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Results for “Adaptive Immunity”

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PubMed1993

[Ophthalmologic findings in graft versus host disease (GvHD)].

BACKGROUND: Since the era of bone marrow transplantation, the picture of acute and/or chronic transplant reaction of the host cells against grafted bone marrow has become more frequent. The so-called adaptive immune therapy bases on the fact that patients who present with a low grade of GvHD less often suffer from a relapse of the malignant leukaemic disease. Therefore, new therapeutic regimen are now performed which keep the patient on a low level of GvHD to prevent a recurrence of leukaemia. Here a close cooperation of oncologists and ophthalmologists becomes more and more important to estimate the stage of GvHD. PATIENTS: Demonstrating two case reports, we report on the ophthalmological symptoms of acute and chronic GvHD. Both patients presented with acute ocular GvHD as well as with signs of chronic ocular GvHD. Concerning the ophthalmological symptoms, in acute or chronic GvHD the conjunctival involvement is most important. There is a lymphocytic infiltration of the conjunctiva and of the lacrimal glands which leads to an extreme sicca-syndrome. The acute GvHD of the conjunctiva can be classified into 4 stages: injection/exudation and chemosis/formation of pseudomembranes/defects of the corneal epithelium. These stages correlate directly to the prognosis of the survival time of the patient. A pathognomonic sign for the chronic GvHD of the conjunctiva are the fibrous-scarry Arlt-lines of the tarsal conjunctiva. CONCLUSIONS: All patients who underwent a bone marrow transplantation for leukaemia need to be followed up closely to estimate the level of GvHD they are in. This applies especially to those patients who are treated according to the regimen of adaptive immune therapy. A close cooperation of oncologists and ophthalmologists during adaptive immune therapy is mandatory, as the ophthalmologist can provide important information to help to grade the level of GvHD, judging by the morphological picture at the slit lamp.

Adult↗

PubMed2004

Pulmonary defenses against fungi.

Pulmonary immunity to fungal pathogens requires both innate and adaptive immune responses. Alveolar macrophages, dendritic cells, and neutrophils are the phagocytic cells of the lung innate system. These cells produce early inflammatory mediators (i.e., reactive oxygen species, cytokines, and chemokines) in response to fungal infection. The production of early cytokines by innate cells, namely tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-12, plays a central role in the development of protective cell-mediated immunity against fungi. T helper 1 (Th1) cell-mediated immunity is essential for limiting a pulmonary fungal infection. Virulence factors produced by the fungi can also modulate the host immune response. Fungal virulence factors include the production of prostaglandins and a polysaccharide capsule. The type of adaptive immune response (T1 vs T2) generated determines whether the fungi are cleared from the lungs or a chronic fungal infection prevails.

Journal Article↗

PubMed2002

Role of the intestinal epithelium in orchestrating innate and adaptive mucosal immunity.

The mucosa that lines the human colon and small intestine is a site of chronic regulated "physiologic" inflammation. This contrasts markedly with other mucosal sites in that if the numbers of T and B cells, eosinophils, mast cells, macrophages, and dendritic cells that are present in the human intestinal tract were to be present in other sites, those sites would be considered to be sites of chronic pathological inflammation. This review examines the role of the intestinal epithelium in the development of "physiologic" intestinal mucosal inflammation and focuses on its role in signalling and mediating host innate and adaptive mucosal immune responses.

Bacteria↗

PubMed2003

Role of the immune system in the pathogenesis, prevention and treatment of Alzheimer's disease.

The dysregulation in the metabolism of beta-amyloid precursor protein and consequent deposition of amyloid-beta (Abeta) has been envisaged as crucial for the development of neurodegeneration in Alzheimer's disease (AD). Amyloid deposition begins 10-20 years before the appearance of clinical dementia. During this time, the brain is confronted with increasing amounts of toxic Abeta peptides and data from the last decade intriguingly suggest that both the innate and the adaptive immune systems may play an important role in the disorder. Innate immunity in the brain is mainly represented by microglial cells, which phagocytose and degrade Abeta. As the catabolism of Abeta decreases, glial cells become overstimulated and start to produce substances that are toxic to neurons, such as nitric oxide and inflammatory proteins. Pro-inflammatory cytokines can be directly toxic or stimulate Abeta production and increase its cytotoxicity. A therapeutic possibility arises from clinical studies, which demonstrate that nonsteroidal anti-inflammatory drugs (NSAIDs) may delay the onset and slow the progression of AD. Recent data show that in addition to the suppression of inflammatory processes in the brain NSAIDs may decrease the production of Abeta peptides. The role of adaptive immunity lies mainly in the fact that Abeta can be recognised as an antigen. Immunisation with Abeta peptides and peripheral administration of Abeta-specific antibodies both decrease senile plaques and cognitive dysfunction in murine models of AD. A recent trial in humans seems still to be hampered by adverse effects. As adaptive immunity decreases with aging while innate immunity remains intact, immunotherapy for AD will have to be adapted to this situation. Strategies that combine vaccination and inflammatory drug treatment could be considered.

