PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Adaptive Immunity”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,153 records · Page 64Linked to original sources
PubMed2002

Activation of NKT cells protects mice from tuberculosis.

The T-cell immune response to Mycobacterium tuberculosis is critical in preventing clinical disease. While it is generally accepted that both major histocompatibility complex class I (MHC-I)-restricted CD8(+) and MHC-II-restricted CD4(+) T cells are important for the immune response to M. tuberculosis, the role of non-MHC-restricted T cells is still not clearly delineated. We have previously reported that CD1d(-/-) mice do not differ from CD1d(+/+) mice in their survival following infection with M. tuberculosis. We now show that, although CD1d-restricted NKT cells are not required for optimum immunity to M. tuberculosis, specific activation of NKT cells by the CD1d ligand alpha-galactosylceramide protects susceptible mice from tuberculosis. Treatment with alpha-galactosylceramide reduced the bacterial burden in the lungs, diminished tissue injury, and prolonged survival of mice following inoculation with virulent M. tuberculosis. The capacity of activated NKT cells to stimulate innate immunity and modulate the adaptive immune response to promote a potent antimicrobial immune response suggests that alpha-galactosylceramide administration could have a role in new strategies for the therapy of infectious diseases.

Animals↗
PubMed2006

GITR modulates innate and adaptive mucosal immunity during the development of experimental colitis in mice.

BACKGROUND: Uncontrolled T cell activation and abnormal function of the innate immune system against normal enteric bacterial flora play a critical part in the pathogenesis of inflammatory bowel disease (IBD). Therefore, pharmacological strategies directed to restore the normal responsiveness of the immune system could be efficacious in the treatment of these pathological conditions. Glucocorticoid-induced tumour necrosis factor receptor (GITR)-related gene is a member of the tumour necrosis factor receptor superfamily that is constitutively expressed at high levels on regulatory T cells and at low levels on unstimulated T cells, B cells and macrophages. GITR triggering leads to activation of T effectors and reversal of suppressive function of regulatory T cells. AIM: To investigate the role of GITR in the development of experimental colitis in mice. RESULTS: Using GITR(-/-) mice, GITR deletion protected against 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis by reducing innate immune responses and effector T cell activity. Effector T cells isolated from GITR(-/-) mice were less effective than T cells isolated from GITR(+/+) mice to transfer colitis in immunodeficient mice. Blocking the GITR/ligand for GITR (GITRL) signal by giving soluble GITR prevented TNBS-induced colitis in normal GITR(+/+) and also in lymphocyte-deficient SCID mice. CONCLUSIONS: Collectively, these data suggest that GITR plays a critical part in regulating both acquired and innate mucosal immune responses during the development of experimental colitis in mice. Therefore, targeting the GITR/GITRL system signalling may represent a potential pharmacological tool for the treatment of IBD.

Animals↗
PubMed2001

MAP kinases in the immune response.

MAP kinases are among the most ancient signal transduction pathways and are widely used throughout evolution in many physiological processes. In mammalian species, MAP kinases are involved in all aspects of immune responses, from the initiation phase of innate immunity, to activation of adaptive immunity, and to cell death when immune function is complete. In this review, we summarize recent progress in understanding the function and regulation of MAP kinase pathways in these phases of immune responses.

Animals↗
PubMed2000

Gamma-delta T cells in midgestation human placental villi.

One question that remains is how the immune system at the maternal-fetal interface supports tolerance of the fetus while at the same time protecting it from infection. A potential answer is that local innate immunity is augmented while adaptive immunity is downregulated. In this study, we focus on T cells of the gamma-delta lineage, thought to be important in certain innate responses. Using tissue from normal pregnancies, we documented the presence of gamma-delta T cells and their counterpart, alpha-beta T cells, in midgestation human placental villi. The variable presence of these two T cell lineages in this anatomic site may suggest differential regulation, and herein we describe potential mechanisms for this phenomenon.

Female↗
PubMed2000

CpG DNA as a Th1 trigger.

