[Animal disease management ridicules Darwin].
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Animal Diseases↗
Biomedical subjects
H F Savelkoul
Publications and source records attributed to H F Savelkoul.
1alpha,25-Dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells.
1alpha,25-Dihydroxyvitamin D3 (vitD3) is an immunoregulatory hormone with beneficial effects on Th1 mediated autoimmune diseases. Although the inhibitory effects of vitD3 on macrophages and dendritic cells are well documented, any direct effects of vitD3 on Th cell development are not clearly defined. Using CD4(+)Mel14(+) T cells derived from mice on a BALB/c and a C57BL/6 genetic background we examined the effect of vitD3 on Th cell development. We demonstrated that vitD3 affects Th cell polarization by inhibiting Th1 (IFN-gamma production) and augmenting Th2 cell development (IL-4, IL-5, and IL-10 production). These effects were observed in cultures driven with splenic APC and Ag, as well as with anti-CD3 and anti-CD28 alone, indicating that CD4(+) cells can also be direct targets for vitD3. The enhanced Th2 development by vitD3 was found in both BALB/c and C57BL/6 mice. An increased expression of the Th2-specific transcription factors GATA-3 and c-maf correlated with the increased production of Th2 cytokines after vitD3 treatment. The vitD3-induced effects were largely mediated via IL-4, because neutralization of IL-4 almost completely abrogated the augmented Th2 cell development after vitD3 treatment. These findings suggest that vitD3 acts directly on Th cells and can, in the absence of APC, enhance the development of a Th2 phenotype and augment the expression of the transcription factors c-maf and GATA-3. Our findings suggest that the beneficial effects of vitD3 in autoimmune diseases and transplantation operate through prevention of strong Th1 responses via the action on the APC, while simultaneously directly acting on the T cell to enhance Th2 cell development.
Animals↗
Inhibition of diabetes in NOD mice by human pregnancy factor.
Clinical symptoms of Th1 mediated autoimmune diseases regress in many patients during pregnancy. A prominent feature of pregnancy is the presence of human chorionic gonadotrophin hormone (hCG) in blood and urine. In this report we tested the effect of clinical grade hCG (c-hCG) on the development of diabetes, a Th1 mediated autoimmune disease, in nonobese diabetic (NOD) mice. We show that treatment of NOD mice with c-hCG before the onset of clinical symptoms lowered the increased blood glucose levels, reversed the established inflammatory infiltrate of pancreatic tissue, and profoundly inhibited the development of diabetes for prolonged time. c-hCG also induced profound inhibition of the functional activity (i.e. production of IFN-gamma) of Th1 cells. Transfer of spleen cells from c-hCG-treated NOD mice into immunocompromised NOD.SCID mice inhibited the development of diabetes in these otherwise nontreated mice. This shows that the treatment of the donor NOD mice induced persistent changes in the immune system. The antidiabetic activity of c-hCG was not caused by heterodimeric hCG or its subunits. Instead, this antidiabetic activity resided in a fraction of c-hCG preparation that contains a 400-2000 Dalton natural (immuno) modulatory pregnancy factor (NMPF).
Animals↗
Differential ultraviolet-B-induced immunomodulation in XPA, XPC, and CSB DNA repair-deficient mice.
Ultraviolet B irradiation has serious consequences for cellular immunity and can suppress the rejection of skin tumors and the resistance to infectious diseases. DNA damage plays a crucial role in these immunomodulatory effects of ultraviolet B, as impaired repair of ultraviolet-B-induced DNA damage has been shown to cause suppression of cellular immunity. Ultraviolet-B-induced DNA damage is repaired by the nucleotide excision repair mechanism very efficiently. Nucleotide excision repair comprises two subpathways: transcription-coupled and global genome repair. In this study the immunologic consequences of specific nucleotide excision repair defects in three mouse models, XPA, XPC, and CSB mutant mice, were investigated. XPA mice carry a total nucleotide excision repair defect, whereas XPC and CSB mice only lack global genome and transcription-coupled nucleotide excision repair, respectively. Our data demonstrate that cellular immune parameters in XPA, XPC, and CSB mice are normal compared with their wild-type (control) littermates. This may indicate that the reported altered cellular responses in xeroderma pigmentosum patients are not constitutive but could be due to external factors, such as ultraviolet B. Upon exposure to ultraviolet B, only XPA mice are very sensitive to ultraviolet-B-induced inhibition of Th1-mediated contact hypersensitivity responses and interferon-gamma production in skin draining lymph nodes. Lipopolysaccharide-stimulated tumor necrosis factor alpha and interleukin-10 production are significantly augmented in both XPA and CSB mice after ultraviolet B exposure. Lymph node cell numbers were increased very significantly in XPA, mildly increased in CSB, and not in XPC mice. In general XPC mice do not exhibit any indication of enhanced ultraviolet B susceptibility with regard to the immune parameters analyzed. These data suggest that both global genome repair and transcription-coupled repair are needed to prevent immunomodulation by ultraviolet B, whereas transcription-coupled repair is the major DNA repair subpathway of nucleotide excision repair that prevents the acute ultraviolet-B-induced effects such as erythema.