Alzheimer Disease↗

PubMed2001

TNFalpha and IFNgamma induced by innate anti-adenoviral immune responses inhibit adenovirus-mediated transgene expression.

The transient nature of adenovirus-mediated transgene expression has been attributed to adaptive immune responses to adenoviral proteins and transgene products. However, the cytokines interferon-gamma (IFNgamma) and tumor necrosis factor-alpha (TNFalpha) inhibit transgene expression from adenoviral vectors in vitro by a transcription-related mechanism, and their early induction following vector administration in vivo suggests a contribution of innate immunity in regulating transgene expression. In this study, the significance of cytokine expression and its relation to adaptive and innate immunities were determined in TNFalpha-knockout mice, IFNgamma-knockout mice, or anti-IFNgamma mAb-injected animals. Adenoviral LacZ reporter expression directed by human cytomegalovirus (HCMV) promoters was greater in magnitude and duration than that by the murine CMV (MCMV) promoter. beta-Galactosidase reporter gene expression up to day 7 was greater in cytokine-deficient animals compared with wild type. Decrements in transgene expression occurred in advance of adaptive immune responses and were not due to alterations in specific adaptive immunity or vector clearance in cytokine-depleted mice. We conclude that TNFalpha and IFNgamma inhibit early adenovirus-mediated transgene expression by HCMV and MCMV promoters in vivo. Cytokine inhibition of expression is independent of adaptive immunity and is likely secondary to innate immune responses to adenovirus infection.

Adenoviridae↗

PubMed2006

Interleukin-21 mRNA expression during virus infections.

Interleukin-21 is a cytokine with profound impact on the proliferation and differentiation of activated leukocytes of both the innate and adaptive immune system. In experiments in vitro, antigen activation induces IL-21 production in CD4+ T cells. Where, when, and how the proliferative and activational effects of IL-21 on different leukocytes come into play in vivo in an immune response has so far not been fully investigated. We show here for the first time in vivo, that IL-21 mRNA is produced in the spleen when mice are challenged with herpes simplex virus type 2 (HSV-2) or lymphocytic choriomeningitis virus (LCMV). We show in HSV-2 challenged mice that this production takes place in CD4+ T cell fractions and is absent in CD4+ T cell-depleted fractions. We also show that the peak of IL-21 mRNA production in both the HSV-2 and LCMV-challenged mice coincides with the onset of the adaptive immune response. Thus, our data suggest a role for IL-21 in the early stages of adaptive immune response against virus infections.

Animals↗

PubMedDate not supplied

Targeting dendritic cells for priming cellular immune responses.

The cardinal role of dendritic cells (DC) in priming adaptive immunity and in orchestrating immune responses against all classes of pathogens and also against tumors is well established. Their unique potential both to maintain self-tolerance and to initiate protective immune responses against foreign and/or dangerous structures is based on the functional diversity and flexibility of these cells. Tissue DC lining antigenic portals such as mucosal surfaces and the skin are specialized to take up a wide array of compounds including proteins, lipids, carbohydrates, glycoproteins, glycolipids and oligonucleotides, particles carrying such structures and apoptotic or necrotic cells. This process is facilitated by specialized receptors with high endocytic capacity, which provides potential targets for delivering designed molecules. The best route for targeting B- and/or T cell epitopes, however, is still the subject of intense investigation. Immature DC, which reside in various tissues, can be activated by pathogens, stress and inflammation or modified metabolic products, which induce mobilization of cells to draining lymph nodes where they act as highly potent professional antigen presenting cells. This is brought about by the ability to present their accumulated intracellular content for both CD4+ helper (Th) and CD8+ cytotoxic/cytolytic T lymphocytes (Tc/CTL). Engulfed proteins are processed intracellularly and their peptide fragments are transported to the cell surface in the context of major histocompatibility complex encoded class I and II molecules for presentation to Th cells and CTLs, respectively. The T cell priming capacity of DC, however, depends not only on antigen presentation but also on other features of DC. Human monocyte-derived DC provide an excellent tool to study the internalizing, antigen-presenting and T cell-activating functions of DC at their immature and activated differentiation states. These biological activities of DC, however, are highly dependent on their migratory potential from the peripheral non-lymphoid tissues to the lymph nodes, on the expression of adhesion molecules, which support the interaction of DC with T lymphocytes, and the cytokines secreted by DC, which polarize immune responses to Th1-mediated cellular or Th2-mediated antibody responses. These results altogether demonstrate that monocyte-derived DC are useful candidates for in vitro or in vivo targeting of antigens to induce efficient adaptive immune responses against pathogens and also against tumors.

