Genetic control of T helper subset differentiation in Leishmania major infection of mice.
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Animals↗
Biomedical subjects
R L Coffman
Publications and source records attributed to R L Coffman.
Immune responses to Aspergillus antigen in IL-4-/-mice and the effect of eosinophil ablation.
BACKGROUND: Exposure to Aspergillus fumigatus allergens results in enhanced total serum IgE and peripheral blood eosinophils in mice. The associated pulmonary inflammation and immunologic responses are comparable to those detected in human allergic bronchopulmonary aspergillosis. Allergen-induced cytokines are thought to regulate the inflammatory and immune responses in these animals. METHODS: In the present study, we exposed C57BL/6 and BALB/c mice to A. fumigatus antigen. Both wild-type and IL-4 knockout phenotypes of animals of both strains were used. Some animals were also treated with anti-IL-5 or anti-IFN-gamma. Total serum IgE, Aspergillus species IgG subclass, peripheral blood eosinophils, and lung histology were studied. RESULTS: The results demonstrate similar lung inflammation in all wild-type and IL-4-/- animals exposed to A. fumigatus antigen. Similarly, in spite of the diverse immune response produced by the anticytokine treatment, no major differences were detected among any of the animal groups studied. CONCLUSIONS: It can be concluded that A. fumigatus exposure in an immunologically unaltered host is predominantly of a Th2 type, and that depletion of the Th2 cytokine leads to a similar lung inflammation but with a characteristic Th1 response, suggesting that the pathogenesis of allergic aspergillosis is the result of multiple induction pathways.
Animals↗
Experimental Leishmania major infection in mice: role of IL-10.
L. major infection of mice induces polarized Th1 and Th2 responses that are correlated with healing of the infection (Th1) or a fatal disease (Th2). The Th subset specific cytokines, IFNgamma and IL-4, themselves were shown to be important factors for the differentiation into the Th1 and Th2 pathways during infection. We studied the role of the Th2 cytokine IL-10 during leishmania infection: removal of endogenous IL-10 by anti-IL-10 treatment did not alter the Th2 cytokine pattern in non-healer mice nor did it modulate DTH reactivity, IgE production or fatal disease progression, but partially blocked the IFNgamma inhibiting effect of rIL-4 in healer mice. During chronic infection similar amounts of IL-10 were produced in both healer and non-healer mice. However, at early time-points during infection IL-10 production was significantly higher in the non-healer Th2 responder animals. IL-10 production in vitro caused significant inhibition of in vitro IFNgamma production. In conclusion IL-10, unlike IL-4 and IFNgamma, does not seem to play a readily detectable role in the Th subset differentiation during L. major infection. However, the high production of IL-10 early during infection in non-healer mice and inhibition of leishmania-specific IFNgamma production may contribute to drive the immune response towards a Th2 response.
Animals↗
Leishmania major infection in interleukin-4 and interferon-gamma depleted mice.
The outcome of experimental Leishmania major infection in mice is closely correlated with the type of CD4+ helper T cell (Th) response. Whereas a Th1 response is host protective, a Th2 response leads to a disseminated, fatal course of disease. Previous studies in this murine model have shown, that the two prominent Th1 and Th2 cytokines, interferon (IFN)-gamma and interleukin (IL)-4, themselves play a major role in the determination of the resulting Th response. Treatment of susceptible mouse strains (BALB/c) with anti-IL-4 induces a Th1 response, allowing the animals to cure the infection. Treatment of resistant strains (e.g. C3H/HeN) with anti-IFN-gamma induces a Th2 response with dissemination of the disease. In this report, we investigated the course of infection and Th response in susceptible and resistant mice treated with anti-IL-4 and anti-IFN-gamma simultaneously. Both mouse strains showed an initial exacerbation of the disease and an overall reduced cytokine response early after infection. Later during infection both strains had a strong Th1 response that was resulting in cure of disease in C3H/HeN mice. BALB/c mice however, could not control the spread of infection despite the strong Th1 response.
Animals↗
Down-regulation of Th1 type of response in early human American cutaneous leishmaniasis.
