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Results for “Adaptive Immunity”

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At least 811 records · Page 45Linked to original sources

PubMed2004

Signaling danger: toll-like receptors and their potential roles in kidney disease.

Toll-like receptors (TLR) are an emerging family of receptors that recognize pathogen-associated molecular patterns and promote the activation of leukocytes and intrinsic renal cells. Ligands of the TLR include exogenous microbial components such as LPS (TLR4), lipoproteins and peptidoglycans (TLR1, -2, -6), viral RNA (TLR3), bacterial and viral unmethylated cytosin-guanosin dinucleotide (CpG)-DNA (TLR9), and endogenous molecules including heat-shock proteins and extracellular matrix molecules. Upon stimulation, TLR induce expression of inflammatory cytokines or costimulatory molecules via the MyD88-dependent and MyD88-independent signaling pathways shared with the interleukin-1 receptors. TLR are differentially expressed on leukocyte subsets and non-immune cells and appear to regulate important aspects of innate and adaptive immune responses. Tubular epithelial cells are among the non-immune cells that express TLR1, -2, -3, -4, and -6, suggesting that these TLR might contribute to the activation of immune responses in tubulointerstitial injury (e.g., bacterial pyelonephritis, sepsis, and transplant nephropathy). In addition, TLR9 has been shown to be involved in antigen-induced immune complex glomerulonephritis and lupus nephritis by regulating humoral and cellular immune responses. TLR are evolutionary conserved regulators of innate and adaptive immune responses. It is likely that TLR are involved in many if not all types of renal inflammation. Here the authors provide an overview on the biology of TLR, summarize the present data on their expression in the kidney, and provide an outlook for the potential roles of TLR in kidney disease.

Animals↗

PubMed2006

Type, density, and location of immune cells within human colorectal tumors predict clinical outcome.

The role of the adaptive immune response in controlling the growth and recurrence of human tumors has been controversial. We characterized the tumor-infiltrating immune cells in large cohorts of human colorectal cancers by gene expression profiling and in situ immunohistochemical staining. Collectively, the immunological data (the type, density, and location of immune cells within the tumor samples) were found to be a better predictor of patient survival than the histopathological methods currently used to stage colorectal cancer. The results were validated in two additional patient populations. These data support the hypothesis that the adaptive immune response influences the behavior of human tumors. In situ analysis of tumor-infiltrating immune cells may therefore be a valuable prognostic tool in the treatment of colorectal cancer and possibly other malignancies.

CD3 Complex↗

PubMed2002

Heat shock proteins as ligands of toll-like receptors.

Toll-like receptors (TLRs) have been described as sensors for pathogen-associated molecular patterns crucial for the initiation of an innate immune response. These mechanisms were developed long before the adaptive immune system evolved. The latest additions to the growing list of TLR ligands are heat shock proteins (HSPs). Interestingly, not only bacterial but also mammalian HSPs interact with TLRs demonstrating that the exclusive association of TLRs with microbial ligands is obsolete. Human HSP60 and Gp96 are the first examples of non-pathogen derived ligands of TLRs. More importantly, Gp96 provides the first example of how the innate and adaptive immune system can be stimulated simultaneously by the same molecule which is released under physiological conditions from necrotic cells. Understanding the mechanisms of innate immune system interaction with HSPs will make it possible to rationally modulate immune responses, either towards immunity or towards tolerance.

Animals↗

PubMed2002

Effects of antigen and genetic adjuvants on immune responses to human immunodeficiency virus DNA vaccines in mice.

