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Transplantation tolerance induced by neonatal injection of semi-allogeneic spleen cells is associated with a pathological syndrome caused by T helper type 2 (Th2) differentiation of donor-specific CD4 T lymphocytes. We have shown previously that this Th2-biased response is inhibited by host CD8 T cells. Herein, we demonstrate that upon neonatal immunization with (A/J × BALB/c)F spleen cells, BALB/c mice expand a population of CD8 T cells expressing both CD25 and forkhead box P3 (FoxP3) markers. In this setting, CD8CD25 T cells predominantly produce interferon (IFN)-γ and interleukin (IL)-10 and are efficient in controlling IL-4, IL-5 and IL-13 production by donor-specific CD4 T cells in vitro. CD8FoxP3 T cells are single producers of IFN-γ or IL-10, whereas CD8FoxP3 T cells are double producers of IFN-γ and IL-10. We further demonstrate that IFN-γ and IL-10 are two major cytokines produced by CD8 T cells involved in the in vivo regulation of Th2-type pathology. In this setting, we conclude that neonatal alloimmunization induces the expansion of several regulatory CD8 T cells which may control Th2 activities via IFN-γ and IL-10. [ABSTRACT FROM AUTHOR]

Characterization of the Toll-like receptor (TLR) family and associated signalling pathways provides a key molecular basis for our understanding of the relationship between exposure to microbial products and susceptibility to immune-mediated disorders. Indeed, ligation of TLR controls innate and adaptive immune responses by inducing synthesis of pro- as well as anti-inflammatory cytokines and activation of effector as well as regulatory lymphocytes. TLRs are therefore considered as major targets for the development of vaccine adjuvants, but also of new immunotherapies. Herein, we review the potential of TLR ligands as a novel class of pharmaceuticals for the prevention or treatment of allergic disorders. [ABSTRACT FROM AUTHOR]

The functional repertoire of T cells in abdominal aortic aneurysm (AAA) and the exact nature of aortic wall adaptive cellular immune responses still remains a matter of debate. In this study, we sought to determine whether type 1 or type 2 responses occur predominantly in human aneurysmal aortic lesions. We first examined the phenotype and cytokine secretion profile of T lymphocytes freshly isolated from aneurysmal aortic wall for comparison with their circulating counterparts using flow cytometry. We found that both populations of infiltrating CD4+ and CD8+T cells displayed a unique activated memory phenotype. In addition, we identified the presence in human aneurysmal aortic lesion of CD4+T cells producing high levels of interferon (IFN)-γ but not interleukin (IL)-4, reflecting their type 1 nature. Quantitative analysis of cytokine gene expression confirmed increased IFN-γ transcript levels in infiltrating cells compared to controls. We next analysed aortic wall responses using LightCycler-based quantitative real-time reverse transcription-polymerase chain reaction. Compared to control non-diseased aortic samples, we demonstrated that whole AAA tissues exhibited high mRNA levels of IFN-γ but not IL-4. Overexpression of the transcription factor T-bet in the absence of significant GATA-3 expression further assessed the type 1 polarization of aortic wall immune responses. These findings indicate that type 1 CD4+T cells predominate in human AAA lesions. This study has important implications for the pathogenesis of aneurysm disease. Through the production of IFN-γ, T cells may indeed contribute to orchestrate extracellular matrix remodelling. [ABSTRACT FROM AUTHOR]

Infections with intracellular pathogens are often more severe or more prolonged in young infants suggesting that T cell-mediated immune responses are different in early life. Whereas neonatal immune responses have been quite extensively studied in murine models, studies of T cell-mediated immunity in human newborns and infants are scarce. Qualitative and quantitative differences when compared with adult immune responses have been observed but on the other hand mature responses to certain vaccines and infectious pathogens were demonstrated during the postnatal period and even during foetal life. Herein, we review the evidence suggesting that under appropriate conditions of stimulation, protective T cell-mediated immune responses could be induced by vaccines in early life. [ABSTRACT FROM AUTHOR]

