from day 20 onwards. Large, hexagonal crystals appeared in the intestine of the adult nematode at about this time and caused blockage of the intestinal-rectal or -cloacal junction. Lambs which were given 1000-2000 infective larvae did not throw off the infection, and adult nematodes from lambs which had been infected for up to 74 days did not contain these crystals. Chemical, histochemical and x-ray microanalysis tests on the crystals indicated that they are lipoprotein in composition. The crystals arise within the lumen of the nematode and appear to be associated with the development of immunity to this nematode in lambs.

Animals↗

Interfering vaccine (defective interfering influenza A virus) protects ferrets from influenza, and allows them to develop solid immunity to reinfection.

Defective interfering (DI) virus RNAs result from major deletions in full-length viral RNAs that occur spontaneously during de novo RNA synthesis. These RNAs are packaged into virions that are by definition non-infectious, and are delivered to cells normally targeted by the virion. DI RNAs can only replicate with the aid of a coinfecting infectious helper virus, but the small size of DI RNA allows more copies of it to be made than of its full-length counterpart, so the cell produces defective virions in place of infectious progeny. In line with this scenario, the expected lethal disease in an influenza A virus-mouse model is made subclinical by administration of DI virus, but animals develop solid immunity to the infecting virus. Hence DI virus has been called an 'interfering vaccine'. Because interfering vaccine acts intracellularly and at a molecular level, it should be effective against all influenza A viruses regardless of subtype. Here we have used the ferret, widely acknowledged as the best model for human influenza. We show that an interfering vaccine with defective RNAs from an H3N8 virus almost completely abolished clinical disease caused by A/Sydney/5/97 (H3N2), with abrogation of fever and significant reductions in clinical signs of illness. Animals recovered fully and were solidly immune to reinfection, in line with the view that treatment converts the otherwise virulent disease into a subclinical and immunizing infection.

Animals↗

Development of immunity against Listeria monocytogenes in athymic nude versus neonatally thymectomized mice.

The thymus requirement for the development of immunological responsiveness was determined by estimation of immune responses raised to Listeria monocytogenes in athymic nude, neonatally thymectomized, and sham-operated mice at 6 weeks of age. Not only sham-operated mice, but also neonatally thymectomized mice could completely eliminate the bacteria from the spleen and liver, while athymic nude mice could not eliminate them and showed a persistent form of infection. A strong delayed footpad reaction and acquired cellular resistance could be raised in neonatally thymectomized mice just as well as in sham-operated mice, but not in athymic nude mice. The delayed footpad reaction could be induced in neonatally thymectomized mice without an accompanying ability to inhibit macrophage migration. These results suggest that T cells responsible for immunity against listerial infection require the presence of the thymus for only a very short period in their development.

Animals↗

[Development of immunizing agents against dengue].

The four serotypes of dengue flaviviruses are transmitted mainly by the Aedes aegypti mosquito, and some epidemics have been attributed to Ae. albopictus, Ae. polynesiensis, and various species of the Ae. scutellaris complex. The risk factors involved in dengue mortality and morbidity are related to the human host (genetic characteristics of infected persons; lifestyles, immune status, and health conditions of people; basic sanitation of dwellings; and water supply) and to the virus (genetic variability between and among serotypes, different pathogenicities, and geographic distribution). Notwithstanding the lack of knowledge of the immunopathobiology of dengue fever, important advances have been made in terms of a protective immune response, using attenuated dengue viruses or antigens produced by means of recombinant technologies. Efforts have been made since the 1940s to develop dengue vaccines. Immunity acquired from natural infection is specific for each serotype, and as many as three different serotype infections have been reported in one individual. For this reason, a tetravalent vaccine may likely be needed. Candidate vaccines against the four serotypes have been tested in volunteers and have proven to be immunogenic and safe. Although attenuated live virus vaccines are promising, more study is needed regarding their effectiveness and safety. Currently, several studies are ongoing to develop dengue vaccines using antigens from structural proteins (particularly E glycoprotein) and nonstructural proteins, with recombinant DNA technology and other biomolecular technologies. With the same goal, various expression vectors are being used, including Escherichia coli, baculovirus, vaccinia virus, and yellow fever virus. Unfortunately, no satisfactory results have been obtained in humans. The need for effective dengue vaccines is great, given the serious worldwide problem of the transmission of the four serotypes. Effective immunization against dengue would contribute to its prevention, with a positive cost-benefit relationship. Endemic dengue affects young children, and they should be immunized through the Expanded Program on Immunization.

Antigens, Viral↗