The effects of genetic adjuvants on humoral and cell-mediated immunity to two human immunodeficiency virus antigens, Env and Nef, have been examined in mice. Despite similar levels of gene expression and the same gene delivery vector, the immune responses to these two gene products differed following DNA immunization. Intramuscular immunization with a Nef expression vector plasmid generated a humoral response and antigen-specific gamma interferon (IFN-gamma) production but little cytotoxic-T-lymphocyte (CTL) immunity. In contrast, immunization with an Env vector stimulated CTL activity but did not induce a high-titer antibody response. The ability to modify these antigen-specific immune responses was investigated by coinjection of DNA plasmids encoding cytokine and/or hematopoietic growth factors, interleukin-2 (IL-2), IL-12, IL-15, Flt3 ligand (FL), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Coadministration of these genes largely altered the immune responses quantitatively but not qualitatively. IL-12 induced the greatest increase in IFN-gamma and immunoglobulin G responses to Nef, and GM-CSF induced the strongest IFN-gamma and CTL responses to Env. A dual approach of expanding innate immunity by administering the FL gene, together with a cytokine that enhances adaptive immune responses, IL-2, IL-12, or IL-15, generated the most potent immune response at the lowest doses of Nef antigen. These findings suggest that intrinsic properties of the antigen determine the character of immune reactivity for this method of immunization and that specific combination of innate and adaptive immune cytokine genes can increase the magnitude of the response to DNA vaccines.

AIDS Vaccines↗

PubMed2006

Death receptor signaling and its function in the immune system.

Death receptors belong to the TNF (tumor necrosis factor)/NGF (nerve growth factor) receptor superfamily. Signaling via death receptors plays a distinct role, e.g. in the immune system, where it contributes to regulation of the adaptive immune response in various ways, most notably by triggering activation-induced cell death (AICD) of T cells. Thus, dysregulation of death receptor signaling, either allowing too much or too little apoptosis, can lead to autoimmune disorders and also impacts on tumorigenesis or other diseases. In this chapter we address components, molecular mechanisms and regulation of death receptor signaling with particular focus on CD95 (APO-1, Fas). We discuss the role of death receptor-mediated AICD in regulation of the adaptive immune response against foreign and self antigens in comparison to cytokine deprivation-mediated death by neglect. Finally, the contribution of dysregulated death receptor/ligand systems to autoimmune diseases such as diabetes, multiple sclerosis and Hashimoto's thyroiditis is discussed.

Animals↗

PubMed2007

[Innate immunity: structure and function of TLRs].

The innate immune system provides the first line of defence against infection. Through a limited number of germline-encoded receptors called pattern recognition receptors (PRRs), innate cells recognize and are activated by highly conserved structures expressed by large group of microorganisms called pathogen-associated molecular patterns (PAMPs). PRRs are involved either in recognition (scavenger receptors, C-type lectins) or in cell activation (Toll-like receptors or TLR, helicases and NOD molecules). TLRs play a pivotal role in cell activation in response to PAMPs. TLR are type I transmembrane proteins characterized by an intracellular Toll/IL 1 receptor homology domain that are expressed by innate immune cells (dendritic cells, macrophages, NK cells), cells of the adaptive immunity (T and B lymphocytes) and non immune cells (epithelial and endothelial cells, fibroblasts). In all the cell types analyzed, TLR agonists, alone or in combination with costimulatory molecules, induce cell activation. The crucial role played by TLR in immune cell activation has been detailed in dendritic cells. A TLR-dependent activation of dendritic cells is required to induce their maturation and migration to regional lymph nodes and to activate naïve T cells. The ability of different cell types to respond to TLR agonists is related to the pattern of expression of the TLRs and its regulation as well as their intracellular localization. Recent studies suggest that the nature of the endocytic and signaling receptors engaged by PAMPs may determine the nature of the immune response generated against the microbial molecules, highlighting the role of TLRs as molecular interfaces between innate and adaptive immunity. In this review are summarized the main biological properties of the TLR molecules.

Epithelial Cells↗

PubMed1998

The role of complement and complement receptors in induction and regulation of immunity.