This study examined the T cell responses in the early phase of Leishmania braziliensis infection. Cytokine profiles, lymphoproliferative responses, and skin test results in 25 patients with early cutaneous leishmaniasis (ECL; illness duration <60 days) were compared with those in persons with late cutaneous leishmaniasis (LCL; illness duration >2 months). Absent or low lymphoproliferative responses were observed in 8 (32%) of 25 patients and an absence of interferon (IFN)-gamma production in 9 (41%) of 22 patients prior to therapy. IFN-gamma production in ECL (mean +/- SD) was lower than in LCL (293+/-346 vs. 747+/-377 pg/mL, respectively; P<.01). In contrast, interleukin (IL)-10 production in ECL (mean +/- SD) was higher than in LCL (246+/-56 vs. 50+/-41 pg/mL, respectively; P<.01). Restoration of lymphoproliferative responses and IFN-gamma production was achieved when monoclonal antibody to IL-10 or IL-12 was added to the cultures. These results show that T cell responses during early-phase infection are down-regulated by IL-10 and may facilitate parasite multiplication.
Animals↗
Targeted disruption of the interferon-gamma receptor 2 gene results in severe immune defects in mice.
To study the role of the interferon- (IFN) gammaR2 chain in IFN-gamma signaling and immune function, IFN-gammaR2-deficient mice have been generated and characterized. Cells derived from IFN-gammaR2 -/- mice are unable to activate either JAK/STAT signaling proteins or gene transcription in response to IFN-gamma. The lack of IFN-gamma responsiveness alters IFN-gamma-induced Ig class switching by B cells from these mice. In vitro cultures of T cells demonstrate that the T cells from the IFN-gammaR2 -/- mice have a defect in Th1 cell differentiation. The IFN-gammaR2 (-/-) mice also produce lower amounts of IFN-gamma in response to antigenic challenge. In addition, IFN-gammaR2 -/- mice are defective in contact hypersensitivity and are highly susceptible to infection by Listeria monocytogenes. These results demonstrate that the IFN-gammaR2 is essential for IFN-gamma-mediated immune responses in vivo.
Animals↗
Suppression of interleukin-5 prevents mortality in BALB/C mice infected with Cowdria ruminantium.
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Animals↗
In vivo IL-4 responses to anti-IgD antibody are MHC class II dependent and beta 2-microglobulin independent and develop normally in the absence of IL-4 priming of T cells.
A crucial role for CD1-responsive, MHC class II-unrestricted T cells in the generation of T cell IL-4 responses is suggested by the: 1) requirement for IL-4 to prime in vitro IL-4 responses by naive CD4+ T cells; 2) ability of TCR cross-linking to induce CD1-responsive T cells, but not conventional naive T cells, to produce IL-4; 3) failure of anti-IgD Ab to induce an IL-4-dependent IgE response in beta 2-microglobulin-deficient mice, which lack CD1; and 4) reported ability of MHC class II-deficient mice to make IgE responses to anti-IgD Ab. In contrast, the Ag specificity of cytokine and Ab responses in anti-IgD-injected mice and the normal IgE responses made by anti-IgD-treated CD1-deficient mice are difficult to reconcile with this view. We now find that the failure of beta 2-microglobulin-deficient mice to make an IgE response to anti-IgD Ab is caused by their rapid degradation of anti-IgD; sustained anti-IgD treatment induces them to make relatively normal IL-4 and IgE responses. Furthermore, in our study, MHC class II-deficient mice make little or no IL-4 or IgE responses to anti-IgD Ab and beta 2-microglobulin-deficient mice make large in vivo IL-4 responses to anti-CD3 mAb. Finally, although IL-4 priming of T cells for IL-4 production is Stat6 dependent, Stat6-deficient mice make normal IL-4 responses to anti-IgD. Thus, CD1-responsive T cells and other beta 2-microglobulin-dependent T cells are not required to prime conventional CD4+ T cells to make IL-4 responses to anti-IgD in vivo; in fact, the large IL-4 response made in this system does not require IL-4 priming.
Animals↗
Aerosol-induced immunoglobulin (Ig)-E unresponsiveness to ovalbumin does not require CD8+ or T cell receptor (TCR)-gamma/delta+ T cells or interferon (IFN)-gamma in a murine model of allergen sensitization.