Adjuvants, Immunologic↗
Selective development of a strong Th2 cytokine profile in high-risk children who develop atopy: risk factors and regulatory role of IFN-gamma, IL-4 and IL-10.
BACKGROUND: The immunological processes in early life and their relation to allergic sensitization leading to a Th2 cytokine profile are still not well understood. OBJECTIVE: To analyse the environmental and genetic risk factors and immunological responses at birth in relation to the development of atopic disease at 12 months of age in a longitudinal study of high-risk children. METHODS: High-risk children were followed from birth till 12 months of age. Mononuclear cells obtained at birth and 6 and 12 months thereafter were analysed for their proliferative and cytokine responses after polyclonal and allergen-specific stimulation. RESULTS: At 12 months of age 25% children had developed an atopic disease. Two atopic parents, parental smoking and atopic dermatitis of at least one of the parents were significant risk factors. In cord blood of newborns who developed atopy, an increased percentage of CD4+CD45RO+ cells and an increased polyclonal-stimulated proliferation were observed. Furthermore, an impaired allergen-induced, but not polyclonal-stimulated IFN-gamma production was found, suggesting a regulatory defect. At 6 and 12 months of age, a strong Th2 profile (characterized by increased levels of IL-4, IL-5, and IL-13) after both polyclonal and, to a lesser extent, allergen-specific stimulation was found in the children developing atopy. Allergen-induced IL-10 production at 12 months of age was only observed in the non-atopic children. CONCLUSION: Our data indicate that the first 6 months of life represent a critical time window for the initiation of immunological changes resulting in the development of atopy. The selective development of a Th2 cytokine profile in high-risk children who develop atopy is due to increased production of Th2 cytokines, possibly caused by impaired allergen-induced IFN-gamma production in the neonatal period. Furthermore, the decreased allergen-induced IL-10 levels observed in the atopic children at 12 months of age may result in a lack of down-regulation of the inflammatory process.
Allergens↗
Clinico-immunological heterogeneity in Comèl-Netherton syndrome.
BACKGROUND: Comèl-Netherton syndrome (CN) is characterized by atopic-eczema-like skin abnormalities combined with linear ichthyotic lesions, hair shaft abnormalities and atopy with high IgE levels. OBJECTIVE: Five children with CN are described. In 2 of the 3 CN patients still alive, analysis of cytokines regulating IgE synthesis was performed. METHODS: In peripheral blood mononuclear cells and cultures of purified T cells, mRNA expression and protein production of interleukin 4 (IL-4), IL-13, IL-5 and interferon gamma were analysed. The results were compared with the values in age-matched atopic dermatitis patients and healthy children. RESULTS: The 5 CN patients showed striking differences in disease severity and evolution. Marked differences were found in several cytokines in the 2 analysed CN patients. Low percentages of natural killer cells were observed in both CN patients. CONCLUSION: The regulation of IgE production in patients with CN is varied and complex. The CN patients were heterogeneous in terms of Th2 skewing.
Child↗
Critical illness polyneuropathy and myopathy (CIPNM): evidence for local immune activation by cytokine-expression in the muscle tissue.