Dendritic cell (DC)-based immunization represents a promising approach for the immunotherapy of cancer. The optimal conditions required to prepare DCs remain to be defined. Monocytes incubated in the presence of interferon (IFN)-β and interleukin (IL)-3 give rise to a distinct type of DCs (IFN-β/IL-3 DCs) that are particularly efficient at eliciting IFN-γ and IL-5 production by allogeneic helper T cells. We assessed the capacity of this new type of DCs to prime antigen-specific naive CD8+ T cells and compared them to the conventional DCs differentiated in the presence of granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-4 (GM-CSF/IL-4 DCs). We demonstrate that IFN-β/IL-3 DCs matured by TLR3 or CD40 ligation efficiently prime Melan-A26−35-specific CD8+ T cellsin vitro, at a similar level as GM-CSF/IL-4 DCs. Activated antigen-specific CD8+ T cells produced IFN-γ and displayed potent cytotoxic activity against peptide-pulsed target cells. Expansion of CD8+ T cell numbers was generally higher following priming with CD40-L than with polyinosinic–polycytidylic acid (poly I:C) matured DCs. Cytolytic activity was induced by both maturing agents. These data indicate that IFN-β/IL-3 DCs represent a promising cell population for the immunotherapy of cancer. [ABSTRACT FROM AUTHOR]

Balb/c mice made chimaeric by neonatal injection or semi-allogeneic(A/J × Balb/c)F1 hybrid spleen cells develop anti-DNA and rheumatoid factor-like antibodies in the context of hypergammaglobulinaemia with marked elevation of IgG 1 and IgE serum levels. Chimaeric mice also display increased levels of antibodies to different haptens and to tobacco mosaic virus (TMV). The allotypic marker of the A/J strain is present on anti-DNA and anti-hapten antibodies. In addition, spleen cells of chimaeric mice spontaneously produce high levels of IgG 1 and anti-DNA antibodies in vitro and this hyperactivity is abolished after lysis of donor lymphocytes. These findings indicate that polyclonal activation of donor B cells plays an important role in this model of autoimmunity. [ABSTRACT FROM AUTHOR]

Balb/c neonates injected with semi-allogeneic (A/J x Balb/c) F1 hybrid spleen cells develop an autoimmune disease associated with an immune-complex glomerulonephritis. The successful induction and maintenance of B cell chimerism is required for the occurrence of autoimmunity. The percentage of chimeric mice displaying autoimmune features increases in parallel with the number of cells injected at birth. T cell depleted inocula although readily inducing B cell chimerism were found unable to induce hypergammaglobulinaemia, circulating immune complexes and glomerulonephritis. IgG1 is the most and IgG3 the least represented IgG isotype among the immunoglobulins deposited in the glomeruli. Immunoglobulins bearing donor (A/J) allotype are detected in the glomeruli of six out of 11 chimeric mice. Rheumatoid factor activity is significantly concentrated within the immunoglobulins eluted from the kidneys, whereas anti-DNA activity is not. [ABSTRACT FROM AUTHOR]