Over the last few years, it has been recognized that along with structural components and products of bacteria, bacterial DNA is also capable of signaling infectious danger to cells of the innate immune system. Particular DNA sequences (CpG motifs), which are abundant in prokaryotic (bacterial) but not in mammalian DNA, cause the activation and stimulation of immune cells. Research has been catalyzed by the finding that certain synthetic oligodeoxynucleotides mimic the action of bacterial DNA. Immunostimulation induced by bacterial DNA or synthetic oligonucleotides not only contributes to our knowledge of the pathogen-host interrelationship during infection, but can also be used therapeutically to condition or modify ongoing immune responses of the adaptive immune system. Accordingly, CpG motifs have been used as vaccine adjuvants as well as instructing agents to selectively induce Th1-dominated immune responses. Hence, CpG motifs might be used in the future as adjuvants and/or immunomodulatory agents to treat or prevent undesired Th2-dominated immune responses, such as allergy.

Adjuvants, Immunologic↗
PubMed2006

Innate and adaptive mucosal immunity in protection against HIV infection.

The appalling toll on the populations of developing countries as a result of the HIV epidemic shows no signs of abatement. While costly drug therapies are effective in developed nations, the sheer scale of the epidemic elsewhere makes the need for a vaccine an ever more urgent goal. The prevalent DNA prime-viral boost strategy aims to elicit cytotoxic lymphocytes (CTL) against HIV, but this approach is undermined by the rapid mutation of HIV, which thereby escapes CTL control. Alloimmunity has been found to be protective in vertical transmission from infected mothers to their babies, in alloimmunization of women with their partners' mononuclear cells, and in monkeys immunized with SIV grown in human T-cells. Vaginal mucosal immunization, as a result of unprotected sex with a regular partner, induced in vitro protection against HIV infection, and this was confirmed in macaques. The second type of natural protection is found in persons with the homozygous 32 CCR5 mutation, a 32-base-pair deletion of the CCR5 gene, which results in a lack of cell-surface expression of CCR5, which is associated with an increase in CC chemokines and the development of CCR5 antibodies. These two 'experiments of nature' have been used to develop vaccine strategies--first, in vaginal immunization of macaques with CCR5 peptides, in addition to HIV envelope (env) and SIV core (gag) antigens, all of which were linked to the 70-kD heat-shock protein (HSP70); and second, in mucosal allo-immunization of macaques, which also gave rise to in vitro protection from infection. Immunization with this vaccine elicited serum and vaginal IgG and IgA antibodies, IFNgamma- and IL-12-producing cells, and increased concentrations of CCL-3 and CCL-4. Vaginal challenge with a simian immunodeficiency virus engineered to carry a human envelope protein (SHIV 89.6) showed significant clearance of SHIV in the immunized macaques. This platform strategy will now be developed to activate the co-stimulatory pathways with the aim of enhancing the primary allogeneic and CCR5-directed responses which are involved in natural protection against HIV infection.

AIDS Vaccines↗
PubMed2003

Thrombopoietin cooperates with FLT3-ligand in the generation of plasmacytoid dendritic cell precursors from human hematopoietic progenitors.

Type 1 interferon-producing cells (IPCs), also known as plasmacytoid dendritic cell (DC) precursors, represent the key effectors in antiviral innate immunity and triggers for adaptive immune responses. IPCs play important roles in the pathogenesis of systemic lupus erythematosus (SLE) and in modulating immune responses after hematopoietic stem cell transplantation. Understanding IPC development from hematopoietic progenitor cells (HPCs) may provide critical information in controlling viral infection, autoimmune SLE, and graft-versus-host disease. FLT3-ligand (FLT3-L) represents a key IPC differentiation factor from HPCs. Although hematopoietic cytokines such as interleukin-3 (IL-3), IL-7, stem cell factor (SCF), macrophage-colony-stimulating factor (M-CSF), and granulocyte M-CSF (GM-CSF) promote the expansion of CD34+ HPCs in FLT3-L culture, they strongly inhibit HPC differentiation into IPCs. Here we show that thrombopoietin (TPO) cooperates with FLT3-L, inducing CD34+ HPCs to undergo a 400-fold expansion in cell numbers and to generate more than 6 x 10(6) IPCs per 10(6) CD34+ HPCs within 30 days in culture. IPCs derived from HPCs in FLT3-L/TPO cultures display blood IPC phenotype and have the capacity to produce large amounts of interferon-alpha (IFN-alpha) and to differentiate into mature DCs. This culture system, combined with the use of adult peripheral blood CD34+ HPCs purified from G-CSF-mobilized donors, permits the generation of more than 10(9) IPCs from a single blood donor.

