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PubMedDate not supplied

Abrogation of resistance to bone marrow transplantation by induction of specific tolerance in natural killer cells?

Hybrid resistance describes the capacity of first generation (F1) hybrids between certain mouse strains to inhibit the growth of tumour or haematopoietic cells of parental origin. The cells that appear to mediate this phenomenon differ from classical T and B lymphocytes in several respects. For example, they are unusually radioresistant, show no immunological memory, are present in thymectomized or congenitally athymic mice, are not functional until about 3 weeks after birth. These characteristics suggest that the effectors are natural killer (NK) cells. Although most of the evidence implicating NK cells in hybrid resistance is circumstantial, the experiments of Warner and Dennert are more direct in that they show that resistance can be restored to mice with a congenital or induced defect in NK activity by the infusion of cells belonging to an NK clone. Conversely, treatment of mice with an antibody to NK cells abrogated hybrid resistance to parental bone marrow grafts. Both NK cells and the effectors of hybrid resistance are generally considered to be nonspecific. We have now investigated this assumption by attempting to prevent hybrid resistance by neonatal tolerance induction with parental strain antigens. Our data indicate that hybrid resistance can be abrogated by this means and that the tolerance is specific and transferable with Thy-1+ spleen cells.

Animals↗
PubMed1997

A non-retroviral RNA virus persists in DNA form.

Infection of adult mice with lymphocytic choriomeningitis virus (LCMV), a non-cytopathic segmented RNA virus, leads initially to generalized infection, followed by clearance and subsequent life-long immunity. Indirect evidence has suggested that viral antigens may persist in lymphoid tissues during the phase of immunological memory, but viral genomic RNA has not been detected in previous studies. During a search for persistent virus in the spleen, we identified LCMV-specific sequences present as DNA by polymerase chain reaction (PCR) in mice over 200 days after infection. In vivo and in vitro studies revealed that reverse transcription of viral RNA into complementary DNA occurred after acute infection of cells of its natural hosts, mouse and hamster, but not of other species and could be inhibited in vitro by azidothymidine (AZT), indicating that this was mediated by endogenous reverse transcriptase activity. These findings reveal a surprising and new pathway of interaction between exogenous RNA viruses and endogenous retroviral, and perhaps other host components, that results in the persistence of virally determined DNA. We speculate that the latter may function in vivo as a form of DNA vaccine.

Animals↗
PubMed1986

Immunological consequences of intestinal helminth infections. Cellular and anamnestic responses to ovalbumin.

Depressed IgG responses to ovalbumin administered with the inflammatory adjuvant, Al(OH)3, have previously been demonstrated in mice immunized 5 to 13 days after infection with Nematospiroides dubius, when the parasite is encysted in the intestinal mucosa or becoming established in the lumen. This report extends these findings to show that primary IgE and delayed-type hypersensitivity (DTH) responses, the generation of antigen-primed cells detectable in syngeneic irradiated recipients or in vitro and the recall of immunological memory are correspondingly impaired. Co-transfer experiments using irradiated recipients demonstrated weak suppressor activity in spleen cells from infected mice which was not attributable to T cells. The results suggest that N. dubius administered before immunization can impair the development of many classes of antigen-primed lymphocytes. The implications of this finding with respect to parasite survival are discussed.

Aluminum Hydroxide↗
PubMed1997

Dependence of the adaptive immune response on innate immunity: some questions answered but new paradoxes emerge.