In a longitudinal prospective study a muscle biopsy was taken from 30/32 (33%) of the 98 patients who developed critical illness polyneuropathy and myopathy (CIPNM). Neuropathic changes were found in 37%, myopathic in 40%, and a combination in 23% of the biopsies. The immunohistopathology showed macrophages and Th-cells in 40% and 60% of the muscle biopsies respectively. Small mainly perivascular infiltrates contained macrophages and Th-cells. ICAM-1, VCAM and MAC were found on the vascular endothelium in 58%, 53% and 79% respectively. In all biopsies there was an upregulation of both HLA-I and HLA-DR. Proinflammatory cytokines and TNFalphaR75 were also produced locally (IL-1beta in 71%, IFN-gamma in 40%, IL-12 in 73%, TNFalphaR75 in 90%). The anti-inflammatory cytokine IL-10 was simultaneously expressed in 96% of the biopsies. HLA-DR, TNFalphaR75 and IL-10 differed significantly when compared with control muscle biopsies. Our data provide evidence that small numbers of activated leukocytes producing both pro- and anti-inflammatory cytokines infiltrate skeletal muscle of CIPNM patients. We propose that the local balance of leukocyte activities is of importance in the pathophysiology of muscle weakness in CIPNM.
Antigens, CD↗
Immune responses during allergic sensitization and the development of atopy.
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Allergens↗
Markers for early sensitization and inflammation in relation to clinical manifestations of atopic disease up to 2 years of age in 133 high-risk children.
BACKGROUND: The combination of genetic susceptibility and environmental factors induce allergic sensitization and subsequently local inflammation, resulting in atopic manifestations. OBJECTIVE: To examine whether immunological features reflecting sensitization (total and specific IgE levels, allergen-induced proliferative responses and skin tests) and markers of inflammation (plasma sE-selectin and blood eosinophils) are related to the clinical expression of atopy and whether they precede atopic disease in children up to 2 years of age. METHODS: The development of these markers during the first 2 years of life was studied prospectively in 133 newborns at high risk to develop atopic disease. RESULTS: The prevalence of atopic disease increased from 25% at 12 months to 32% at 24 months of age. The children with food allergy at 12 months, who all had atopic dermatitis (AD), turned out to have asthma-like disease in 40% and AD in 100% at the age of 24 months. Total IgE levels increased with time and from 12 months onward levels started to differ markedly between atopics and nonatopics. Food-specific IgE antibodies were significantly associated with AD (relative risk [RR] = 2.39), food (RR = 1.32) and upper-airway allergy (RR = 1.20), and house dust mite-specific IgE antibodies with upper-airway allergy (RR = 5.00). A positive skin test was significantly associated with AD (RR = 2.90) and food allergy (RR = 1.36). The inflammation markers investigated, were not related to the clinical expression or preceded atopic disease at 2 years of age in high-risk children. CONCLUSION: Positive skin tests and specific IgE to food or inhalant allergens were related to the clinical expression of different atopic diseases. The combination of AD and food allergy at 12 months reflected the strongest risk factor in this high risk cohort for the development of asthma-like disease at 24 months of age.
Allergens↗
UVB irradiation modulates systemic immune responses by affecting cytokine production of antigen-presenting cells.
The immunosuppressive effects of UVB irradiation have been well documented. The production of cytokines by keratinocytes is considered to play a major role in the induction of local as well as systemic immunosuppression. It is thought that partly due to the interaction of locally produced cytokines with antigen-presenting cells (APC) systemic effects, like antigen-specific tolerance, can be induced. In this study we examined the effect of UVB irradiation on cytokine profiles of peripheral APC as well as the functional consequences. Our results indicate that UVB irradiation impairs T(h)1-mediated immune responses in vivo by suppression of the systemic IL-12p70 production. Splenic APC from UVB-exposed mice showed an enhanced production of prostaglandin E(2), IL-1, IL-6 and tumor necrosis factor-alpha after in vitro stimulation. Also, spleen cells from UVB irradiated IL-4(-/-) mice showed increased IL-6 levels. These APC were less efficient in inducing IFN-gamma production by CD4(+) T cells and suppressed IgM production by B cells. We conclude that the altered cytokine profile of peripheral APC can be responsible for the systemic effects of UVB irradiation on the T(h)1/T(h)2 balance as well as on B cell responses.
Animals↗
Distinctions between critical illness polyneuropathy and axonal Guillain-Barré syndrome.
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Humans↗
Immune parameters in high-risk atopic individuals during early childhood.
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Age Factors↗
UV exposure alters respiratory allergic responses in mice.
