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PubMed2025

Impact of the maternal microbiome on neonatal immune development.

Historically, multigenerational health and disease transmission have primarily focused on genetic inheritance. However, the discovery that beneficial microorganisms known as commensal microbiota outnumber human genes tenfold has reshaped this perspective, highlighting their critical role in maintaining homeostasis and protecting against pathogens. Unlike the human genome, commensal microbiota is not genetically inherited but is acquired anew with each generation. with initial gut colonization playing a pivotal role in shaping an infant's immune system, neurodevelopment, and long-term health, all heavily influenced by maternal factors. In this review, we examine emerging research on maternal microbial influences on the fetus beginning in utero. We provide an updated overview of the current insights into the impact of the vaginal microbiome during parturition on offspring immunity and discuss the potential long-term health implications for infants born via cesarean section. We explore the advantages and limitations of techniques designed to mitigate these effects, such as vaginal seeding and emphasize that the development of the neonatal immune system is a dynamic process influenced by maternal factors beyond birth, including the transfer of microbiota through breast milk and skin contact. Finally, we present gaps in current research and propose future research directions to deepen our understanding of the impacts of the maternal microbiome on her child. Together, these insights demonstrate how maternal influence on offspring health and immunity extends beyond genetic factors, encompassing the transmission of microbiota, which, in turn, has profound long-term implications for health and disease resilience, offering a novel perspective on intergenerational health dynamics.

Humans↗
PubMed2005

Regenerative capacity and the developing immune system.

Many components of the vertebrate immune system have evolved with dual, interrelated functions of both protecting injured tissues from infection and providing for tissue maintenance and repair of injuries. The capacity for organ regeneration, prominent among invertebrates and certain phylogenically primitive vertebrates, is poorly developed in mammals. We have proposed that evolution of the mammalian immune system has produced inflammatory cellular interactions at sites of injury which have optimized tissue defense and facilitated tissue repair, but that these improvements included concomitant loss of regenerative capacity. This chapter briefly reviews work in two regenerating systems: scar-free repair of fetal mammalian skin and regeneration of amputated limbs in larval frogs. In both organs the potential to regenerate anatomically and functionally complete new structures is lost gradually during ontogeny and this loss coincides with development of an immune system producing an inflammatory response in injured tissues. Failure of organ regeneration has long been associated with scarring or fibrosis and this phenomenon is a direct result of inflammatory interactions of immune cells and fibroblasts at sites of injury. Several aspects of immunity related to repair are reviewed, including the importance of antigen-presenting cells and lymphocytes, relevant cytokines and growth factors released by these and other cells, immune functions of extracellular matrix components, and immunological functions of fibroblasts. Skin repair in various transgenic mouse models has been especially informative. Further study of immune mechanisms associated with the loss of regenerative capacity in the skin and amphibian limb will be useful for efforts to promote mammalian organ regeneration.

Animals↗
PubMed2000

Polysaccharide coated liposomes for oral immunization--development and characterization.

Polysaccharide coated liposomes were prepared, characterized and evaluated for their potential use in oral immunization. Liposomes were prepared by reverse phase evaporation method. Bovine serum albumin (BSA) was chosen as the model antigen. Pulluan, a naturally occurring polysaccharide produced by a yeast like fungus, was chemically modified into its palmitoyl derivative (O-palmitoylpullulan; OPP) and was used for coating of the liposomes. The synthesized OPP was characterized by IR and NMR spectroscopy. The liposomes prepared were characterized for their size, shape, surface charge, encapsulation efficiency and stability in simulated gastric fluid. The immune stimulating activity was studied by measuring the serum IgA and IgG following oral administration of the prepared polysaccharide coated liposomes. Similarly, other formulations were studied and the results were compared. BSA loaded liposomes coated with OPP and plain polysaccharide could produce better IgG and IgA titre levels as compared to plain alum adsorbed BSA. The plain liposomes containing BSA could however produce significantly higher IgG and IgA levels as compared to equivalent BSA-alum based oral immunization. The results indicate that chemically modified polysaccharide coated liposomes can be used as a potential adjuvants for effective oral immunization.

Administration, Oral↗
PubMed2001

Neonatal immunity develops in a transgenic TCR transfer model and reveals a requirement for elevated cell input to achieve organ-specific responses.