Covalent attachment of activated complement C3 (C3d) to antigen links innate and adaptive immunity by targeting antigen to follicular dendritic cells (FDC) and B cells via specific receptors CD21 and CD35. Recent characterization of knockout mice deficient in complement components C3, C4, or the receptors CD21 and CD35 as well as biochemical studies of the CD21/CD19/Tapa-1 coreceptor on B cells have helped to elucidate the mechanism of complement regulation of both B-1 and B-2 lymphocytes. Interestingly, natural antibody of the adaptive immune system provides a major recognition role in activation of the complement system, which in turn enhances activation of antigen-specific B cells. Enhancement of the primary and secondary immune response to T-dependent antigens is mediated by coligation of the coreceptor and the B cell antigen receptor, which dramatically increases follicular retention and B cell survival within the germinal center. Most recent evidence suggests that complement also regulates elimination of self-reactive B cells, as breeding of mice that are deficient in C4 or CD21/CD35 with the lupus-prone strain of lpr mice demonstrates an exacerbation of disease due to an increase in autoantibodies.

Animals↗

PubMed2006

Direct stimulation of T cells by type I IFN enhances the CD8+ T cell response during cross-priming.

Type I IFN (IFN-alphabeta), which is produced rapidly in response to infection, plays a key role in innate immunity and also acts as a stimulus for the adaptive immune response. We have investigated how IFN-alphabeta induces cross-priming, comparing CD8+ T cell responses generated against soluble protein Ags in the presence or absence of IFN-alphabeta. Injection of IFN-alpha was found to prolong the proliferation and expansion of Ag-specific CD8+ T cells, which was associated with marked up-regulation of IL-2 and IL-15 receptors on Ag-specific cells and expression of IL-15 in the draining lymph node. Surprisingly, neither IL-2 nor IL-15 was required for IFN-alpha-induced cross-priming. Conversely, expression of the IFN-alphabetaR by T cells was shown to be necessary for effective stimulation of the response by IFN-alpha. The finding that T cells represent direct targets of IFN-alphabeta-mediated stimulation reveals an additional mechanism by which the innate response to infection promotes adaptive immunity.

Adoptive Transfer↗

PubMed2006

High mobility group B1 protein suppresses the human plasmacytoid dendritic cell response to TLR9 agonists.

Plasmacytoid dendritic cells (PDC) are innate immune effector cells that are recruited to sites of chronic inflammation, where they modify the quality and nature of the adaptive immune response. PDCs modulate adaptive immunity in response to signals delivered within the local inflammatory milieu by pathogen- or damage-associated molecular pattern, molecules, and activated immune cells (including NK, T, and myeloid dendritic cells). High mobility group B1 (HMGB1) is a recently identified damage-associated molecular pattern that is released during necrotic cell death and also secreted from activated macrophages, NK cells, and mature myeloid dendritic cells. We have investigated the effect of HMGB1 on the function of PDCs. In this study, we demonstrate that HMGB1 suppresses PDC cytokine secretion and maturation in response to TLR9 agonists including the hypomethylated oligodeoxynucleotide CpG- and DNA-containing viruses. HMGB1-inhibited secretion of several proinflammatory cytokines including IFN-alpha, IL-6, TNF-alpha, inducible protein-10, and IL-12. In addition, HMGB1 prevented the CpG induced up-regulation of costimulatory molecules on the surface of PDC and potently suppressed their ability to drive generation of IFN-gamma-secreting T cells. Our observations suggest that HMGB1 may play a critical role in regulating the immune response during chronic inflammation and tissue damage through modulation of PDC function.

Cell Proliferation↗

PubMed1996

The immune system of ectothermic vertebrates.

The adaptive immune system, as defined by T cell receptors, immunoglobulins, and the major histocompatibility complex (MHC), has been described definitively at the level of teleost fish. Cartilaginous fish, which display many of the hallmarks of such an adaptive system, nevertheless have several features of their responses that seem primitive. Data are presented suggesting that some adaptive mechanisms in cartilaginous fish, including MHC restriction and somatic diversification, are present to the same "degree' as compared to mammals, and that these animals may possess other molecules and functions previously overlooked. MHC linkage studies in amphibians suggest that the entire genetic complex, including class I, class II, and class III genes, arose early in the vertebrate line (at least 350 x 10(6) years ago) and has been maintained intact, at least for those genes involved in immunity. Studies of MHC in polyploid Xenopus have demonstrated that there is a maximal number of expressed MHC genes 'permitted' to be expressed in any individual, regardless of the number of potential MHC-bearing chromosomes present in the species. A speculative hypothesis is presented on the origins of adaptive immunity based on ectothermic models.