We have tested the hypothesis that exposure to ultraviolet light would inhibit T helper-1 (Th1) responses and stimulate T helper-2 (Th2) responses, and that thus in a mouse model of allergic (i.e. extrinsic) asthma (using ovalbumin [OVA] as the allergen) increased symptoms would be observed, while in a model of Th1-dependent occupational asthma (in which picryl chloride is the allergen) decreased symptoms would be observed. Whereas reduced interferon (IFN)-gamma production, decreased inflammatory responses in the airways, and reduced airway reactivity to nonspecific stimuli were observed in UV-preexposed picryl chloride sensitized and challenged mice, the results in the OVA model were less clear. Increased interleukin (IL)-10 production as a result of UV exposure was observed, together with unchanged IL-4 and IFN-gamma. In addition, decreased OVA-specific immunoglobin, IgG1 and IgE, titers were noted, as well as decreased nonspecific airway hyperreactivity. Eosinophilic inflammatory responses were not influenced. The results indicate that UV exposure can have systemic effects that influence ongoing immune responses in the respiratory tract. The effects are not only restricted to immune responses that are predominantly Th1 dependent (i.e. pulmonary delayed-type hypersensitivity and IFN-gamma production in response to picryl chloride) but also to immune response that are predominantly Th2 dependent, i.e. decreased specific IgE titers.
Animals↗
Cytokines in the muscle tissue of idiopathic inflammatory myopathies: implications for immunopathogenesis and therapy.
The inflammatory myopathies (IM), dermatomyositis (DM), polymyositis (PM) and idiopathic inclusion body myositis (IBM) are acquired immune-mediated myopathies. About their pathogenesis and etiology no definitive insights are available yet. Here we present a review of cytokine studies in IM. Combined with cellular immunohistochemical findings a model is presented describing a common mechanism of immune activation in IM. This model is based on a "hit" triggering local cytokine production with dominance of pro-inflammatory cytokines, like IFN-gamma and Th1-mediated activities. The altered Th1-Th2 balance necessitates detection of the anti-inflammatory arm of immune activation, which includes Th2-derived IL-4, IL-1, and Th3/Tr1 derived IL-10 and TGF-beta. Redirection of the ratio provides targets for novel immunotherapy by direct inhibition of the IFN-gamma-mediated Th1 response, stimulation of Th3/Tr1, or IL-4-secreting Th2-cells, negative feedback inhibition with IFN-beta and IFN-gamma and inactivation of MHC molecules.
Cytokines↗
Interleukin 4 receptors on human bronchial epithelial cells. An in vivo and in vitro analysis of expression and function.
Asthma is considered a Th2-like disease, characterized by locally increased levels of interleukin (IL) 4. The bronchial epithelium plays an important role in the initiation and perpetuation of inflammatory reactions within the airways. However, little is known about the presence of IL-4 receptors on human bronchial epithelial cells, or the effects of IL-4 on these cells. In this report, definitive evidence of IL-4 receptor expression on human bronchial epithelial cells using several methods is presented. IL-4 receptor expression on human bronchial epithelial cells in vivo was demonstrated using in situ hybridization and immunohistochemistry. No difference in IL-4 receptor protein expression was observed between bronchial biopsies of healthy subjects compared to allergic asthmatics. Cultured human bronchial epithelial cells also expressed IL-4 receptor mRNA and protein (as determined by RT-PCR analysis and flow cytometry, respectively). IL-4 receptor protein expression by bronchial epithelial cells could be increased by stimulation with PMA+calcium ionophore, whereas IL-1beta and IL-6 decreased IL-4 receptor expression. A cyclic AMP analogue and IL-4 had no effect. Finally, it is shown that the IL-4 receptor is functionally active as IL-4 stimulates the release of IL-8, monocyte chemoattractant protein 1, and particularly IL-1 receptor antagonist by human bronchial epithelial cells. It is concluded that human bronchial epithelial cells express IL-4 receptors both in vivo and in vitro. Stimulation of human bronchial epithelial cells by IL-4 may result in the release of both pro- and anti-inflammatory mediators known to be upregulated in asthmatic airways.
Asthma↗
A mouse model to study immunity against pseudorabies virus infection: significance of CD4+ and CD8+ cells in protective immunity.