In recent years, it has become clear that neonatal exposure to Ag induces rather than ablates T cell immunity. Moreover, rechallenge with the Ag at adult age can trigger secondary responses that are distinct in the lymph node vs the spleen. The question addressed in this report is whether organ-specific secondary responses occur as a result of the diversity of the T cell repertoire or could they arise with homogeneous TCR-transgenic T cells. To test this premise, we used the OVA-specific DO11.10 TCR-transgenic T cells and established a neonatal T cell transfer system suitable for these investigations. In this system, neonatal T cells transferred from 1-day-old DO11.10/SCID mice into newborn (1-day-old) BALB/c mice migrate to the host's spleen and maintain stable frequency. The newborn BALB/c hosts were then given Ig-OVA, an Ig molecule carrying the OVA peptide, and challenged with the OVA peptide in CFA at the age of 7 wk; then their secondary responses were analyzed. The findings show that the lymph node T cells were deviated and produced IL-4 instead of IFN-gamma and the splenic T cells, although unable to proliferate or produce IFN-gamma, secreted a significant level of IL-2. Supply of exogenous IL-12 during Ag stimulation restores both proliferation and IFN-gamma production by the splenic T cells. This restorable form of splenic unresponsiveness referred to as IFN-gamma-dependent anergy required a transfer of a high number of neonatal DO11.10/SCID T cells to develop. Thus, the frequency of neonatal T cell precursors rather than repertoire diversity exerts control on the development of organ-specific neonatal immunity.

Amino Acid Sequence↗
PubMed2004

Childhood infections, the developing immune system, and the origins of asthma.

Asthma is an immune-mediated inflammatory condition characterized by increased responsiveness to bronchoconstrictive stimuli. Viruses have been shown to play an important role in asthma, with viral infection being present during about 85% of exacerbations. However, the role they play in the onset of asthma is more controversial. Some respiratory viral infections might be protective, but there is a strong association between respiratory syncytial virus-induced bronchiolitis in infancy and recurrent wheeze up to 12 years of age. Both the respiratory tract and the immune system undergo rapid maturation during the first year of life, and it seems that postnatal development is affected by and affects responses to viral infections. Understanding postnatal developmental changes in the immune system might help to explain the origins and pathogenesis of asthma and thus the effectiveness or ineffectiveness of specific asthma therapies.

Age Factors↗
PubMed1985

Chemiluminescence of bovine alveolar macrophages as an indicator of developing immunity in calves vaccinated with aromatic-dependent Salmonella.

Chemiluminescence of bovine alveolar macrophages was used to study the development of opsonins in calves vaccinated parenterally with live aromatic-dependent strains of either S. dublin or S. typhimurium. These calves responded by producing Salmonella-specific opsonins detected by increased chemiluminescent responses, and were able to survive oral challenge with live virulent organisms of either serotype. Non-vaccinated calves of the same age lacked Salmonella-specific opsonins and were not able to survive challenge. Thus it was concluded that the ability to produce opsonins is among the immunological responses that are associated with protection against salmonellosis in calves. Antigenic similarities between S. dublin and S. typhimurium were shown by the ability of either organism to absorb significant amounts of opsonic capacity from the sera of calves vaccinated with either of the two vaccines. These antigenic similarities are thought to explain in part the ability of either vaccine to protect against challenge with either the homologous or heterologous Salmonella serotype.

Animals↗
PubMed1996

The potential of Lactobacillus as a carrier for oral immunization: development and preliminary characterization of vector systems for targeted delivery of antigens.

Oral administration of lactobacilli evokes mucosal and systemic immune responses against epitopes associated with these organisms (Gerritse et al., 1990, 1991). The adjuvant function of different Lactobacillus species was investigated under the conditions of intraperitoneal (i.p.) injection or oral administration. After i.p. injection of trinitrophenylated chicken gamma-globulin, high DTH responses were observed with Lactobacillus casei and Lactobacillus plantarum, but low responses with Lactobacillus fermentum and Lactobacillus delbrueckii subsp. bulgaricus. In different experimental model systems L. casei and L. plantarum consistently showed significant adjuvanticity. A series of expression and expression-secretion vectors containing the strong constitutive promoter of the L. casei L-ldh gene or the regulatable promoter of the Lactobacillus amylovorus amy gene (Pouwels and Leer, 1995) was used for the intracellular, extracellular and surface-bound expression of an influenza virus antigenic determinant fused to Escherichia coli beta-glucuronidase. Intracellular expression of the fusion protein amounted to 1-2% of total soluble protein. Lactobacilli synthesizing the fusion protein intracellularly evoked an oral immune response after subcutaneous priming.

Administration, Oral↗
PubMed1986

Loss of proliferative capacity and T cell immune development potential by bone marrow from mice undergoing a graft-vs-host reaction.