Mice exposed for 20 min daily to aerosolized ovalbumin (OVA) for 10 d at concentrations from 1 to 0.01% OVA made greatly reduced immunoglobulin (Ig)-E responses to subsequent immunogenic OVA challenges, given either intraperitoneally or by aerosol. This IgE-specific unresponsiveness lasted for at least four months. However, these aerosol-treated mice were primed for larger OVA-specific IgG1 and IgG2a responses. The specific reduction in IgE responses was not due to preferential induction of a T helper (Th)-1 response as aerosol OVA- primed mice made greatly reduced Th2 and no detectable Th1 response after rechallenge in vitro. Consistent with this, the increase in circulating eosinophils observed in control Th2-primed mice was absent in aerosol OVA-treated animals. Interferon (IFN)-gamma was not required for this unresponsiveness, as IFN-gamma knockout mice and anti-IFN-gamma antibody-treated wild-type mice had greatly reduced levels of IgE similar to wild-type controls. CD8+ T cells played a relatively small role as IgE responses were reduced to about the same extent in beta2 microglobulin-deficient, or in anti-CD8-treated wild-type mice as in normal mice after aerosol OVA treatment. Similarly, T cell receptor (TCR)-gamma/delta T cells were not required for maximal inhibition of the IgE response. These results demonstrate that exposure to inhaled protein antigens can induce a state of unresponsiveness of CD4+ T cells that results in a prolonged loss of IgE and eosinophil responses to subsequent challenges. This T cell unresponsiveness was shown not to require CD8+ or TCR-gamma/delta+ T cells or IFN-gamma.
Aerosols↗
The induction of a protective response in Leishmania major-infected BALB/c mice with anti-CD40 mAb.
A protective immune response to the intracellular parasite Leishmania major requires the development of a Th1 CD4+ T cell phenotype. We demonstrate herein that BALB/c mice, which normally develop a susceptible Th2 response to L. major infection, are protected when co-injected with an agonistic anti-murine CD40 mAb. Anti-CD40 mAb-mediated protection in this system was found to be T cell dependent, since it was not observed in C57BL/6 x 129 mice that were rendered T cell deficient (TCR beta-/- x TCR delta-/-) and L. major susceptible. Anti-CD40 mAb stimulation of L. major-infected BALB/c mice was accompanied by increased IL-12 and IFN-gamma production in draining lymph nodes, analyzed either by direct expression, or in an antigen-specific in vitro recall assay. The protective role of these cytokines was indicated by the finding that anti-CD40 mAb-mediated protection of L. major-infected BALB/c mice could be reversed by co-treating the animals with neutralizing anti-IL-12 and/or anti-IFN-gamma mAb. Collectively, these data suggest that BALB/c mice develop a protective Th1 CD4+ T cell response to L. major infection when co-injected with anti-CD40 mAb. While the CD40-CD40L interaction has been previously shown to be vital in the control of murine Leishmaniasis, the current study establishes in vivo that anti-CD40 mAb treatment alone is sufficient to protect BALB/c mice from L. major infection and raises the possibility of utilizing this approach for vaccination strategies.
Animals↗
Genetic control of the T cell response to Leishmania major infection.
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Animals↗
Human Schistosomiasis mansoni: IL-10 modulates the in vitro granuloma formation.
Granuloma formation and modulation around Schistosoma mansoni eggs that are trapped in host tissues play a pivotal role during schistosomiasis. It has been demonstrated that the granuloma reactions differ in patients with the different clinical forms of the disease. The pathology during murine schistosomiasis has been correlated with a Th2 response while resistance to infection with a Th1 type response. In humans, very little is known about the role of different cytokines on the development of the disease. Here we demonstrate that IL-10 is an important cytokine regulating the in vitro granulomatous reactivity of PBMC from intestinal (INT) patients. This was evidenced by the fact that blockage of this cytokine in the in vitro granuloma assay lead to a significant increase in granuloma size with cells from INT patients but not with individuals in the acute phase or with the hepatosplenic (HS) form of schistosomiasis. These results demonstrate for the first time that, in context with the model, a Th2 cytokine in human schistosomiasis plays an important role in controlling morbidity.
Acute Disease↗
The role of IL-4 and IL-10 cytokines in controlling an anti-tumor response in vivo.