Recently a new model of vertebrate immunity has been gaining popularity. In this new model it is hypothesized that activation of innate immunity is a prerequisite for an adaptive immune response to an antigen. Following activation the innate system induces key costimulator molecules on APC, which are essential for antigen-driven clonal expansion of T and B cells. The model largely explains the need for adjuvants in the induction of adaptive immunity, provides a possible mechanism for the immune system to perceive the biological nature of a pathogen and thereby produce the most effective immune response, and transfers much of the onus of self-non-self discrimination from the adaptive to the innate immune system. In the present article we highlight two paradoxes raised by the new model. First, by linking adaptive immunity to innate recognition the immune system is unable to take full advantage of the genetic diversity of T and B cell antigen receptors. Thus, the ability of the immune system to combat a pathogen is totally dependent on the efficiency of recognition by the innate system and, therefore, the germ-line mutation rate of the genes involved in the innate response. Second, if signals from the innate system induce costimulatory molecules on APC, then one would expect the accidental clonal expansion of many autoreactive T and B cells. We suggest that one means of resolving the first paradox is to propose that the major reason for the evolution of adaptive immunity was to provide, via immunological memory, resistance to reinfection, rather than simply to combat the primary infection by the pathogen. In the case of autoreactivity we suggest that autodestruction is prevented by immune responses being tightly regulated at the effector T cell level. Finally, we argue that the two paradoxes, rather than undermining the new model of immunity, highlight our lack of understanding of key elements of the vertebrate immune system.

Adaptation, Physiological↗
PubMed1997

Immunity to Plasmodium falciparum malaria sporozoites by somatic transgene immunization.

Immunity against the human malaria parasite Plasmodium falciparum was induced using somatic transgene immunization, a method to effectively target B lymphocytes in vivo. A single inoculation of plasmid DNA containing an immunoglobulin heavy-chain gene coding in the complementarity-determining region 3 for three repeats of the sequence Asn-Ala-Asn-Pro (NANP), a B-cell epitope of P.falciparum sporozoites, induced antibodies against NANP in all mice. A booster with an antibody antigenized with the NANP peptide, or challenge with P. falciparum sporozoites, demonstrated the establishment of immunologic memory. Immunity to a parasite antigen can be induced by exploiting mechanisms in which B lymphocytes are both the source of the immunogen as well as the effector mechanism of immunity. The results indicate that somatic transgene immunization is a potential approach for vaccination against foreign pathogens.

Animals↗
PubMed2002

CD94-NKG2A receptors regulate antiviral CD8(+) T cell responses.

CD8(+) T lymphocytes mediate immunosurveillance against persistent virus infections and virus-induced neoplasia. Polyoma virus, a highly oncogenic natural mouse DNA virus, establishes persistent infection, but only a few mice are highly susceptible to tumors induced by the virus. Mature antiviral CD8(+) T cells expand in tumor-susceptible mice, but their cytotoxic effector activity is nonfunctional in vivo. Here we show that the natural killer cell inhibitory receptor, CD94-NKG2A, is up-regulated by antiviral CD8(+) T cells during acute polyoma infection and is responsible for down-regulating their antigen-specific cytotoxicity during both viral clearance and virus-induced oncogenesis.

Animals↗
PubMed2000

Interleukin-12 gene therapy of a weakly immunogenic mouse mammary carcinoma results in reduction of spontaneous lung metastases via a T-cell-independent mechanism.

In our previous studies using gene gun-mediated delivery of interleukin 12 (IL-12) cDNA in vivo, we observed T-cell-mediated regression of established murine tumors and demonstrated the induction of systemic immunity in test animals. In this study, we further characterized the antitumoral and anti-metastatic effect of this gene therapy approach by employing two murine metastatic mammary tumor models: the immunogenic TS/A adenocarcinoma and the weakly immunogenic 4T1 adenocarcinoma. In the TS/A model, gene transfer into the skin overlying an established intradermal tumor with an IL-12 cDNA expression vector resulted in complete tumor regression in 50% of mice followed by the development of immunological memory. In contrast, the growth of the intradermal 4T1 tumors was not affected by the IL-12 gene therapy protocol. However, this treatment resulted in a substantial reduction of spontaneous metastases in the lungs of 4T1 tumor-bearing mice and significantly prolonged their survival time. T cells were not required for this anti-metastatic effect, because it was also observed in nude mice and in mice depleted of CD4+ and CD8+ T cells. Tumor-draining lymph node cells obtained from 4T1 tumor-bearing mice treated with IL-12 cDNA exhibited increased natural killer (NK) activity and produced enhanced levels of interferon-gamma (IFN-gamma) compared with similar mice treated with luciferase cDNA. In addition, in vivo depletion of NK cells or neutralization of IFN-gamma resulted in partial suppression of the anti-metastatic effect of IL-12 gene therapy, suggesting the involvement of both NK cells and IFN-gamma in this effect.