The inoculation of parental T lymphocytes into healthy, immune-competent F1 hybrid mice can result in severe immunologic abnormalities including immune deficiency in the recipients. To test whether stem cell function could also be affected in F1 mice undergoing a parental-induced graft-vs-host (GVH) reaction, T cell-depleted bone marrow from parentally injected F1 mice was tested for stem cell proliferative capacity and for differentiation into functional T cells by transplantation of bone marrow from GVH mice into lethally irradiated, syngeneic F1 test recipients. Stem cell proliferative capacity was assessed in the repopulating spleens of the test mice by the in vivo [125I]Iodo-2'-deoxyuridine assay. An eightfold to 10-fold reduction could be observed in the proliferative capacity of marrow from mice in which a GVH reaction had been induced 6 wk earlier. The GVH-induced hematopoietic defect required parental T cell recognition of both class I and class II H-2 alloantigens expressed by the F1 host. No suppressor cell activity was detected in the marrow of GVH mice. We did not detect a defect in the microenvironment of mice injected with parental marrow, but we did observe a severe and long-lasting defect in the ability of GVH F1 recipients to support the growth of F1 bone marrow. Spleen cells of test recipients repopulated with marrow from GVH donors exhibit in vitro defects in T and B lymphocyte functions. These findings indicate that the GVH reaction can affect early stages in the development of the hematopoietic system, both in terms of stem cell proliferative capacity and of long-term T lymphocyte functional potential.

Animals↗
PubMed1987

The effect of in utero exposure to hexachlorobenzene on the developing immune response of BALB/c mice.

BALB/c mice were exposed to 0.0, 0.5 and 5.0 mg/kg maternal body weight hexachlorobenzene (HCB) throughout gestation by daily per os dosing of the females. At 45 days of age selected immune functions of the offspring were assessed. The delayed-type hypersensitivity (DTH) response to oxazolone was severely depressed in animals exposed to either 0.5 or 5.0 mg/kg HCB, however, only those animals exposed to 5.0 mg/kg HCB showed a significant decrease in their mixed lymphocyte response (MLR) levels. The ability of isolated spleen cells to undergo a blastogenic response to concanavalin A (ConA), phytohemagglutinin (PHA) and lipopolysaccharide (LPS) showed no significant changes due to HCB exposure. Similarly, no significant difference in the induction of direct hemolytic plaque-forming cells was seen. A significant increase in the relative distribution of splenic T cells and a significant decrease in splenic B cells was measured in the offspring of HCB-treated females. These results suggest that HCB is capable of affecting the development or maturation of the immune response in mice, perhaps at the T cell level.

Animals↗
PubMed1997

Alterations in the developing immune system of the F344 rat after perinatal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin I. [correction of II]. Effects on the fetus and the neonate.

Perinatal exposure of rodents to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been shown to result in thymic atrophy and cell-mediated immune suppression at lower doses than are required to produce those effects following adult exposure. This study was designed to examine the effects that in utero TCDD exposure has on thymocyte development in the rat. Timed-bred pregnant F344 rats were given 0, 1.0, or 3.0 mcg TCDD/kg body weight by gavage on gestational day 14 (GD14). On GD19 or GD22/postnatal day one (PD1), the dams were euthanized, and the dams and their offspring were examined for organ weight and thymus phenotypic alterations. GD19 fetuses from the 3.0 mcg TCDD/kg maternal exposure group exhibited decreases in relative thymus weight and thymic cellularity. There were a decreased percentage of CD3-/CD4+ CD8+ thymocytes and an increased percentage of CD3-/CD4-CD8+ thymocytes in these fetuses, but there were no alterations in the CD3+ subsets. No effects were seen in the GD19 fetuses from the 1.0 mcg TCDD/kg dosage group. In the TCDD-exposed GD22/PD1 offspring thymic atrophy was no longer present, but there was an increase in the relative liver weight. In addition, there were decreased percentages of CD3-/CD4-CD8-, CD3+/CD4-CD8-, and CD3+/CD4+CD8+ thymocytes and an increased percentage of CD3+/CD4-CD8+ thymocytes. The CD3+/CD4-CD8- and CD3+/CD4-CD8+ cell populations were the most sensitive, with changes appearing at both 1.0 and 3.0 mcg TCDD/kg maternal exposures. The TCDD-exposed GD19 dams exhibited an increased relative liver weight, a decreased relative thymus weight, and alterations in thymic CD3+ populations. Three days later the relative organ weights had recovered in the dams, but the phenotypic alterations were seen in CD3- as well as CD3+ thymocyte subsets. These results indicate that the developing rat fetal thymus is susceptible to the effects of TCDD. In addition, pregnant rats and their offspring showed similar alterations in thymocytic phenotypes.