Animals↗

PubMed2001

Toxin levels in serum correlate with the development of staphylococcal scalded skin syndrome in a murine model.

Staphylococcal scalded skin syndrome (SSSS) is an exfoliative dermatitis that results from infection with exfoliative toxin-producing Staphylococcus aureus. SSSS is seen primarily in infants and children. Here we ask if there is a specific maturation process that protects healthy adults from this syndrome. For these studies, an active recombinant exfoliative toxin A (rETA) was used in a neonatal mouse model. A time course generated on the susceptibility to the toxin as a function of mouse age indicated that BALB/c mice developed the characteristic symptoms of SSSS until day 7 of life. Between day 7 and day 8 of life there was a dramatic decrease in susceptibility, such that mice at day 9 of life were resistant to the effects of the toxin. This time course corresponds approximately to the time needed for maturation of the adaptive immune response, and SSSS in adults is often identified with immunocompromised states. Therefore, mice deficient in this response were examined. Adult mice thymectomized at birth and adult SCID mice did not develop the symptoms of SSSS after injection with the toxin, indicating that the adaptive immune response is not responsible for the lack of susceptibility observed in the older mice. SSSS in adults is also associated with renal disorders, suggesting that levels of toxin in serum are important in the development of the disease. rETA was not cleared as efficiently from the serum of 1-day-old mice compared to clearance from 10-day-old mice. Ten-day-old mice were given repeated injections of toxin so that the maximal level of toxin was maintained for a sustained period of time, and exfoliation occurred in these mice. Thus, whereas the adaptive immune response is not needed for protection of adult mice from SSSS, efficient clearance of the toxin from the bloodstream is a critical factor.

Aging↗

PubMed2001

Roles of Toll-like receptors in innate immune responses.

Innate immunity recognizes invading micro-organisms and triggers a host defence response. However, the molecular mechanism for innate immune recognition was unclear. Recently, a family of Toll-like receptors (TLRs) was identified, and crucial roles for these receptors in the recognition of microbial components have been elucidated. The TLR family consists of 10 members and will be expanding. Each TLR distinguishes between specific patterns of microbial components to provoke innate immune responses. The activation of innate immunity then leads to the development of antigen-specific adaptive immunity. Thus, TLRs control both innate and adaptive immune responses.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Host innate defenses in the lung: the role of cytokines.

PURPOSE OF REVIEW: The lung has a unique relationship with the environment. Through evolution the lung has developed strategies to defend itself from microbial invasion. As we encounter increasing multidrug-resistant microorganisms, we need to further our knowledge of innate defense systems in order to design novel strategies to deal with these microbes without inducing over-exuberant inflammation and lung injury. RECENT FINDINGS: The development of lung innate immunity requires microbial molecular pattern recognition by the recently described Toll like receptors, the release of early response cytokines that further activate the 'master switch', nuclear factor-kappaB, leading to amplified host defense to invading microbes. A balance of Type 1 and Type 2 cytokines modulates the intensity of innate immunity. Cytokines/chemokines orchestrate the polarization and transition of innate to adaptive immunity. SUMMARY: The elucidation of the pathways involved in innate immunity and factors controlling the transition to adaptive immunity will improve our understanding of the host response to infection and improve our ability to design new therapies for the treatment of infectious disease.

Chemokines↗

PubMed1997

Genetic association of bovine lymphocyte antigen DRB3 alleles with immunological traits of Holstein cattle.