Antigens, CD↗
PubMed2006

Activation of NK cells by an endocytosed receptor for soluble HLA-G.

Signaling from endosomes is emerging as a mechanism by which selected receptors provide sustained signals distinct from those generated at the plasma membrane. The activity of natural killer (NK) cells, which are important effectors of innate immunity and regulators of adaptive immunity, is controlled primarily by receptors that are at the cell surface. Here we show that cytokine secretion by resting human NK cells is induced by soluble, but not solid-phase, antibodies to the killer cell immunoglobulin-like receptor (KIR) 2DL4, a receptor for human leukocyte antigen (HLA)-G. KIR2DL4 was constitutively internalized into Rab5-positive compartments via a dynamin-dependent process. Soluble HLA-G was endocytosed into KIR2DL4-containing compartments in NK cells and in 293T cells transfected with KIR2DL4. Chemokine secretion induced by KIR2DL4 transfection into 293T cells occurred only with recombinant forms of KIR2DL4 that trafficked to endosomes. The profile of genes up-regulated by KIR2DL4 engagement on resting NK cells revealed a proinflammatory/proangiogenic response. Soluble HLA-G induced secretion of a similar set of cytokines and chemokines. This unique stimulation of resting NK cells by soluble HLA-G, which is endocytosed by KIR2DL4, implies that NK cells may provide useful functions at sites of HLA-G expression, such as promotion of vascularization in maternal decidua during early pregnancy.

Chemokines↗
PubMed2005

Dendritic cells and natural killer cells in the pathogenesis of HIV infection.

Dendritic cells (DC) and natural killer (NK) cells, the main cellular components of the innate immune system, participate in the most ancient first line of defense against infections. Both types of cells patrol peripheral tissues, whereas their rapid recruitment and activation at mucosal surfaces [the major entry point for the human immunodeficiency virus (HIV)] is a hallmark of acute inflammatory response. The ability of HIV to survive and replicate in the human host relies upon several molecular mechanisms eluding the immune surveillance of both adaptive immunity and of DC and NK cells beginning with the acute phase of primary HIV infection. DC and NK cells, unlike CD4+ T cells, are impaired more functionally rather than being depleted by HIV infection. In this article we will review some of the aspects of DC/NK cells interaction with HIV infection both in vitro and in vivo, and we will also speculate on the potential consequence for HIV pathogenesis and for the capacity of the virus to escape the surveillance of the innate immune system.

Dendritic Cells↗
PubMed2006

Therapeutic targeting of toll-like receptors in gastrointestinal inflammation.

Toll-like receptors (TLRs) are sensors of microbial products that initiate host defense responses in multicellular organisms. They are mainly linked to innate immunity and bridging to adaptive immunity, signaling through different TLRs responsible for a wide range of biological responses. The intracellular signaling pathways through Toll/interleukin-1 receptor (IL-1R) domains result in recruitment of the cytoplasmic adaptor molecules, with subsequent activation of a signaling cascade leading to nuclear factor-kappa B (NF-kappaB). TLR-signaling induces host inflammatory response and the inflammation becomes more severe in the absence of several extra and intra cellular negative regulators of TLR-signaling. In the intestine, TLR-dependent activation of NF-kappaB plays a vital role in maintaining epithelial homeostasis as well as regulating infections and inflammation, while dysregulation of TLR-signaling is associated with the pathogenesis of inflammatory bowel diseases (IBD). Recent findings regarding innate immunity-mediated regulation of intestinal pathophysiology prove that development of new drugs targeting TLRs including antagonists of TLR-signaling and agonists of their negative regulators has a potential impact on therapeutic strategies for intestinal inflammatory diseases.