Adenocarcinoma↗
PubMed1999

Phenotypic and functional characterization of lymphocytes derived from normal and HIV-1-infected human lymph nodes.

Lymph nodes are the major site of cell-to-cell transmission and replication of HIV-1. Trafficking of CD4+ T lymphocytes into lymph nodes provides a continual supply of susceptible target lymphocytes, and conversely, recruitment of CD8+ T lymphocytes may be critical for the host response that attempts to control HIV-1 replication. The present study was undertaken as no detailed assessment of lymphocyte subpopulations in HIV-1-infected lymph nodes has previously been reported. Peripheral blood and single-cell suspensions prepared from lymph nodes of patients with HIV-1 and control subjects were analysed using three-colour flow cytometry. Approximately 80% of the lymphocytes in control lymph nodes were CD3+ T lymphocytes, of which over 65% were CD4+. The majority of the CD4+ and CD8+ T lymphocytes obtained from both lymph nodes and blood of control subjects were immunologically naive (CD45RA+). By contrast, in HIV-1-infected patients there was a significant reduction in the proportion of CD4+ T lymphocytes and an expansion of the CD8+ T lymphocyte subset in both lymph nodes and peripheral blood. Furthermore, a high proportion of these T lymphocytes displayed a marker for immunological memory (CD45RO+). T lymphocytes derived from HIV-1-infected lymph nodes also showed altered expression of the adhesion molecules, L-selectin and very late antigen-4 (VLA-4), but not leucocyte function-associated antigen-1 (LFA-1). In an in vitro adhesion assay, lymphocytes from HIV-1-infected nodes were significantly more adhesive than control lymphocytes on fibronectin, as well as recombinant human intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) substrates. This combination of altered lymphocyte subpopulations in the HIV-1-infected lymph nodes, as well as enhanced adhesion phenotype and function, suggests that T lymphocyte traffic to lymph nodes in HIV disease may be an important determinant of pathogenesis.

Adult↗
PubMed2000

The proportion of circulating gammadelta T cells increases after the first week of onset of tularaemia and remains elevated for more than a year.

In various human intracellular bacterial diseases, an increase of the proportion of circulating Vgamma9Vdelta2 T cells has been observed. The prevalence of the finding among infected subjects and the time course of the elevation remain to be investigated. In the present study, comprising blood samples from a large number of cases of ulceroglandular tularaemia, the percentage of Vgamma9Vdelta2 T cells within the first week of onset of disease (5.3 +/- 0.7% (mean +/- s.e.m.)) did not differ from that of control subjects (5.3 +/- 0. 8%). Thereafter, percentages increased rapidly and within the interval of 8-40 days mean levels were > 20% (P < 0.001). Of 45 individuals sampled within 3 months of onset, 42 showed a percentage of Vgamma9Vdelta2 T cells of > 10%. Significantly increased levels were still recorded at 18 months (13.8 +/- 2.4%; P < 0.05) but not at 24 months (10.2 +/- 2.1%; P > 0.10). Thus, a consistent increase of circulating Vgamma9Vdelta2 T cells was demonstrated in tularaemia. The initial delay and the prolonged course of elevation may suggest a role in immunoregulation and/or immunological memory. Furthermore, the percentage of gammadelta T cells expressing tumour necrosis factor-alpha in response to phorbol myristate acetate was decreased during the first week and up to 40 days after onset, possibly reflecting the modulation of an inflammatory response.

Adolescent↗
PubMed1996

Regulation of T-cell activation in the lung: alveolar macrophages induce reversible T-cell anergy in vitro associated with inhibition of interleukin-2 receptor signal transduction.