The associations between alleles at the BoLA (bovine lymphocyte antigen) DRB3 locus and 20 indicator traits of innate and adaptive immunity were investigated. Periparturient Holsteins (n = 127) were genotyped at the BoLA DRB3 locus using polymerase chain reaction and restriction fragment length polymorphism. Twenty-two alleles were observed in the study population, and frequencies ranged from 21 to < 1%. The same cattle were tested for a total of 20 innate and adaptive immunity traits, including lymphocyte response to mitogens (proliferative responses and Ig secretion), serum Ig, complement and conglutinin concentrations, total leukocyte count, and selected assays for neutrophil function. Models with gene substitution effects were used to investigate associations between BoLA DRB3 alleles and each of the immunological variables. Significant associations were found with 13 of the leukocyte functions tested. The number of immune parameters with significant associations with any allele ranged from 0 (with alleles DRB3.2*23 and DRB3.2*27) to 7 (with DRB3.2*8). The immunological parameter that had the most associations with alleles was serum IgG2 concentration with 6 alleles. One group of 4 alleles (representing 46% of the total allele frequency) was uniformly associated with increased IgM and complement and decreased mononuclear cell numbers. Thus, we demonstrated that the BoLA DRB3 genotype can influence measures of innate and adaptive immunity.

Alleles↗

PubMed2004

Innate immunity via Toll-like receptors and Nod proteins.

Host defense against microbes requires the development of an efficient immune response aimed to eradicate the source of infection. Through the expression of a battery of germ-line encoded receptors, including the Toll-like receptors and Nod proteins, the innate immune system, which is a prerequisite to the adaptive immune response, detects microbial motifs and initiates pro-inflammatory signaling. Current research into innate immune function focuses on the nature of the ligands detected by this system, the cell signaling that occurs downstream of receptor activation and finally, how these signals culminate into a tailored adaptive immune response directed to eradicate a specific infection.

Animals↗

PubMed2002

Emerging evidence that molecules expressed by mammalian tissue grafts are recognized by the innate immune system.

The innate immune system existed prior to the emergence of adaptive immunity in sharks and higher vertebrates. Homologues of many mammalian innate immune-system elements such as the toll-like receptors exist in species as distant as Drosophila. Selective pressure has led to the development of highly conserved, soluble, and cell-surface receptors that recognize functionally essential molecules shared by microbial pathogens. It is thought that molecular patterns that exquisitely distinguish pathogenic cells from mammalian cells are recognized. Therefore, it would seem unlikely that innate immune-system elements should recognize mammalian tissues. However, there is increasing evidence to suggest that this is the case and that innate immunity promotes rejection of transplanted mammalian tissues, particularly those from other species (xenografts). Evidence for innate recognition of mammalian grafts, the nature of this recognition, and the bi-directional interactions between innate and adaptive immunity that contribute to graft rejection are discussed in this review, with the emphasis on nonvascular xenografts.

Animals↗

PubMed2003

[Pulmonary anti-Aspergillus defences].

The lung, constantly exposed to inhaled infectious particles, uses a very efficient immune system to insure sterility of the airways. It has to be tightly regulated for the tissues to be kept from its potentially deleterious effects. Pulmonary anti-Aspergillus defences are based upon the concurrent action of innate immunity, non specific but rapidly mobilisable, and of adaptative immunity. The former first consists in natural barriers, namely the respiratory epithelium and its antimicrobial peptides (complement, defensins, collectins). Then come the phagocytic cells (macrophages and neutrophils), but also the dendritic cells, able to stimulate adaptative responses through the presentation of antigens they have phagocytised ans processed. The Toll-like receptors are among the key ones involved in the recognition of fungal components. Chemokines have a crucial role for the recruitment, maturation and activation of neutrophils, while anti-inflammatory cytokines tightly influence T lymphocytes functional differentiation. These latter, cornerstones of the adaptative immunity, differentiate into two mutually exclusive pathways according to the type of cytokines which they produce. The Th1 one is largely protective in the context of Aspergillus, while the Th2 one is deleterious. However, a good cooperation between these 2 pathways is required for an efficient protection. Pulmonary anti-Aspergillus defences are multifactorial. Innate immunity is crucial but a capacity of the host to generate specific responses is also warranted.

Antibody Formation↗

PubMed2005

Close encounters of neutrophils and DCs.