Administration, Oral↗
PubMed1985

Immune response to ultraviolet-induced tumors. I. Transplantation immunity developing in syngeneic mice in response to progressor ultraviolet-induced tumors.

Ultraviolet-light-induced murine skin tumors were analyzed for the ability to induce transplantation immunity and cytotoxic lymphocytes in syngeneic mice. A correlation was found between tumor regression and the induction of cytotoxic T cells with specificity for a unique tumor-associated antigen. Processing tumors possessed tumor-associated transplantation antigens (TATA), which could be demonstrated by transplantation in hyperimmunized mice. Progression correlated with a lack of splenic cytotoxic T cell reactivity. High levels of in situ cytotoxic reactivity could be induced by presenting the tumor-specific antigen on nongrowing tumor cells. Tumor-bearer hosts were shown to be sensitized to TATA because cultured tumor-bearer T cells adoptively transferred protection against tumor outgrowth. Mechanisms of the in vivo suppression of antitumor immunity are discussed.

Animals↗
PubMed1978

Prevalence of antibody to the Norwalk agent by a newly developed immune adherence hemagglutination assay.

An immune adherence hemagglutination assay (IAHA) for the detection of antibody to the Norwalk agent of acute epidemic nonbacterial gastroenteritis was developed using as antigen virus purified from stool from an experimentally infected volunteer. The assay was sensitive and specific and was efficient for detecting Norwalk antibody seroresponses. The prevalence of Norwalk antibody in various groups in the United States was studied. Antibody to the Norwalk agent was acquired gradually, beginning slowly in childhood and accelerating in the adult period so that by the fifth decade 50% possessed antibody. This pattern of antibody acquisition contrasted sharply with that for the human rotavirus of infantile gastroenteritis. Rotavirus antibody was acquired during early childhood by almost all individuals in the pediatric groups studied. Antibody to the Norwalk agent was also found in rural Bangladesh; in a small prevalence survey of 39 children and adults 21% possessed Norwalk IAHA antibody, whereas 95% possessed antibody to the human rotavirus.

Adolescent↗
PubMed2003

Dynamics and responsiveness of T-lymphocytes in secondary lymphoid organs of rabbits developing immunity to Eimeria intestinalis.

Primary infection with Eimeria intestinalis confers very effective immunity against further infections in rabbits. This study was designed to determine the onset of the immune response in primary-infected rabbits and to characterise the immune status of protected rabbits. Variations in kinetics of CD4+ and CD8+ T-cell subpopulations were followed after primary infection at the intestinal sites of penetration (duodenum) and development (ileum), in mesenteric lymph nodes (MLN) and in the spleen. The response against the parasite was measured by specific lymphocyte proliferation in the spleen and MLN and by determining specific IgG titres in serum. The mucosal immune response was strong after primary infection and was characterised by (i) transient increase in the percentages of intestinal CD4+ lymphocytes and MLN CD8+ lymphocytes 14 days PI and (ii) strong increase in the percentages of intestinal CD8+ lymphocytes from 14 days PI persisting throughout further infections. Extensive infiltration of the lamina propria with CD8+ lymphocytes was observed 14 days PI. The specific proliferative response started between 7 and 14 days PI in MLN but remained undetectable in spleens for up to 21 days, in contrast to "immunised" rabbits. The fact that systemic immune responses were low after primary infection, in contrast to indicators of mucosal immune responsiveness, suggests that protection of rabbits against E. intestinalis infection is due to an effective mucosal immune response, and that systemic responses that increase after successive infections are only reflections of repeated encounters with parasite antigens.

Animals↗
PubMed1986

Systemic immunity developing from intrauterine antigen exposure in the nonpregnant rat.

This report provides a simplified model for investigating the antigen handling mechanisms of the mammalian uterus. The effectiveness of the uterus as a site for systemic immunization has been studied using a hapten-protein conjugate (DNP-BGG) as antigen in nonpregnant virgin rats. The data indicate that although the uterus is inefficient as an antigen delivery site, strong systemic immune responses can be generated under appropriate conditions. Intrauterine (i.u.) immunization with alum-precipitated DNP-BGG did not induce significant antibody activity but primed the females so that vigorous anamnestic responses were produced after a second exposure to (soluble) antigen. The following results were obtained: (1) The optimal immunization dose was 100-2000 micrograms. (2) Alum-precipitation of the immunizing antigen was necessary in order to sensitize the female, while inclusion of killed Bordetella pertussis organisms was not. (3) The site of challenge after i.u. immunization affected the level of serum antibody activity. (4) Retention of antigen within the uterus for as little as 1 day sensitized the females as effectively as 28 days' exposure. (5) The presence or absence of ovarian hormones had no apparent effect in this system.

Animals↗