Animals↗
PubMed2005

Therapeutic cancer vaccines: at midway between immunology and pharmacology.

The pursuit of active specific immunotherapy of cancer re-emerged vigorously in the 90s. More than 50 vaccines are currently under clinical testing, and more than 400 clinical trials have been conducted. This wave of enthusiasm is rooted in fundamental immunology, as new paradigms, such as the dominant tolerance through T-regulatory cells and the instructive role of the innate immune system on the adaptive immune system, opened the possibility that an efficient cancer vaccination could be achieved even without the need of cancer neoantigens, provided that antigen presentation could be increased, and that regulatory circuits could be controlled. However, recent failures in some large trials have brought disappointment and have highlighted the differences between experiments in young, healthy mice with small transplanted tumours, and clinical testing in aged, ill patients with advanced spontaneous tumours, driving the attention to issues such as tumour editing, tumour-induced immunosuppression, and immunosenescence. The molecular basis of these phenomena is only partially known. Additionally, the inherent complexity of the immune system as a network of multiple interactions and redundant control loops among a huge diversity of components sets another barrier to the translation of in vitro reductionist knowledge into rationally designed clinical trials. All this calls for a new therapeutic paradigm in cancer vaccines, moving beyond the analogy with the classic drug-target approach, and targeting the immune system regulation as a whole, and its interaction with the tumour, in all its complexity. Early mathematical modelling of cancer immunotherapy has suggested how to go about it. This re-evaluation of the cancer vaccine landscape, suggests that future successful cancer immunotherapy will be combined immunotherapy, will be exquisitely schedule-dependent and will need new experimental models allowing for the exploration of the mechanisms of resistance and tumour escape, such as tumour editing and tumour induced immunosuppression, in the context of the physiology of the immune system of the elderly. These shifts will put cancer vaccines closer to pharmacology than to conventional preventive vaccinology, or at least at the midway. A change in the design and the ultimate goals of the clinical trials will also be needed, identifying long term stabilization of the disease and quality of life as main endpoints, again closer to the clinical management of most chronic noncommunicable diseases.

Animals↗
PubMed1999

Macrophage suppression of T cell activation: a potential mechanism of peripheral tolerance.

The mechanisms of induction and maintenance of tolerance in self-reactive T cells in the periphery are poorly understood. Current models assume that successful T cell activation only occurs if ligation of the T cell receptor (signal 1) by antigen presenting cells (APCs) is accompanied by a costimulatory signal (signal 2), and that signal 1 in the absence of signal 2 is either ignored or is tolerizing. However, there is also evidence for the existence of macrophages (M phi) capable of suppressing T cell activation both in vitro and in vivo. The possibility of a more actively induced tolerance exists, in which the M phi itself responds to T cell-mediated signals in a tolerogenic fashion. This would help to resolve the paradox that tissue M phi, which act as scavengers of self-antigen, can also act as professional APCs. The ability of tissue macrophages to actively suppress T cells would further underscore the importance of the innate immune system in regulating adaptive immune responses.

Animals↗
PubMed2003

A blunted blood plasmacytoid dendritic cell response to an acute systemic viral infection is associated with increased disease severity.