We examined the effects of IL-10 on tumour necrosis factor-alpha (TNF-α) and NO production by LPS-activated macrophages and on the ability of these cells to control Trypanosoma cruzi infection. We first observed that the addition of rIL-10 to macrophages of the J774 cell line decreased their synthesis of TNF-α but increased their release of NO in a dose-dependent manner. In parallel, treatment of J774 cells with rIL-10 resulted in a better control of T. cruzi infection involving up-regulation of NO synthesis, as it was not observed in presence of N-nitro-L-arginine methyl ester (L-NAME), a competitive inhibitor of NO synthase. The enhancing effect of rIL-10 on NO production was not observed on peritoneal macrophages from wild-type C57Bl/6 mice, but well on macrophages from IL-10 knock-out mice. The control of NO production by endogenous IL-10 was confirmed by the demonstration that neutralization of IL-10 secreted by LPS-activated macrophages from wild-type mice inhibited their production of NO and, in parallel, their ability to control T. cruzi infection. Taken together, these data demonstrate that both exogenous and endogenous IL-10 up-regulate the production of NO by LPS-activated macrophages and improve thereby their ability to clear T. cruzi infection. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by polyclonal B cell activation and by the production of anti-double-stranded (ds) DNA antibodies. Given the inhibitory effects of IL-12 on humoral immune responses, we investigated whether IL-12 displayed such an activity on in vitro immunoglobulin production by SLE PBMC, Spontaneous IgG, IgG1, IgG2, IgG3 and IgM antibody production was dramatically reduced by addition of IL-12, These results were confirmed by Elispot assays detecting IgG- and anti-dsDNA-secreting cells. While IL-6 and TNF titres measured in PBMC supernatants were not modified by addition of IL-12, interferon-gamma (IFN-γ) titres were up-regulated and IL-10 production down-regulated. Since addition of IFN-γ did not down-regulate immunoglobulin production and since the inhibitory activity of IL-12 on immunoglobulin synthesis was not suppressed by anti-IFN-γ antibody, we concluded that the effect of IL-12 on immunoglobulin production was not mediated through IFN-γ. Our data also argue against the possibility that down-regulation of endogenous IL-10 production was responsible for the effect of IL-12, Thus, inhibition of IL-10 production by IFN-γ was not accompanied by inhibition of immunoglobulin production, and conversely, restoration of IL-10 production by anti-IFN-γ antibody did not suppress the inhibitory activity exerted by 11-12 on immunoglobulin production. Taken together, our data indicate that reduction of excessive immunoglobulin and anti-dsDNA antibody production by lupus PBMC can be achieved in vitro by IL-12, independently of IFN-γ and IL-10 modulation. [ABSTRACT FROM AUTHOR]

The injection of the 145-2C11 anti-CD3 MoAb in mice induces a polyclonal T cell activation resulting in the release of several cytokines, including interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α). As these cytokines are known to be involved in the host defence against Trypanosoma cruzi, we measured serum levels of IFN-γ and TNF-α after injection of the 145-2C11 MoAb in the course of experimental murine Chagas' disease. Compared with control mice, T. cruzi-infected BALB/c mice were found to be primed to secrete very high levels of IFN-γ and TNF-α from the second and the first week of infection, respectively, up to the chronic phase. In vivo cell depletion experiments indicated that CD8+ T cells were responsible for these dramatic hyperproductions of IFN-γ and TNF-α. While all control mice survived anti-CD3 MoAb injection, a high lethality rate was observed in T. cruzi-infected mice within 24 h after anti-CD3 MoAb challenge. Pretreatment with neutralizing anti-IFN-γ MoAb or depletion of CD8+ T cell population dramatically decreased the mortality induced by anti-CD3 MoAb in T. cruzi-infected mice. Finally, we showed that anti-CD3 MoAb injection in T. cruzi-infected mice was followed by a massive release of nitric oxide (NO) metabolites, which was partially reduced by IFN-γ or TNF-α neutralization. The administration of the NO synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) before anti-CD 3 MoAb challenge did not prevent and even enhanced lethality in T. cruzi-infected mice, suggesting that NO overproduction and lethal shock are not causally related. We conclude that injection of anti-CD3 MoAb in the course of experimental Chagas' disease induces a CD8+ cell-dependent shock mediated by IFN-γ and TNF-α. [ABSTRACT FROM AUTHOR]

Thoracic trauma or pneumothorax can result in pleural fluid eosinophilia. in this study we investigated the role of the eosinophilopoietic cytokine IL-5 in three cases of post-traumatic eosinophilic pleural effusions (EPE). Using a specific immunoenzymatic assay, significant levels of IL-S were found in EPE (range 100-3000 pg/mi), white IL-S was undetectable (<25 pg/mI) in corresponding serum samples and in non-eosinophilic pleural fluids. 1L-5 present in pleural fluids was found bioactive in a proliferative assay using a mouse CTLL-2 cell line transfected with the cDNA corresponding to the α chain of the human IL-S receptor. Using a reverse polymerase chain reaction (PCR) method, we found IL-5 mRNA expression within pleural mononuclear cells from patients with EPE, but not in corresponding peripheral blood mononuclear cells (PBMC), confirming that IL- 5 is synthesized locally in the pleural cavity. In the two cases in which pleural CD4+ cells were purified, these cells were identified as the major source of IL-5. Taken together, these data indicate that the development of post-traumatic EPE is related to a local secretion of IL-S by CD4+ cells present in the pleural cavity. [ABSTRACT FROM AUTHOR]