The effect of systemic administration of anti-inflammatory cytokines (IL-4 and IL-10) on the development and maintenance of an anti-tumor rejection response in vivo was studied by following the growth patterns of P815.B7 tumors on B6D2F1 [(C57BI/6 x DBA/2)F1] mice. The anti-P815.B7 rejection response was found to be T cell dependent, involving both CD4 and CD8 cells. IL-4 treatment resulted in a compromised rejection response; IL-10 treatment alone had little or no effect. These results demonstrate that treatment with an anti-inflammatory cytokine can compromise an otherwise effective anti-tumor rejection response. For the anti-inflammatory cytokine IL-4, the immunosuppressive effects of the cytokine appear to outweigh any possible anti-tumor activities as have been reported using tumor cells genetically altered to produce IL-4. Relatively high systemic doses of IL-10, in contrast, were not immunosuppressive and, when given in combination with IL-4, countered the IL-4 suppressive effect. Pathologically, IL-4 treatment led to splenomegaly characterized by a marked increase in neutrophils and NK activity. The possible linkages between neutrophils, NK activity and IL-12 are discussed.
Animals↗
IFN-gamma in human Chagas' disease: protection or pathology?
An apparently paradoxical role for IFN-gamma in human Chagas' disease was observed when studying the pattern of cytokine production by peripheral blood mononuclear cells (PBMC) obtained from two groups of chagasic patients after specific stimulation with Trypanosoma cruzi-derived antigens. The groups studied were 1) patients treated with benznidazole during the acute phase of Trypanosoma cruzi infection and 2) chronically infected untreated patients. In the treated group, higher levels of IFN-gamma were produced by PBMC from individuals cured after treatment when compared to non-cured patients. In contrast, in the chronically infected group (not treated) higher levels of IFN-gamma were produced by PBMC from cardiac patients in comparison with asymptomatic (indeterminate) patients. This apparently paradoxical role for IFN-gamma in human Chagas' disease is discussed in terms of the possibility of a temporal difference in IFN-gamma production during the initial stages of the infection (acute phase) in the presence or absence of chemotherapy. The maintenance of an immune response with high levels of IFN-gamma production during the chronic phase of the infection may favor cure or influence the development of the cardiac form of the disease.
Chagas Disease↗
Cytokines as determinants of resistance and pathology in human Schistosoma mansoni infection.
The role of different cytokines in the peripheral blood mononuclear cell (PBMC) proliferative response and in in vitro granuloma formation was evaluated in a cross-sectional study with patients with the different clinical forms and phases of Schistosoma mansoni infection, as well as a group of individuals "naturally" resistant to infection named normal endemic (NE). The blockage of IL-4 and IL-5 using anti-IL-4 and anti-IL-5 antibodies significantly reduced the PBMC proliferative response to soluble egg (SEA) and adult worm (SWAP) antigens in acute (ACT), chronic intestinal (INT) and hepatosplenic (HS) patients. Similar results were obtained in the in vitro granuloma formation. Blockage of IL-10 had no significant effect on either assay using PBMC from ACT or HS. In contrast, the addition of anti-IL-10 antibodies to PBMC cultures from INT patients significantly increased the proliferative response to SEA and SWAP as well as the in vitro granuloma formation. Interestingly, association of anti-IL-4 and anti-IL-10 antibodies did not increase the PBMC proliferative response of these patients, suggesting that IL-10 may act by modulating IL-4 and IL-5 secretion. Addition of recombinant IL-10 decreased the proliferative response to undetectable levels when PBMC from patients with the different clinical forms were used. Analysis of IFN-gamma in the supernatants showed that PBMC from INT patients secreted low levels of IFN-gamma upon antigenic stimulation. In contrast, PBMC from NE secreted high levels of IFN-gamma. These data suggest that IL-10 is an important cytokine in regulating the immune response and possibly controlling morbidity in human schistosomiasis mansoni, and that the production of IFN-gamma may be associated with resistance to infection.
Animals↗
Second-hand smoke is an adjuvant for T helper-2 responses in a murine model of allergy.