At least two distinct human dendritic cell (DC) subsets are produced in the bone marrow and circulate in the peripheral blood-precursor myeloid DCs (pre-mDCs) and plasmacytoid DCs (PDCs). Both lineages of DCs are instrumental in antiviral innate immunity and shaping Th1 adaptive immune responses. PDCs are the most potent IFN-alpha-producing cells to viral pathogens. Dengue, an acute flavivirus disease, provides a model to study DC responses to a self-limited human viral infection. We analyzed circulating DC subsets in a prospective study of children with dengue across a broad range of illness severities: healthy controls; mild, nondengue, presumed viral infections; moderately ill dengue fever; and, the most severe form of illness, dengue hemorrhagic fever. We also examined PDC responses in monkeys with asymptomatic dengue viremia and to dengue virus exposure in vitro. The absolute number and frequency of circulating pre-mDCs early in acute viral illness decreased as illness severity increased. Depressed pre-mDC blood levels appeared to be part of the typical innate immune response to acute viral infection. The frequency of circulating PDCs trended upward and the absolute number of circulating PDCs remained stable early in moderately ill children with dengue fever, mild other, nondengue, febrile illness, and monkeys with asymptomatic dengue viremia. However, there was an early decrease in circulating PDC levels in children who subsequently developed dengue hemorrhagic fever. A blunted blood PDC response to dengue virus infection was associated with higher viremia levels, and was part of an altered innate immune response and pathogenetic cascade leading to severe disease.

Acute Disease↗
PubMed2004

T cell biasing by activated dendritic cells.

We have previously reported that the ligation of FcgammaRs on activated macrophages affected their production of cytokines and their ability to influence T cell activation. Dendritic cells (DC) are important APCs that also express FcgammaR. In the present work, we sought to determine whether DC responded to immune complexes in a manner similar to macrophages. We confirmed that activated murine DC produced IL-12, and, as a result, induced naive T cells to produce primarily IFN-gamma upon stimulation. However, DC activated in the presence of immune complexes shut off their production of IL-12p70 and induced a Th2-like cytokine response. Thus, DC respond to immune complexes by altering their cytokine production, which, in turn, influences T cell responses. A DC transfer experiment was performed to determine the extent that APC exposure to immune complexes could influence adaptive immune responses. Vaccination of mice with Ag, along with DC that were activated in the presence of immune complexes, resulted in higher levels of Ag-specific IgG1 Ab, relative to mice that were vaccinated with activated DC and Ag alone. The mechanism by which DC altered their cytokine production in response to immune complexes was different from macrophages. Macrophages down-regulated the transcription of both the p40 and p35 subunits of IL-12, whereas DC decreased only p35 expression. We conclude that APCs expressing FcgammaR on their surface can respond to immune complexes by shutting off IL-12 biosynthesis, to prevent the Th1-type T cell biasing that normally accompanies innate immune activation.

Animals↗
PubMed2005

Conjugated linoleic acid suppresses NF-kappa B activation and IL-12 production in dendritic cells through ERK-mediated IL-10 induction.

Polyunsaturated fatty acids (PUFA) have been shown to modulate immune responses and have therapeutic effects in inflammatory disorders. However, the influence of PUFA on dendritic cells (DC), key cells of the innate immune system in shaping adaptive immune responses, has not yet been defined. In this study, we examine the effects of the cis-9, trans-11 isomer of conjugated linoleic acid (c9, t11-CLA), a dietary PUFA found in meat and dairy products, on murine DC activation. Treatment of DC with c9, t11-CLA suppressed LPS-induced IL-12, enhanced IL-10R expression, and enhanced IL-10 production at the transcriptional and protein level. The suppression of IL-12 by c9, t11-CLA was found to be IL-10 dependent. We investigated the involvement of the MAPK, ERK, and the transcription factor, NF-kappaB, in this IL-10-mediated effect. c9, t11-CLA enhanced ERK activation after LPS stimulation, and inhibition of ERK resulted in abrogation of IL-10 and recovery of IL-12 production. c9, t11-CLA decreased NF-kappaB:DNA binding after LPS stimulation, which was concomitant with delayed translocation of NF-kappaBp65 into the nucleus and an increase in IkappaBalpha. These effects were reversed by addition of a neutralizing anti-IL-10 Ab. Our findings demonstrate that c9, t11-CLA suppresses IL-12 production by LPS-stimulated DC by ERK mediated IL-10-induction. Furthermore, these IL-10-mediated effects are dependent on inhibition of NF-kappaB activation. This is the first study to demonstrate that c9, t11-CLA can enhance transcription and production of the anti-inflammatory cytokine IL-10, while inhibiting the Th1-promoting cytokine IL-12, and may explain certain of its immunosuppressive properties.

