Predominant Th1 Immune Response Research Articles

Immunostimulatory oligodeoxynucleotides promote protective immunity and provide systemic therapy for leishmaniasis via IL-12- and IFN-gamma-dependent mechanisms.

Resistance to murine leishmaniasis correlates with development of a CD4(+) T helper 1 (Th1)-predominant immune response. To determine whether immunostimulatory CpG-containing oligodeoxynucleotides (CpG-ODN), known to promote a Th1 immune response, could provide protection from Leishmania infection, CpG-ODN and freeze-thawed (F/T) Leishmania major were coinjected intradermally into susceptible BALB/c mice. A Leishmania-specific Th1-predominant immune response was induced, and 40% of animals were protected from subsequent challenge with infectious organisms, with 0% protection of animals injected with F/T Leishmania organisms and PBS, F/T organisms and control ODN, or F/T organisms alone. More striking protection (65-95%) was seen in mice first infected with intact Leishmania organisms and then injected with CpG-ODN, either at the site of infection or at a remote site. To determine whether the therapeutic protection provided by CpG-ODN depended on IL-12 and IFN-gamma production, both IFN-gamma-deficient BALB/c mice and BALB/c mice treated with neutralizing anti-IL-12 mAb were first inoculated with Leishmania and then treated with either CpG-ODN, ODN, or PBS. None of these IFN-gamma-deficient mice survived (0/20, 0/20, and 0/20 respectively). Furthermore, neutralization of IL-12 completely abolished the therapeutic protection provided by CpG-ODN (0/20 mice surviving). We conclude that immunostimulatory DNA sequences likely exert systemic effects via IL-12 and IFN-gamma-dependent mechanisms and hold considerable promise as both vaccine adjuvants and potential therapeutic agents in the prevention and treatment of leishmaniasis.

Bacterial DNA and CpG–Containing Oligodeoxynucleotides Activate Cutaneous Dendritic Cells and Induce IL–12 Production: Implications for the Augmentation of Th1 Responses

Background: Unmethylated CpG sequences in bacterial DNA act as adjuvants selectively inducing Th1 predominant immune responses during genetic vaccination or when used in conjunction with protein Ag. The precise mechanism of this adjuvant effect is unknown. Because dendritic cells (DC) are thought to be crucially involved in T cell priming and Th1/Th2 education during vaccination via skin, we characterized the effects of bacterial DNA and CpG–containing oligodeoxynucleotides (CpG ODN) on cutaneous DC. Methods and Results: Stimulation with CpG ODN 1826 (6 μg/ml) induced activation of immature Langerhans cell (LC)–like DC as determined by an increased expression of MHC class II and costimulatory molecules, loss of E–cadherin–mediated adhesion and increased ability to stimulate allogeneic T cells. Composition–matched control ODN 1911 lacking CpG sequences at equal concentrations was without effect. In comparison to LPS and ODN 1911, CpG ODN 1826 selectively stimulated DC to release large amounts of IL–12 (p40) and little IL–6 or TNF–α within 18 h and detectable levels of IL–12 p70 within 72 h. Stimulation with Escherichia coli DNA, but not calf thymus DNA, similarly induced DC maturation and IL–12 p40 production. Injection of CpG ODN into murine dermis induced enhanced expression of MHC class II and CD86 by LC in the overlying epidermis and intracytoplasmic IL–12 p40 accumulation in a subpopulation of activated LC. Conclusion: Bacterial DNA and CpG ODN stimulate DC in vitro and in vivo and may preferentially elicit Th1–predominant immune responses because they can activate and mobilize DC, inducing them to produce IL–12.

Th1 and Th2 T helper cell subsets affect patterns of injury and outcomes in glomerulonephritis

The recognition that human immune responses can be directed by two different subsets of T helper cells (Th1 and Th2) has been an important development in modern immunology. Immune responses polarized by either the Th1 or Th2 subset predominance result in different inflammatory effector pathways and disease outcomes. Many autoimmune diseases are associated with either Th1- or Th2- polarized immune responses. Although these different immune response patterns are relevant to glomerulonephritis (GN), little attention has been paid to the consequences of Th1 or Th2 predominance of nephritogenic immune responses for the pattern and outcome of GN. Unlike other autoimmune conditions, GN results from a variety of different immune responses and has a range of histologic features and immune effectors in glomeruli. This review assesses the data available from studies of experimental and human GN that address the Th1 or Th2 predominance of nephritogenic immune responses and their relevance to the different histopathological patterns and outcomes of GN. In particular, the evidence that Th1-predominant nephritogenic immune responses are associated with severe proliferative and crescentic GN is presented.