Animals↗

PubMed2005

The absence of platelet-derived growth factor-B in circulating cells promotes immune and inflammatory responses in atherosclerosis-prone ApoE-/- mice.

Both innate and adaptive immunity contribute to the progression of inflammatory-fibrotic lesions of atherosclerosis. Although platelet-derived growth factor (PDGF)-B has been investigated as a stimulant of smooth muscle cells in vascular diseases, its effects on the immune response during disease have not been evaluated in vivo. We used hematopoietic chimeras generated after lethal irradiation of ApoE-/- recipients to test the role of PDGF in atherosclerosis. Monocyte accumulation in early atherosclerotic lesions increased 1.9-fold in ApoE-/-/PDGF-B-/- chimeras. Lymphocytes from null chimeras showed a 1.6- to 2.0-fold increase in the number of activated CD4(+) T cells and a 2.5-fold elevation of interferon-gamma-secreting CD4(+) T cells on ex vivo challenge with modified low-density lipoprotein. Splenocyte transcript levels were also altered with a twofold decrease in interleukin-10 and 1.7- and 3.0-fold increases in interleukin-18 and CCR 5, respectively. These cellular and molecular changes were consistent with a shift to a proinflammatory phenotype in null chimeras. Our data also demonstrated for the first time the presence of a recently discovered family of negative regulators of innate and adaptive immunity, the suppressors of cytokine signaling (SOCS), in developing atherosclerotic lesions. Thus, our studies identify two independent negative immune regulatory pathways-PDGF-B and SOCS-that may help limit lesion expansion.

Animals↗

PubMed2006

Differential polarization of immune responses by genetic cotransfer of chemokines changes the protective immunity of DNA vaccine against pseudorabies virus.

Chemokines play a key role in eliciting adaptive immune responses by selectively attracting the innate cellular components to the site of antigen presentation. To evaluate the effect of the genetic adjuvant of chemokines on the adaptive immune responses induced by a plasmid DNA vaccine expressing glycorotein B (gB) of the pseudorabies virus (PrV), a PrV DNA vaccine was co-inoculated with plasmid DNA expressing certain chemokines including CCL3 (MIP-1alpha), CCL4 (MIP-1beta), CCL5 (RANTES), CXCL8 (MIP-2), and CXCL10 (IP-10). A co-injection of the CCL3 plasmid DNA induced immunity that was biased to the T helper type 2 (Th2) pattern, as judged by the ratio of immunoglobulin G isotypes and the production of interleukin-4 cytokine generated from stimulated immune T cells. However, CCL5 and CXCL10 induced immune responses of the Th1-type, which rendered the recipients more resistant to a virulent virus infection. CXCL8 also showed enhanced humoral and cell-mediated immunity (mixed-type pattern) providing effective protection against a viral challenge. However, there was no change in the immune responses induced by the PrV DNA vaccine in CCL4 recipients. These results suggest that co-injection of a chemokine, in the form of an adjuvant preparation, causes a rebalancing of the immunity, which subsequently affects the protective efficacy against a virulent virus infection.

Animals↗

PubMedDate not supplied

Dendritic cells and toll-like receptors in allergy and asthma.

