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Results for “Adaptive Immunity”

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At least 883 records · Page 49Linked to original sources

PubMed2005

Cooperation between platelet-derived CD154 and CD4+ T cells for enhanced germinal center formation.

It has been demonstrated previously that platelet-derived CD154 communicates with the adaptive immune compartment, enhancing B and T cell responses in CD154(-/-) mice. The presence of platelets was also shown to be necessary for optimal production of immunoglobulin G (IgG) in normal C57BL/6 mice. These data led us to hypothesize that platelets perform a sentinel function, quickly relaying activating signals to the adaptive immune compartment. Here, we report that platelet-derived CD154 increases serum IgG levels and germinal center formation under conditions where antigen-specific CD4(+) T cell numbers are limiting. We propose that in the physiologic setting where antigen-specific B and T cells are rare, platelets function to enhance signals required for robust adaptive humoral immunity.

Animals↗

PubMed2002

Autoimmunity as the body's defense mechanism against the enemy within: Development of therapeutic vaccines for neurodegenerative disorders.

Insults to the central nervous system (CNS), whether of microbial or microbe-free origin, result in tissue damage. Until recently, it was generally believed that only microbe-related damage elicits an adaptive immune response, the purpose of which is to eliminate the offending microorganisms. Recent studies in the author's laboratory suggest, however, that the body exhibits an adaptive immune response to microbe-free injuries as well. The immune response in this case is directed against dominant self-antigens residing in the damaged site, where such an adaptive anti-self immune response reinforces the protective activity of local resident cells by providing them with factors that can augment and regulate their capacity for buffering troublemakers such as destructive self-compounds emerging from the injured neural tissue. Because the specificity of this autoimmune response apparently depends not on the type but on the site of lesion, the response can be boosted by therapeutic vaccination for acute and chronic neurodegenerative conditions irrespective of their primary etiology. The results have far-reaching implications, both for microbial infections and for neurodegenerative diseases of the CNS.

Autoimmunity↗

PubMed2001

Cell surface targeting of heat shock protein gp96 induces dendritic cell maturation and antitumor immunity.

gp96 is a residential heat shock protein of the endoplasmic reticulum that has been implicated in the activation of dendritic cells (DCs) for the initiation of adaptive immunity. By genetic targeting of gp96 onto the cell surface, we demonstrate that direct access of gp96 to DCs induces their maturation, resulting in secretion of proinflammatory cytokines IL-1beta, IL-12, and chemokine monocyte chemoattractant protein-1 and up-regulation of the expression of MHC class I, MHC class II, CD80, CD86, and CD40. Furthermore, surface expression of gp96 on tumor cells renders them regressive via a T lymphocyte-dependent mechanism. This work reinforces the notion that gp96 is an endogenous DC activator and unveils that the context in which Ag is delivered to the immune system, in this case surface expression of gp96, has profound influence on immunity. It also establishes a principle of bridging innate and adaptive immunity for cancer immunotherapy by surface targeting of an intracellular heat shock protein.

Animals↗

PubMed2003

Synthetic vaccines: the role of adjuvants in immune targeting.

A clear understanding of the mechanism of function of immune stimulatory adjuvants, which commonly accompany vaccines, is beginning to emerge. Recent investigations have demonstrated that Toll-like receptors (TLRs) are the critical link between the innate and the adaptive immunity. This link, which is normally activated as a result of collaboration between adjuvants and TLRs in triggering adaptive immunity, has been a subject of several recent investigations. With the advent of well-defined synthetic small molecules, which are designed to either mimic the adjuvants or, as in many cases, to structurally represent pathogen associated molecular patterns, it is now possible to design reproducible experiments and to draw credible conclusions. An adjuvant alerts the host immune system through a mechanism similar to that of an infection by a pathogen, which involves interaction with a TLR followed by a lsqou;danger signal' to the immune system. Secretion of cytokines and regulation of the expression of co-stimulatory molecules induced by innate response shape the magnitude and quality of adaptive response. Synthetic vaccines containing specific epitopes to which immune responses are desired, are expected to be far superior in target specificity while the benefits may be long-lasting. The immune responses by therapeutic vaccines are generally adaptive in nature and such responses often require the participation of the components of innate immunity, most importantly the TLRs and their pathogen-associated binding compliments. Structurally well-defined synthetic molecules derived from lipid A, muramyl di-peptide (MDP), and CpG motifs from bacterial DNA offer a wide range of immune stimulants for the development of fully synthetic vaccines. Lipo-peptide and self-adjuvanted antigens, in combination with additional immune stimulatory adjuvants in liposome delivery system, may be important in vaccine design. Combinations of synthetic mimics of microbial products are known to display synergistic effects in stimulating the immune system. Either alone or in combination with chemotherapy, innate immune therapy using TLR ligands to stimulate the immune system may offer an alternate therapeutic approach against rapidly mutating viral infections-(HIV/AIDS), and cancers.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed2003

Identification of specific gene expression profiles in human mast cells mediated by Toll-like receptor 4 and FcepsilonRI.