Activation of Cutaneous Dendritic Cells by CpG-Containing Oligodeoxynucleotides: A Role for Dendritic Cells in the Augmentation of Th1 Responses by Immunostimulatory DNA

Genetic vaccination depends at least in part on the adjuvant properties of plasmids, properties that have been ascribed to unmethylated CpG dinucleotides in bacterial DNA. Because dendritic cells (DC) participate in the T cell priming that occurs during genetic vaccination, we reasoned that CpG-containing DNA might activate DC. Thus, we assessed the effects of CpG oligodeoxynucleotides (CpG ODN) on Langerhans cell (LC)-like murine fetal skin-derived DC (FSDDC) in vitro and on LC in vivo. Treatment with CpG ODN as well as LPS induced FSDDC maturation, manifested by decreased E-cadherin-mediated adhesion, up-regulation of MHC class II and costimulator molecule expression, and acquisition of enhanced accessory cell activity. In contrast to LPS, CpG ODN stimulated FSDDC to produce large amounts of IL-12 but only small amounts of IL-6 and TNF-alpha. Injection of CpG ODN into murine dermis also led to enhanced expression of MHC class II and CD86 Ag by LC in overlying epidermis and intracytoplasmic IL-12 accumulation in a subpopulation of activated LC. We conclude that immunostimulatory CpG ODN stimulate DC in vitro and in vivo. Bacterial DNA-based vaccines may preferentially elicit Th1-predominant immune responses because they activate and mobilize DC and induce them to produce large amounts of IL-12.

Asthma and respiratory syncytial virus infection in infancy: is there a link?

Asthma and respiratory syncytial virus infection in infancy: is there a link?

Interferon-gamma expression by Th1 effector T cells mediated by the p38 MAP kinase signaling pathway

Signal transduction via MAP kinase pathways plays a key role in a variety of cellular responses, including growth factor-induced proliferation, differentiation and cell death. In mammalian cells, p38 MAP kinase can be activated by multiple stimuli, such as pro-inflammatory cytokines and environmental stress. Although p38 MAP kinase is implicated in the control of inflammatory responses, the molecular mechanisms remain unclear. Upon activation, CD4+ T cells differentiate into Th2 cells, which potentiate the humoral immune response or pro-inflammatory Th1 cells. Here, we show that pyridinyl imidazole compounds (specific inhibitors of p38 MAP kinase) block the production of interferon-gamma (IFNgamma) by Th1 cells without affecting IL-4 production by Th2 cells. These drugs also inhibit transcription driven by the IFNgamma promoter. In transgenic mice, inhibition of the p38 MAP kinase pathway by the expression of dominant-negative p38 MAP kinase results in selective impairment of Th1 responses. In contrast, activation of the p38 MAP kinase pathway by the expression of constitutivelyactivated MAP kinase kinase 6 in transgenic mice caused increased production of IFNgamma during the differentiation and activation of Th1 cells. Together, these data demonstrate that the p38 MAP kinase is relevant for Th1 cells, not Th2 cells, and that inhibition of p38 MAP kinase represents a possible site of therapeutic intervention in diseases where a predominant Th1 immune response leads to a pathological outcome. Moreover, our study provides an additional mechanism by which the p38 MAP kinase pathway controls inflammatory responses.

Interstitial pneumonitis in bone marrow transplant recipients is associated with local production of TH2-type cytokines and lack of T cell-mediated cytotoxicity.

Interstitial pneumonitis, especially associated with cytomegalovirus (CMV) infection, is a serious complication after bone marrow transplantation (BMT), with a high fatality rate despite adequate antiviral treatment. The aim of this study was to elucidate the local immunopathogenesis of interstitial pneumonitis caused by CMV or other agents in BMT recipients. Cryopreserved lung tissue obtained from 12 patients with interstitial pneumonitis following BMT was analyzed for cytokine production at the single-cell level using a cytokine-specific monoclonal antibody and immunohistochemical technique. Cytokine production in individual cells was analyzed using monoclonal antibodies to 23 different human cytokines: interleukin (IL)-1 to IL-13, tumor necrosis factor (TNF)-alpha, TNF-beta, interferon-gamma (IFNgamma), granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and transforming growth factor (TGF)-beta1 to 3. Marrow transplant patients with interstitial pneumonia had increased numbers of infiltrating alveolar macrophages, CD3+, CD4+ T cells, and CD40+ B cells and significantly increased numbers of IL-4-, IL-10-, IL-1-, TGF-beta1-, TGF-beta2-, and TGF-beta3-producing cells than controls. IL-2-, IFN-gamma-, and TNF-beta-producing cells were undetectable in most patients with CMV pneumonitis (n=7). Neither perforin-positive CD8+ T lymphocytes nor up-regulation of the apoptotic pathway was detected in lung tissue from patients with interstitial pneumonia. In contrast, extensive local production of IgA, IgG, and IgM was demonstrated in all patients. Intracellular and extensive extracellular deposition of CD68, the L-1 antigen synthesized in CD14+ macrophages, was found. The cytokine profile suggested that Th1-type cytokine production was absent, whereas production of Th2-type cytokines was significantly up-regulated. Interstitial pneumonitis in BMT recipients with fatal outcome (11/12 patients) was associated with dysregulation in the local cytokine network notable for a predominant Th2 immune response with minimal or absent T cell-mediated cytotoxicity.