Epidemiologic studies have suggested that "second-hand smoke" increases the incidence and severity of allergies and asthma. To address this, we developed a murine model that included generation of and exposure to environmental tobacco smoke (ETS) followed by aerosolized Ag challenge. We report herein that exposure of OVA-sensitized BALB/c mice to ETS elicits a rapid and prolonged exaggerated response with respect to IgE, IgG1, eosinophils, and Th2 cytokines (particularly IL-4 and IL-10). There was a significant increase (p = 0.0159) in the total cells of the bronchoalveolar lavage in OVA-sensitized mice exposed to ETS when compared with those in ambient air. This is the first experimental data to demonstrate that "second-hand smoke" up-regulates the allergic response to inhaled Ag. The results have important health implications for children and allergic individuals residing in households with smokers.
Adjuvants, Immunologic↗
Induction of human T helper cell type 1 differentiation results in loss of IFN-gamma receptor beta-chain expression.
Differential expression of cytokine receptors accounts for an important regulatory mechanism in differentiation of Th1/Th2 subsets. Here, we report that human Th0 and Th2 clones constitutively express transcripts for the IFN-gammaR beta-chain, whereas mRNA for this signaling component of the IFN-gamma receptor is absent in Th1 clones. Activation of T cell clones, however, resulted in a transient induction or enhancement of IFN-gammaR beta-chain mRNA expression in Th1 clones and Th0/Th2 clones, respectively. IL-12-mediated Th1 cell differentiation of naive CD4+, CD45RA+ cord blood T cells, which constitutively express IFN-gammaR beta-chain mRNA, resulted in a loss of expression of this cytokine receptor chain after 6 to 12 days of culture. In contrast, Th2 populations, differentiated from CD4+, CD45RA+ cord blood T cells in the presence of IL-4, continued to express high levels of IFN-gammaR beta-chain transcripts. The loss of IFN-gammaR beta-chain expression in Th1 populations was accompanied by a failure of IFN-gamma to induce the expression of the IFN-gamma-inducible gene, IFN response factor-1, whereas IFN-gamma was effective in inducing IFN response factor-1 mRNA expression in Th0 and Th2 cells. These results indicate that down-regulation of the IFN-gammaR beta-chain correlates with impaired IFN-gamma-induced signaling in Th1 cells. Finally, Th2 populations, generated in the presence of both IL-4 and IFN-gamma, expressed levels of IFN-gammaR beta-chain transcripts similar to those produced by cells differentiated in the presence of IL-4 only, demonstrating that IFN-gamma does not modulate the expression of its receptor. Together, these data indicate that human Th0/Th2 and Th1 subsets, respectively, can be distinguished based on the expression of the IFN-gammaR beta-chain.
CD4-Positive T-Lymphocytes↗
Behavior of visceral Leishmania donovani in an experimentally induced T helper cell 2 (Th2)-associated response model.
Although implicated in the clinical expression of human visceral leishmaniasis, a disease-exacerbating T helper cell 2 (Th2)-associated immune response involving interleukin-4 (IL-4) and/ or IL-10 is not readily detectable in experimental visceral infection. To overcome this obstacle to analyzing visceral Leishmania donovani in this relevant immunopathogenetic environment, we sought a model in which a Th2 response induces noncuring infection. Four initial approaches were tested primarily in BALB/c mice which control intracellular L. donovani via an IL-12- and interferon-gamma (IFN-gamma)-dependent Th1 mechanism: (a) modifying the cytokine milieu when the parasite is first encountered (treatment with exogenous IL-4 or anti-IL-12), (b) providing sustained endogenous exposure to a Th2 cytokine (infection of IL-4 transgenic mice), (c) increasing the parasite challenge inoculum, and (d) injecting heat-killed L. major promastigotes (HKLMP) to induce a cross-reactive Th2 response to live L. donovani. Only the last approach generated a functional Th2-type response that induced disease exacerbation accompanied by inhibition of tissue granuloma assembly. In HKLMP-primed BALB/c mice, prophylaxis with anti-IL-4, anti-IL-10, or exogenous IL-12 (but not IFN-gamma) readily restored resistance. In primed mice with established visceral infection, treatment with either IL-12 or IFN-gamma also successfully induced antileishmanial activity. The results in this model (a) suggest that rather than acting alone, IL-4 and IL-10 may act in concert to prevent acquisition of resistance to L. donovani, (b) reemphasize the capacity of IL-12 to reverse early Th2-related effects, and (c) demonstrate that Th1 cytokines (IL-12, IFN-gamma) have therapeutic action in an established systemic infection despite the presence of a disease-exacerbating Th2-type response.
Animals↗