Administration of HgCl2 to the susceptible Brown-Norway (BN) rats induces an autoimmune disease characterized by a T-dependent polyclonal activation of B cells responsible for a dramatic increase in serum IgE concentration. The resistant Lewis (LEW) rats injected with HgCl2 do not exhibit such autoimmune manifestations. We show here that, upon HgCl2 injections, major histocompatibility complex (MHC) class II molecule expression is increased very early in lymph nodes and spleen B cells from both strains. So far, it is the earliest marker (day 3) of the effect of HgCl2 on the immune system. In both strains this enhancement is transient, but regulatory mechanisms are much more efficient in the resistant LEW strain than in the susceptible BN strain. In addition, we observed that MHC class II molecule expression on B cells differs according to the organ and the rat strain tested. All these findings are discussed in an attempt to underline the role of MHC class II molecule expression in the occurrence of mercury-induced autoimmunity. [ABSTRACT FROM AUTHOR]

BALB/c mice made tolerant to A/J alloantigens by neonatal injection of (A/J × BALB/c)F1 spleen cells develop a host-versus-graft (HVG) disease due to the activation of donor B cells by a subset of host alloreactive helper T cells. We have investigated the effects of a single neonatal injection of the 145-2C11 anti-mouse CD3 monoclonal antibody (MoAb) on the establishment of allotolerance and on the development of the immunopathological features of HVG disease. First, this treatment did not modify the specific anti-donor cytotoxic T lymphocyte (CTL) unresponsiveness or the persistence of circulating immunoglobulins bearing donor allotype. Second, the hyper IgE, the hyper IgG 1 and the increased expression of Ia antigens on B cells found in untreated HVG mice were not observed after injection of the 145-2C11 MoAb. Likewise, treated mice displayed lower levels of anti-DNA IgG antibodies and less glomerular immune deposits as compared with untreated HVG mice. We conclude that the administration of the anti-CD3 MoAb did not interfere with the induction of allotolerance but exerts a pronounced inhibitory effect on the associated immunopathological syndrome. [ABSTRACT FROM AUTHOR]

Intravenous injection of 2 × 108 DBA/2 spleen cells into adult intact (C57BL/6 × DBA/2) Fl mice results in a stimulatory graft-versus-host reaction (GVHR) linked to the recognition by donor CD4+ T cells of Ia alloantigens on host B cells. In the experiments presented here, we found that this GVHR is associated with a major increase in IgE serum levels which was already present 7 days after the cell transfer. At 6 weeks, mean IgE levels were more than 200-fold above the control values. Host B cells were responsible for the hypersecretion of IgE in stimulatory GVHR since it was also observed when the DBA/2 donor inoculum was depleted of B cells but not when the Fl recipients were irradiated. The induction of IgE secretion required donor CD4+ T cells as treatment of the donor inoculum with lytic anti-CD4 monoclonal antibody (MoAb) completely prevented the occurrence of the hyper IgE whereas depletion of CD8+ cells had no influence on this parameter. The role played by interleukin-4 (IL-4) in this model was analysed in vivo by the administration of the 11B11 anti-IL-4 rat MoAb (total dose 36 mg) during the first 12 days following induction of stimulatory GVHR by 8 × 107 DBA/2 spleen cells. This treatment completely prevented the development of hyper IgE whereas the administration of a control rat MoAb had no significant effect. We conclude that stimulatory GVHR in mice is associated with a major increase in serum IgE which is mediated by IL-4. [ABSTRACT FROM AUTHOR]