Rodent mast cells (MCs) are reported to play a pivotal role in both innate and adaptive immunity. However, there is so far no evidence that human MCs are involved in innate immunity. We found that a functional Toll-like receptor 4 (TLR4) was expressed on human MCs when it was up-regulated by interferon gamma (IFN-gamma). To systematically explore how human MCs modulate the immune system following TLR4-mediated activation and FcepsilonRI aggregation, we used high-density oligonucleotide probe arrays (GeneChip) to compare the lipopolysaccharide (LPS)-induced gene expression profile with the IgE/anti-IgE-mediated profile in MCs. Both a shared core response, and LPS- or anti-IgE-specific programs of gene expression were observed in MCs. Furthermore, MCs exhibited an antiviral response gene program in response to IFN-gamma, and LPS sustained that expression. Compared with the LPS-stimulated gene expression profile of human peripheral blood mononuclear cells, LPS-stimulated MCs specifically induced a subset of genes that included a Th2 cytokine and chemokines that recruit Th2 cells and eosinophils. These results reveal that human MCs express tailored pathogen- and antigen-specific immune responses and that human MCs may play important roles in innate and adaptive immunity.

Chemokine CCL1↗

PubMed2005

IL-21 enhances tumor rejection through a NKG2D-dependent mechanism.

IL-21 is a cytokine that can promote the anti-tumor responses of the innate and adaptive immune system. Mice treated with IL-21 reject tumor cells more efficiently, and a higher percentage of mice remain tumor-free compared with untreated controls. In this study, we demonstrate that in certain tumor models IL-21-enhanced tumor rejection is NKG2D dependent. When engagement of the NKG2D receptor was prevented, either due to the lack of ligand expression on the tumor cells or due to direct blocking with anti-NKG2D mAb treatment, the protective effects of IL-21 treatment were abrogated or substantially diminished. Specifically, IL-21 only demonstrated a therapeutic effect in mice challenged with a retinoic acid early inducible-1delta-bearing lymphoma but not in mice bearing parental RMA tumors lacking NKG2D ligands. Furthermore, treatment with a blocking anti-NKG2D mAb largely prevented the therapeutic effect of IL-21 in mice challenged with the 4T1 breast carcinoma, the 3LL lung carcinoma, and RM-1 prostate carcinoma. By contrast, IL-21 did mediate beneficial effects against both the parental DA3 mammary carcinoma and DA3 tumors transfected with H60, a NKG2D ligand. We also observed that IL-21 treatment could enhance RMA-retinoic acid early inducible-1delta tumor rejection in RAG-1(-/-) deficient mice, thereby demonstrating that the IL-21-induced protective effect can be mediated by the innate immune system and that, in this case, IL-21 does not require the adaptive immune response. Collectively, these findings suggest that IL-21 therapy may work optimally against tumors that can elicit a NKG2D-mediated immune response.

Adjuvants, Immunologic↗

PubMed2006

Multi-directional cross-regulation of NK cell function during innate immune responses.

In recent years a number of studies allowed major advances in our understanding of different cell types of the innate immunity and of the role they play during the early phases of infections. Some of these cells, such as mast cells, endothelial cells and certain immature dendritic cells (iDCs), are resident within peripheral tissues, while others, including NK cells, are rapidly recruited from blood stream. These studies indicated that innate immunity cells interact each other in inflamed tissues and in secondary lymphoid organs leading to modulation or amplification of different innate effector mechanisms and that a large array of microbial products can directly activate different effector cells of the innate immunity, also including NK cells. The final outcome of these cellular interactions may have dramatic impact on the quality and strength of down-stream adaptive immune responses. Noticeably, the effect on the adaptive immunity can result not only from the action of polarizing cytokines such as IL12 or IL4, but also from the NK-mediated "DC editing" leading to the selection of the most suitable DCs for subsequent priming of Th1 cell responses. Thus classical innate effector cells can also be viewed as regulatory cells that play a pivotal role in defenses against pathogens.