Neutrophils have a major function in innate immunity that involves phagocytosis and the killing of bacteria. Neutrophils also release pro-inflammatory chemokines and cytokines in response to pathogens that attract and stimulate other immune cells. This provides neutrophils with the potential to orchestrate adaptive immune responses. Here, we propose that neutrophils regulate adaptive immunity through interactions with dendritic cells (DCs). Neutrophils might function as danger sensors that communicate the presence of infection to DCs and instruct them to tailor ensuing immune responses to the type of pathogen. We also discuss how neutrophils trigger DC maturation and instruct DCs to induce Th1-type T-cell responses, and define the underlying molecular mechanisms that involve binding of Mac-1 on neutrophils to DC-SIGN on DCs.

Animals↗

PubMed2006

Transforming growth factor beta expression during an inner ear immune response.

OBJECTIVES: The involvement of transforming growth factor beta (TGF-beta), a strong mediator of fibrogenesis, during cochlear immune responses was investigated. METHODS: An inner ear adaptive immune response to antigen was created in mice that were painlessly sacrificed 3 to 48 hours and 7 days after initiation of the immune response. The cochleas were assayed by immunocytochemistry for TGF-beta and latency-associated peptide (LAP). RESULTS: We found LAP expressed in normal cochleas and the endolymphatic sac, in the small round cells in the cochlear scalae and the mesothelial cells under the basilar membrane, and in the endolymphatic sac perisaccular area. We found TGF-beta expressed in infiltrated, inflammatory cells in the scalae and the endolymphatic sac lumen 3 hours after cochlear antigen challenge. At this time, LAP immunoreactivity was decreased. This rapid shift in immunoreactivity provides evidence for activation of TGF-beta during an immune response. This reversal of expression persisted for 48 hours, but conditions reverted to normal after 7 days. Surgical controls did not show TGF-beta expression. CONCLUSIONS: We conclude that TGF-beta activation occurs in the early phase of a cochlear adaptive immune response and is down-regulated as the response resolves. This finding suggests that the process of cochlear fibrosis starts early and that proper treatment could prevent cochlear fibrosis.

Animals↗

PubMed2004

Is innate enough? The innate immune response in Drosophila.

In recent years, the innate immune system has emerged from the shadow of adaptive immune responses as a major area of research in its own right. One of the most significant model systems that has been used to investigate this phenomenon has been the fruit fly, Drosophila melanogaster. Exploration of the differential immune response presented by Drosophila led to the discovery of important signalling events and transduction pathways, which were thereafter shown to be specific for the type of infecting pathogen. These factors and pathways were subsequently found to have homologues in many other organisms, including those with adaptive immune responses. In light of the present status of studies in innate immunity, this review describes the current state of understanding of the Drosophila immune response.

Animals↗

PubMed2002

Cancer immunotherapy with interleukin 12 and granulocyte-macrophage colony-stimulating factor-encapsulated microspheres: coinduction of innate and adaptive antitumor immunity and cure of disseminated disease.

Tumor cells, injected s.c., were maintained until spontaneous metastases to the lungs were established in all of the mice. Mice were then treated with a single dose of cytokine-encapsulated biodegradable microspheres injected directly into primary s.c. tumors to achieve a local and sustained release of interleukin 12 (IL-12), granulocyte-macrophage colony-stimulating factor (GM-CSF), or a combination of these cytokines to the tumor microenvironment. The s.c. tumors were surgically excised 6 days after microsphere injections, and the mice were monitored for recurrence of the primary tumor, survival, and progression of metastatic disease. Combined neoadjuvant treatment with IL-12 and GM-CSF microspheres was superior to all other treatments in reducing the recurrence of primary tumors, enhancing postoperative survival, and suppressing established metastatic disease. Long-term survival analysis demonstrated that intratumoral injection of IL-12 + GM-CSF-loaded microspheres resulted in the complete cure of disseminated disease in the majority of the animals. The addition of systemic low-dose IL-2 therapy to the treatment protocol resulted in the loss of the antitumor activity induced by IL-12 + GM-CSF treatment. In vivo lymphocyte subset depletions established that both T- and natural killer-cell subsets were required for the suppression of primary and metastatic tumors. Long-term, tumor-specific T-cell activity was demonstrated by immunohistochemical analysis of metastatic lesions, IFN-gamma enzyme-linked immunosorbent spot (ELISPOT) assays and tumor challenge studies. These results establish that neoadjuvant in situ tumor immunotherapy with IL-12 + GM-CSF microspheres induces both innate and adaptive antitumor immune responses resulting in the eradication of disseminated disease.

Animals↗