Epithelia represent a major portal of entry for pathogen microorganisms and allergens and are equipped with innate and adaptive immunity for their protection. Pattern recognition receptors (PRR), including Toll-Like Receptors (TLR), recognize pathogen-associated molecular patterns (PAMP) shared by numerous microorganisms. TLR engagement is involved in innate immunity but also participates in the control of the adaptive immune response, which may be involved in the pathophysiology of allergic diseases like asthma. Experimental studies have largely demonstrated the implication of TLR in both development and control of the allergic reaction. Dendritic cells (DC), which play a key role in these processes, are a privileged target for PAMP. During the allergic reaction, TLR engagement on DC directs the polarization of the T cell response and, while TLR2 and TLR4 may favour both Th1 and Th2 responses, TLR9 induces the development of regulatory T cells.

Asthma↗

PubMed2004

Airway peptidoglycan and immunostimulatory DNA exposures have divergent effects on the development of airway allergen hypersensitivities.

BACKGROUND: Environmental exposures to toll-like receptor (TLR) ligands have been suggested to provide immunologic protection against allergic diseases. However, some TLRs use unique intracellular signaling pathways, suggesting that ambient TLR ligand exposures might induce a range of host responses. OBJECTIVE: These investigations compared peptidoglycan (PGN; TLR2)-induced and immunostimulatory sequence DNA oligodeoxynucleotide (ISS-ODN; TLR9)-induced innate responses and determined how airway exposures to these TLR ligands affect adaptive immunity and the asthmatic phenotype. METHODS: In in vitro and in vivo studies innate responses to PGN and ISS-ODN were compared. Alternatively, mice were intranasally immunized with ovalbumin (OVA) alone or OVA plus PGN or ISS-ODN, and adaptive immune profiles and responses to airway OVA challenge were assessed. RESULTS: PGN and ISS-ODN induced divergent innate responses predictive of their having TH2- and TH1-biasing adjuvant potential, respectively. Consistent with these findings, mice intranasally immunized with OVA alone had relatively weak adaptive responses, whereas intranasal OVA/PGN- and OVA/ISS-ODN-coimmunized mice had much stronger humoral and cellular responses that were TH2 and TH1 biased, respectively. Finally, on airway allergen challenge, mice intranasally immunized with OVA alone had modest TH2-biased airway hypersensitivity responses, whereas airway responses were greatly exaggerated for intranasal OVA/PGN-immunized mice. In contrast, intranasal OVA/ISS-ODN-immunized mice had little evidence of airway hypersensitivity after airway allergen challenge. CONCLUSIONS: Considered in a larger context, these results suggest that inspired air is likely to contain TLR ligands capable of both preventing and precipitating the asthmatic phenotype.

Adjuvants, Immunologic↗

PubMed2004

Yersinia enterocolitica induces apoptosis and inhibits surface molecule expression and cytokine production in murine dendritic cells.

Yersinia enterocolitica evades innate immunity by expression of a variety of pathogenicity factors. Therefore, adaptive immunity including CD4(+) T cells plays an important role in defense against Y. enterocolitica. We investigated whether Y. enterocolitica might target dendritic cells (DC) involved in adaptive T-cell responses. For this purpose, murine DC were infected with Y. enterocolitica wild-type and mutant strains prior to incubation with ovalbumin (OVA) as antigen and 5-(6)-carboxyfluorescein diacetate N-succinimidyl ester-labeled OVA-specific T cells from DO11.10 mice. While T-cell proliferation was partially affected by infection of DC with plasmid-cured and YopP-deficient Yersinia mutant strains, no T-cell proliferation occurred after infection of DC with wild-type Y. enterocolitica. Infection of DC with Y. enterocolitica wild type resulted in decreased up-regulation of major histocompatibility complex class II, CD54 (intercellular adhesion molecule 1), CD 80, and CD86 expression. Experiments with plasmid-cured Y. enterocolitica or a YopP-deficient mutant strain revealed that YopP accounts for inhibition of surface molecule expression. Wild-type Y. enterocolitica suppressed the release of KC, tumor necrosis factor alpha, interleukin-10 (IL-10), and IL-12 by DC, while infection of DC with plasmid-cured Y. enterocolitica or with the YopP-deficient mutant resulted in the production of these cytokines. Moreover, infection with wild-type Y. enterocolitica induced apoptosis in DC mediated by YopP. Apoptosis occurred despite translocation of NF-kappaB to the nucleus, as demonstrated by electromobility shift assays. Together, these data demonstrate that Y. enterocolitica targets functions of murine DC that are required for T-cell activation. This might contribute to evasion of adaptive immune responses by Y. enterocolitica.