Cytokines↗

PubMed2005

Saturated and polyunsaturated fatty acids reciprocally modulate dendritic cell functions mediated through TLR4.

TLRs provide critical signals to induce innate immune responses in APCs such as dendritic cells (DCs) that in turn link to adaptive immune responses. Results from our previous studies demonstrated that saturated fatty acids activate TLRs, whereas n-3 polyunsaturated fatty acids inhibit agonist-induced TLR activation. These results raise a significant question as to whether fatty acids differentially modulate immune responses mediated through TLR activation. The results presented in this study demonstrate that the saturated fatty acid, lauric acid, up-regulates the expression of costimulatory molecules (CD40, CD80, and CD86), MHC class II, and cytokines (IL-12p70 and IL-6) in bone marrow-derived DCs. The dominant negative mutant of TLR4 or its downstream signaling components inhibits lauric acid-induced expression of a CD86 promoter-reporter gene. In contrast, an n-3 polyunsaturated fatty acid, docosahexaenoic acid, inhibits TLR4 agonist (LPS)-induced up-regulation of the costimulatory molecules, MHC class II, and cytokine production. Similarly, DCs treated with lauric acid show increased T cell activation capacity, whereas docosahexaenoic acid inhibits T cell activation induced by LPS-treated DCs. Together, our results demonstrate that the reciprocal modulation of both innate and adaptive immune responses by saturated fatty acid and n-3 polyunsaturated fatty acid is mediated at least in part through TLRs. These results imply that TLRs are involved in sterile inflammation and immune responses induced by nonmicrobial endogenous molecules. These results shed new light in understanding how types of dietary fatty acids differentially modulate immune responses that could alter the risk of many chronic diseases.

Animals↗

PubMed2006

Cytokine receptor signalling and aging.

With ageing the immune system is deregulated and this leads to the development of immunosenescence mainly affecting the adaptive immune response. There is much knowledge accumulated concerning various receptor functions and signalling with ageing such as TCR, FcRs, TLRs. Cytokines are playing a major role in haematopoietic cell functions and in the harmonious and integrated coordination of the innate and adaptive immune response. There exists a large amount of data on cytokine production changes with ageing, as IL-2 production is decreasing, while IL-6 production is increasing. In contrast, there is only scarce knowledge concerning the cytokine receptors and their signalling in ageing. However, there is some evidence that the signalling of IL-2 receptors is altered in T cells and macrophages, mainly in relation to the JAK/STAT pathway. We present here evidence that the IL-6 induced signalling is also altered in T cells with ageing. An alteration in the JAKs and STATs activations in T cells and macrophages was demonstrated. The exact cause of these altered activations is not known and future studies are needed to elucidate them. In this review we summarise our present knowledge on cytokine signalling with ageing, mainly focusing on IL-2 and IL-6 receptors signalling.

Aged↗

PubMed2005

The immune response to human metapneumovirus is associated with aberrant immunity and impaired virus clearance in BALB/c mice.

Human metapneumovirus (HMPV), recently identified in isolates from children hospitalized with acute respiratory tract illness, is associated with clinical diagnosis of pneumonia, asthma exacerbation, and acute bronchiolitis in young children. HMPV has been shown to cocirculate with respiratory syncytial virus (RSV) and mediate clinical disease features similarly to RSV. Little is known regarding the pathophysiology or immune response associated with HMPV infection; thus, animal models are needed to better understand the mechanisms of immunity and disease pathogenesis associated with infection. In this study, we examine features of the innate and adaptive immune response to HMPV infection in a BALB/c mouse model. Primary HMPV infection elicits weak innate and aberrant adaptive immune responses characterized by induction of a Th2-type cytokine response at later stages of infection that coincides with increased interleukin-10 expression and persistent virus replication in the lung. Examination of the cytotoxic T lymphocyte and antibody response to HMPV infection revealed a delayed response, but passive transfer of HMPV-specific antibodies provided considerable protection. These features are consistent with virus persistence and indicate that the immune response to HMPV is unique compared to the immune response to RSV.

Animals↗

PubMed2006

A distinct Toll-like receptor repertoire in human tonsillar B cells, directly activated by PamCSK, R-837 and CpG-2006 stimulation.