Adjuvants, Immunologic↗
PubMed2006

Tyk2 negatively regulates adaptive Th1 immunity by mediating IL-10 signaling and promoting IFN-gamma-dependent IL-10 reactivation.

The Jak, Tyk2, is activated in response to IL-12 and IFN-alphabeta and promotes IFN-gamma production by Th1-type CD4 cells. Mice deficient in Tyk2 function have been previously shown to be resistant to autoimmune arthritis and septic shock but are acutely susceptible to opportunistic pathogens such as Toxoplasma gondii. In this study, we show that Tyk2, in addition to mediating the biological effects of IL-12 and IFN-alphabeta, is an important regulator for the signaling and expression of the immunosuppressive cytokine IL-10. In the absence of Tyk2, Ag-reactive CD4 cells exhibit impaired IL-10 synthesis following rechallenge of T. gondii vaccine-primed mice. The impaired IL-10 reactivation leads to unopposed antimicrobial effector mechanisms which results in a paradoxically superior protection of immune Tyk2(-/-) mice against virulent T. gondii challenge. We further demonstrate that Tyk2 indirectly controls CD4 IL-10 reactivation by signaling for maximal IFN-gamma secretion. The unexpected role of IFN-gamma in mediating IL-10 reactivation by Th1 cells provides compelling evidence that conditions driving Th1 responses establish a negative feedback loop, which will ultimately lead to its autoregulation. Thus, Tyk2 can be viewed as a dual-function Jak, mediating both pro and anti-inflammatory cytokine responses.

Animals↗
PubMed2006

[Inhibitory effect of mesenchymal stem cells carrying murine beta defensin 2 on malignant ascites in mice].

BACKGROUND & OBJECTIVE: Murine beta defensin 2 (MBD2) is a small antimicrobial peptide of the innate immune system. It provides a critical link between the innate immune system and the adaptive immune response. This study was to develop a set of MBD2-lentivirus system, and observe its inhibitory effect on malignant ascites in mice. METHODS: MBD2 RNA was extracted from kidneys of BALB/c mice, and the fragment of MBD2 was amplified by reverse transcription-polymerase chain reaction (RT-PCR). MBD2 plasmid was constructed, and the lentivirus system expressing MBD2 was produced in 293FT cells. Mesenchymal stem cells (MSCs) were then infected with MBD2-Lentivirus, and stably infected cells (MBD2-MSCs) were selected. The expression of MBD2 was detected by RT-PCR. The biological function of MBD2 was evaluated by dendritic cell (DC) migration experiment. BALB/c mice bearing intraperitoneal MethA tumors were injected intraperitoneally with MBD2-MSCs at the 2nd, 4th, 6th, and 8th day after inoculation. Ascites status and survival status of the mice were observed. Long-term survivors were inoculated intraperitoneally with MethA tumor cells again to observe their survival status. RESULTS: The expression of MBD2 in MBD2-MSCs was verified by RT-PCR. Numbers of migrated DCs were significantly increased in MBD2-MSC group than in normal saline (NS) group, MSC group, and null lentivirus (Null) group (43+/-8 vs. 8+/-1, 14+/-2, and 12+/-3, P<0.01). The volume of tumor ascites was significantly less in MBD2-MSC group than in NS group, MSC group, and Null group [(3.0+/-1.0) ml vs. (10.8+/-1.0) ml, (10.2+/-1.3) ml, and (9.8+/-1.6) ml, P<0.05]. Some mice in MBD2 group were still alive 40 days after tumor inoculation, while none in control groups survived up to 20 days after tumor inoculation (P<0.05). After inoculated with MethA tumor cells again, the mice in MBD2-MSC group still survived longer than those in control groups. CONCLUSION: MBD2-lentivirus gene therapy system is constructed successfully, and can inhibit the formation of malignant ascites.

Animals↗