In this study we firstly established a vaccination/challenge model to study pseudorabies virus infection in mice. The mouse model was used to investigate the significance of CD4+ and CD8+ cells and of IFN gamma production in protective immunity. Functional depletion of CD4+ and CD8+ and IFN gamma was obtained in vivo by intraperitoneal injection of alginate-encapsulated anti-CD4, -CD8 or -IFN gamma producing hybridoma's before and at the moment of vaccination. The observed protective immunity was correlated with underlying immunologic responses such as PRV-specific DTH reactivity, lymphoproliferation and cytotoxicity. The significance of CD4+ and CD8+ cells and of IFN gamma production was also investigated for these immunological responses by the same in vivo depletion technique. The results demonstrated that protective vaccination of mice, that could be induced by immunization with 10(7) plaque forming units of the avirulent PRV mutant NIA3 TK-, was characterized by a typical anti-viral Th1 type immune response. A clear PRV-specific, CD4-dependent DTH reactivity and a classical CD8-dependent, MHC-restricted cytotoxicity was induced after protective immunization and the humoral immune response had a bias towards PRV-specific IgG2a formation. In vivo treatment with anti-CD8 and anti-IFN gamma demonstrated that the cytotoxic response and humoral IgG2a response, respectively, were strongly reduced, whereas protection against lethal challenge was unaffected. On the other hand anti-CD4 treatment reduced the induced protection so that 30% of the mice died after lethal challenge. The results of our study demonstrated that CD4+, DTH like effector cells are a crucial effector mechanism for protective immunity against PRV.
Animals↗
Soluble E-selectin, other markers of inflammation and disease severity in children with atopic dermatitis.
E-selectin, P-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are membrane-bound adhesion molecules which mediate the attachment of leucocytes to endothelial cells. These molecules are preferentially expressed on activated endothelium. The soluble forms of these molecules (sE-selectin, sP-selectin, sICAM-1 and sVCAM-1) are present in the circulation as a result of shedding. Some of the soluble adhesion molecules have been thought to reflect disease activity in atopic dermatitis (AD). To evaluate their potential to reflect disease activity in AD, we correlated their plasma concentration with clinical severity measured by objective SCORAD (SCORing Atopic Dermatitis). Furthermore, levels of total IgE, specific IgE, and eosinophil cationic protein (ECP) were determined. SCORAD and sE-selectin levels were significantly increased in children with specific IgE for both food and inhalation allergens (P < 0.05). ECP consistently showed an increase with the scores of SCORAD, but no statistical significance was reached. Disease activity was significantly correlated with the plasma levels of sE-selectin (rs = 0.6, P < 0.0005) but not with sP-selectin, sICAM-1 and sVCAM-1. This agrees with recent studies performed in adults with AD, and supports the potential of sE-selection as a parameter for monitoring disease activity in young children with AD.
Allergens↗
CD4+ cells proliferate after peanut-extract-specific and CD8+ cells proliferate after polyclonal stimulation of PBMC of children with atopic dermatitis.
BACKGROUND: Few studies describe in vitro food-allergen induced proliferative responses and cytokine production of PBMC of children with atopic dermatitis. This is especially true for peanut-allergen. OBJECTIVES: To analyse the specificity of the T cell in proliferative responses, in children with atopic dermatitis with or without peanut allergy and healthy age-matched children. METHODS: Proliferative responses were measured by [3H]-thymidine incorporation and by expression of the intracellular Ki67-antigen using flow cytometry after antigen-specific stimulation of PBMC with peanut-extract (day 7) or polyclonal stimulation with Phorbol-12myristate-13acetate and Ca-ionophore (day 3). Cytokine mRNA (Interferon-gamma (IFNgamma), IL-4) was detected by semiquantitative RT-PCR. Cytokine production (IL-4, IFNgamma) was measured by ELISA. RESULTS: Peanut-extract induced proliferative responses of PBMC from children with atopic dermatitis and peanut allergy (AD+PA+) were significantly higher as compared with the other groups studied. Ki67-antigen double staining revealed that 80-100% of the proliferating cells were CD4+. These proliferative responses correlated significantly with the increase in IL-4 mRNA expression after peanut-extract specific stimulation. After polyclonal stimulation, however, CD8+ cells preferentially proliferated. The degree of proliferation after polyclonal stimulation correlated inversely with the ratio of IL-4/IFNgamma production. CONCLUSIONS: The principal responding population of T cells in proliferative responses is different after peanut-extract specific and polyclonal stimulation of PBMC from AD+PA+ patients. Furthermore, we found indirect evidence that the PBMC fraction of AD+PA+ children contains increased frequencies of peanut-specific T helper-2 cells.
Antibodies, Monoclonal↗