Toll-like receptors (TLRs) recognize specific pathogen-associated molecular patterns (PAMPs), which subsequently trigger innate immunity. Recent data also suggest a role for TLRs in the direct activation of adaptive immune cells. In the present study, the expression and function of TLR1-TLR10 were characterized in purified human tonsillar B cells, focusing on differences among CD19+ CD38- CD27- (naïve B cells), CD19+ IgD- CD27-[germinal centre (GC) B cells] and CD19+ CD38- CD27+ (memory B cells) cells. The study was also designed to compare the TLR expression in B cells obtained from infected and hyperplastic tonsils that served as controls. The results demonstrated a distinct repertoire of TLRs, in which TLR1, TLR2, TLR7, TLR9 and TLR10 predominated. No differences were found among naïve, GC and memory B cells. Tonsillar infection did not substantially alter the TLR expression profile in ex vivo-isolated B-cell subsets. Purified CD19+ B cells stimulated with Pam3CSK4, R-837 and CpG oligodeoxynucleotide (ODN) 2006, via TLR1/TLR2, TLR7 and TLR9, respectively, showed an induction of interleukin-6 secretion and an up-regulated expression of human leucocyte antigen (HLA)-DR. Collectively, the present study demonstrates that B cells exhibit constitutively high levels of specific TLRs, which are not developmentally regulated during the B-cell differentiation process. Ongoing microbial infections, such as chronic tonsillitis, do not appear to affect the TLR profile in B cells. Furthermore, the distinct expression of TLRs allows B cells to respond directly to the cognate PAMPs. This further emphasizes the role of TLRs in directly activating adaptive immune cells.

Adolescent↗

PubMed2005

New insights into alternative mechanisms of immune receptor diversification.

The clonal commitment, selection, and expansion of B and T lymphocytes expressing diversified receptors provide the underlying basis for the jawed vertebrates adaptive immune response. At the core of this process is the rearrangement and somatic modification of segmental genetic elements that encode the constituent components of immunoglobulins and T-cell antigen receptors. No evidence has been found for a similar mechanism outside of jawed vertebrates; however, invertebrates and jawless vertebrates are subjected to continuous exposure to pathogenic bacteria, viruses, and parasites. The invertebrates and jawless vertebrates as well as jawed vertebrates all encode a variety of mediators of innate immunity. Several reports of extensive germline diversification of conventional innate receptors, as well as molecules that resemble innate receptors but undergo germline and somatic modification, have been made recently. The range of such molecules, which include the fibrinogen-related proteins (FREPs) in a mollusc, variable region-containing chitin-binding proteins (VCBPs) in a cephalochordate, variable lymphocyte receptors (VLRs) in jawless vertebrates, and novel immune-type receptors (NITRs) in bony fish, encompasses both the immunoglobulin gene superfamily (IgSF) and leucine-rich repeat (LRR) proteins. Although these molecules vary markedly in form and likely in function, growing evidence suggests that they participate in various types of host defense and thereby represent significant alternatives to current paradigms of innate and adaptive immune receptors. Unusual genetic mechanisms for diversifying recognition proteins may be a widespread characteristic of animal immunity.

Adaptation, Physiological↗

PubMed1989

Genetic control of the immune repertoire in nematode infections.

Mammals vary considerably, both within and between species, in the way in which their innate and adaptive immune systems respond to infections. An understanding of the processes involved in such variability will not only contribute to explaining heterogeneity in susceptibility and pathology, but will also be relevant to vaccination. This will be particularly important for the new generation of vaccines that are likely to be composed of one or a few cloned or synthesized antigens. For helminth infections, this could have particular relevance to hypersensitivity responses. The adaptive immune response is fundamentally constrained by the genetic constitution of an individual, and the need to avoid reactivity to self. This will have important implications for the dynamic relationship between host defences and parasite evasion mechanisms at both physiological and evolutionary levels. In this review, Malcolm Kennedy examines the genetic control of the specificity of the immune response to nematode infections, and in particular, the role of the major histocompatibility complex.

Journal Article↗

PubMed2006

Multifaceted antiviral actions of APOBEC3 cytidine deaminases.

To defend against external pathogens, metazoan organisms have evolved numerous defenses that generally fall within the innate and adaptive immune responses. Considerable effort continues to focus on developing a vaccine to manipulate the adaptive immune system to protect against or control HIV-1. However, recent advances in our understanding of the innate immune system have revealed that cells have a potent intrinsic antiretroviral defense in the form of APOBEC3G, which is a member of a larger family of cytidine deaminases that are active against HIV-1 and other retroviruses. Insights into how the action of A3G is circumvented by HIV-1 through the action of its Vif protein, and the surprising mechanisms by which A3G is regulated within the cell, offer exciting new opportunities for developing novel anti-HIV-1 therapies that exploit this intrinsic antiretroviral system.