Animals↗

PubMed2006

CCL19-IgG prevents allograft rejection by impairment of immune cell trafficking.

An adaptive immune response is initiated in the T cell area of secondary lymphoid organs, where antigen-presenting dendritic cells may induce proliferation and differentiation in co-localized T cells after T cell receptor engagement. The chemokines CCL19 and CCL21 and their receptor CCR7 are essential in establishing dendritic cell and T cell recruitment and co-localization within this unique microenvironment. It is shown that systemic application of a fusion protein that consists of CCL19 fused to the Fc part of human IgG1 induces effects similar to the phenotype of CCR7-/- animals, like disturbed accumulation of T cells and dendritic cells in secondary lymphoid organs. CCL19-IgG further inhibited their co-localization, which resulted in a marked inhibition of antigen-specific T cell proliferation. The immunosuppressive potency of CCL19-IgG was tested in vivo using murine models for TH1-mediated immune responses (delayed-type hypersensitivity) and for transplantation of different solid organs. In allogeneic kidney transplantation as well as heterotopic allogeneic heart transplantation in different strain combinations, allograft rejection was reduced and organ survival was significantly prolonged by treatment with CCL19-IgG compared with controls. This shows that in contrast to only limited prolongation of graft survival in CCR7 knockout models, the therapeutic application of a CCR7 ligand in a wild-type environment provides a benefit in terms of immunosuppression.

Animals↗

PubMed2006

Targeting the networks that underpin contiguous immunity in asthma and chronic obstructive pulmonary disease.

Recent advances in the field of innate immunity have driven an important reappraisal of the role of these processes in airway disease. Various strands of evidence indicate that resident cells, such as macrophages and epithelial cells, have central importance in the initiation of inflammation. Macrophage activation has the potential to regulate not just typical aspects of innate immunity but also, via a variety of intricate cell-cell networks, adaptive responses and responses characterized by Th2-type cytokine production. In turn, such adaptive immune processes modify the phenotype and function of the innate immune system. Cooperative responses between monocytic cells and tissue cells are likely to be crucial to the generation of effective inflammatory responses, and a realization of the importance of these networks is providing a new way of identifying antiinflammatory therapies. Importantly, the repeated cycles of allergic and nonallergic inflammation that comprise chronic human airway disease are not necessarily well described by current terminology, and we propose and describe a concept of contiguous immunity, in which continual bidirectional cross-talk between innate and adaptive immunity describes disease processes more accurately.

Animals↗

PubMed2004

The role of dendritic cells in shaping the immune response.

Dendritic cells are central to the initiation of primary immune responses. They are the only antigen-presenting cell capable of stimulating naive T cells, and hence they are pivotal in the generation of adaptive immunity. Dendritic cells also interact with and influence the response of cells of the innate immune system. The manner in which dendritic cells influence the responses in cells of both the innate and adaptive immune systems has consequences for the bias of the adaptive response that mediates immunity to infection after vaccination or infection. It also provides an opportunity to intervene and to influence the response, allowing ways of developing appropriate vaccination strategies. Mouse and human studies have identified myeloid, lymphoid and plasmacytoid dendritic cells. Studies in domesticated animals with agents of specific infectious diseases have confirmed the applicability of certain of the generic models developed from mice or from in vitro studies on human cells. In vivo and ex vivo studies in cattle have demonstrated the existence of a number of subpopulations of myeloid dendritic cells. These cells differ in their ability to stimulate T cells and in the cytokines that they produce, observations clearly having important implications for the bias of the T-cell response. Dendritic cells also interact with the innate immune system, inducing responses that potentially bias the subsequent adaptive response.

Animals↗