Alveolar macrophages (AM) are recognized as archetypal 'activated' macrophages with respect to their capacity to suppress T-cell responses to antigen or mitogen, and this function has been ascribed an important role in the maintenance of local immunological homeostasis at the delicate blood:air interface. The present study demonstrates that this suppression involves a unique form of T-cell anergy, in which 'AM-suppressed' T cells proceed normally through virtually all phases of the activation sequence including Ca2+ flux, T-cell receptor (TCR) modulation, cytokine [including interleukin-2 (IL-2)] secretion and IL-2 receptor (IL-2R) expression. However, the 'suppressed' T cells fail to up-regulate CD2, and do not re-express normal levels of TCR-associated molecules after initial down-modulation; moreover, they are unable to transduce IL-2 signals leading to phosphorylation of IL-2R-associated proteins, and remained locked in G0/G1. The induction of this form of anergy is blocked by an NO-synthase inhibitor, and is reversible upon removal of AM from the T cells, which then proliferate in the absence of further stimulation. We hypothesize that this mechanism provides the means to limit the magnitude of local immune responses in this fragile tissue microenvironment, while preserving the capacity for generation of immunological memory against locally encountered antigens via clonal expansion of activated T cells after their subsequent migration to regional lymphoid organs. In an accompanying paper, we demonstrate that a significant proportion of T cells freshly isolated from lung exhibit a comparable surface phenotype.

Animals↗
PubMedDate not supplied

Comparative immunization study using RNA and DNA constructs encoding a part of the Plasmodium falciparum antigen Pf332.

Development of nucleic acid-based vaccines against parasitic diseases shows great promise, although certain concerns about safety aspects of conventional DNA vaccines have been raised. This study presents a comparison of antibody responses induced in mice by DNA and RNA-based immunization with vectors encoding a part of the P. falciparum antigen Pf332. Two types of plasmids were used, one conventional DNA plasmid containing a cytomegalovirus promoter and one suicidal DNA plasmid encoding the Semliki Forest virus (SFV) replicase. RNA, encoding the SFV replicase and the relevant antigen, was delivered either as naked RNA or packaged in SFV suicide particles. In general, the antibody responses induced by the DNA plasmids were low and peaking after three injections, the conventional plasmid giving the highest responses. Also the RNA delivered in SFV particles consistently induced antibody responses, although comparatively low. Analyses of the ratio of immunoglobulin (Ig)G1/IgG2a subclasses in the responses indicated that all plasmids resulted in a bias for a Th2-type of response, while the SFV-particles elicited a Th1 type of response. Importantly, all these immunogens induced an immunological memory, which could be efficiently activated by a booster injection with the corresponding protein, with unchanged patterns of IgG subclasses.

Animals↗
PubMed2002

Current state of pneumococcal vaccines.

Streptococcus pneumoniae is a leading cause of bacterial pneumonia, meningitis, and acute otitis media in children and adults worldwide. According to World Health Organization estimates, at least 1 million children under 5 years of age die each year from pneumococcal pneumonia. The emergence of resistant strains necessitates the development of an effective vaccine with a large serotype coverage. The 11 most common serotypes cause 72-83% of all serious pneumococcal diseases worldwide. Currently marketed 23-valent pneumococcal polysaccharide vaccine provides large serotype coverage and offers a less expensive option. However, it is efficacious only in adults but not in infants. Conjugate vaccines offer a solution by generating immunological memory already at early age. A recently licensed 7-valent conjugate vaccine is immunogenic and efficacious in infants. Its serotype coverage might be sufficient in Europe and North America, but not in Africa, Asia and Oceania. A need exists to develop pneumococcal vaccines with lower cost and larger serotype coverage. Several 11-valent pneumococcal conjugate vaccines are being evaluated in phase I-III trials. This study reviews the current state of pneumococcal problem and pneumococcal vaccines in clinical use.

Adult↗
PubMed2003

Mucosal vaccination against encapsulated respiratory bacteria--new potentials for conjugate vaccines?