APOBEC-3G Deaminase↗

PubMed2005

The Helicobacter felis model of adoptive transfer gastritis.

The bacterium Helicobacter pylori is a major human pathogen and the principal cause of acute and chronic gastritis, gastric and duodenal ulcer disease, and gastric adenocarcinoma. Infection with gastric Helicobacter results in an early infiltration of neutrophils, monocytes, and natural killer cells, followed by an influx of T cells and plasma cells. Although the critical components of this gastric infiltrate that lead to disease are unclear, the Helicobacter felis-infected mouse and other mouse models of Helicobacter-associated gastritis have demonstrated the critical nature of adaptive immunity in the development of gastric epithelial pathology. To further investigate the role of adaptive immunity in this disease, adoptive transfer models of disease have also been utilized. These models clearly demonstrate that it is the host CD4+ T lymphocyte response that is crucial for the development of Helicobacter-associated gastric epithelial changes.

Adoptive Transfer↗

PubMed2004

Atherosclerosis and the immune system.

The immune system is involved at all stages of the atherosclerotic disease process. Innate immunity, represented by macrophages and other cells, is directly activated by microbial components and possibly also by autologous lipids and proteins. It elicits inflammatory activity, which is a key component of the atherosclerotic lesion. Adaptive immunity is initiated by recognition of disease-related antigens, which include oxidatively modified lipoproteins, heat shock proteins and microbial macromolecules. In the artery wall, adaptive immune recognition mainly leads to Thl effector responses, which are characterized by secretion of proinflammatory cytokines and by activation of macrophages and vascular cells. Therefore, both the innate and adaptive arms of the immune system lead to inflammation in the developing atherosclerotic lesion. Interestingly, several effector pathways of cellular as well as humoral immunity tend to counteract proatherogenic, proinflammatory immunity. The notion that immunity plays an important role in the development of atherosclerosis has focused attention on a number of potential novel targets for intervention based on modulation of such immune responses.

Arteriosclerosis↗

PubMed2006

Presence of neutrophil-bearing antigen in lymphoid organs of immune mice.

Neutrophils play a crucial early role during the innate response, but little is known about their possible contribution when an adaptive immune response is installed. A robust neutrophilia and a T helper 1 (Th1) immune response are present after immunization with Complete Freund Adjuvant (CFA). We show that when FITC-labeled OVA was injected into the footpad of OVA/CFA immunized mice, the main OVA-FITC+ cells recruited in draining popliteal lymph nodes (LNs) were neutrophils, with most of them arriving at the LN by means of lymphatic vessels. The development of this OVA-FITC+ neutrophil influx requires an immune response against OVA. The OVA-FITC+ neutrophils present in LNs displayed mainly intracellular TNF-alpha, and their depletion resulted in an increase in the specific IL-5 levels. These data provide new evidence about the role played by neutrophils in vivo in adaptive immunity.

Animals↗

PubMed2004

Dendritic cells and natural killer cells interact via multiple TNF family molecules.

Dendritic cells (DC) and natural killer (NK) cells are essential components of the innate immune system, which rapidly sense and eliminate invading pathogens and transformed cells, mediate inflammation, and initiate adaptive immune responses. During the early immune events, DC and NK cells interact and regulate each other. The cellular "cross talk" and its molecular mediators are believed to be critical to the quality and magnitude of innate and adaptive immune responses. The goal of the present manuscript is to identify and initially assess major molecular mediators of DC-NK cell interaction. We have previously shown that DC and NK cells constitutively express several tumor necrosis factor family ligands (TNFfLs) and corresponding TNF family receptors (TNFfRs). Therefore, DC and NK cells might be able to interact via cognate interplays of TNFfLs and TNFfRs. Here, we provide initial experimental evidence supporting this possibility. We found that combined but not individual ligation of several TNFfRs induced substantial increases in secretion of interleukin-12 and interferon-gamma by DC and NK cells, respectively. In contrast, specific, individual disruptions of the engagements of the corresponding TNfL-TNFfR pairs greatly impaired DC and NK cell abilities to reciprocally mediate the increases in cytokine secretion. These findings indicate that multiple TNFfLs mediate DC-NK cell interaction.

Animals↗