Polysaccharide (PS)-encapsulated bacteria such as Haemophilus influenzae type b (Hib), Streptococcus pneumoniae (pneumococcus), Neisseria meningitides (meningococcus) and group B streptococcus (GBS), cause a major proportion of disease in early childhood. Native PS vaccines are immunogenic and provide protection against disease in healthy adults but do not induce immunological memory. PSs are T-cell-independent antigens and do not elicit antibodies in infants and young children, but by conjugating PS to proteins they become T-cell dependent and immunogenic at an early age. Despite excellent efficacy of PS-protein conjugate vaccines against invasive disease, protection against mucosal infections such as pneumococcal otitis media has been less efficacious. Circulating PS-specific antibodies may protect against infections at mucosal sites, but mucosal immunoglobulin A antibodies may also contribute significantly to protection against mucosal infections. Mucosal immunization of experimental animals with conjugate vaccines against Hib, pneumococcus, meningococcus and GBS induces systemic and mucosal immune responses, which provide protection against carriage, otitis media and invasive disease in a variety of challenge models, providing new means for protection against encapsulated bacteria. In addition, mucosal immunization of neonatal mice with a pneumococcal conjugate and the nontoxic adjuvant LT-K63 has been superior to parenteral immunization in eliciting protective antibodies and PS-specific memory, and thus circumventing the limitations of antibody responses to PS that are responsible for enhanced susceptibility of neonates and infants to infections caused by encapsulated bacteria. Through T-cell dependent enhanced immunogenicity of PS-protein conjugate vaccines, mucosal immunization could be an attractive approach for early life immunization against encapsulated bacteria.

Adult↗
PubMed1998

Surgical management of equine recurrent uveitis with single port pars plana vitrectomy.

Current information suggests that equine recurrent uveitis (ERU) is an immune-mediated reaction to infectious agents or to autologous ophthalmic tissue. Recurrences are associated with progression of irreversible ocular damage. This report describes the intraoperative technique, complications, and long-term results of 38 eyes in 35 horses with ERU that underwent pars plana vitrectomy. The majority of the horses were warm-blooded. Recurrence of ERU was prevented in 35 of the 38 eyes. Some horses, especially in patients with incipient cataracts, developed vision loss in postoperative, quiescent eyes which was usually associated with cataract formation. Vision was stable in 85% of all eyes that underwent vitrectomy. Pars plana vitrectomy in horses appears successful in interrupting the cycle of repeated episodes of ERU, and the subsequent globe destruction in the majority of eyes. Removal of uveitis-induced 'immunologic memory' in the vitreous by vitrectomy may reduce adverse interaction between the vitreous and the uveal tract, and therefore reduce the recurrence of ERU.

Journal Article↗
PubMed1979

Immune response of a patient with deficiency of the fourth component of complement and systemic lupus erythematosus.

The clinical details of a five-year-old boy with systemic lupus erythematosus and an inherited deficiency of the fourth component of complement (C4) have been reported elsewhere. In this study of his immune responses, immunization with bacteriophage phi X 174 demonstrated diminished antibody formation, abnormal immunologic memory and failure to switch from IgM to IgG during secondary response. We also noted persistent lymphopenia and reductions in peripheral-blood T lymphocytes, lymphocyte responses to mitogens and allogeneic cells and granulocyte chemotaxis. Kinetic studies revealed that delayed activation of the alternative pathway was corrected by purified C4 only if the classical pathway was not blocked. This finding is consistent with the concept that minute amounts of C3b provided through the classical pathway are necessary to prime the properdin system. Inability to activate the classical complement pathway, abnormal kinetics of alternative-pathway activation and depressed antibody responses to a T-cell-dependent antigen may predispose C4-deficient patients to viral infection or immune-complex formation.

Antibodies, Bacterial↗
PubMed2001

Antibody responses to bacteriophage phi X-174 in human subjects exposed to the antarctic winter-over model of spaceflight.

BACKGROUND: It has been proposed that exposure to long-term spaceflight conditions (stress, isolation, sleep disruption, containment, microbial contamination, and solar radiation) or to ground-based models of spaceflight will alter human immune responses, but specific antibody responses have not been fully evaluated. OBJECTIVE: We sought to determine whether exposure to the 8-month Antarctic winter-over model of spaceflight would alter human antibody responses. METHODS: During the 1999 Australian National Antarctic Research Expeditions, 11 adult study subjects at Casey, Antarctica, and 7 control subjects at Macquarie Island, sub-Antarctica, received primary and secondary immunizations with the T cell-dependent neoantigen bacteriophage phi X-174. Periodic plasma samples were analyzed for specific antibody function. RESULTS: All of the subjects from Casey, Antarctica, cleared bacteriophage phi X-174 normally by 1 week after primary immunization, and all had normal primary and secondary antibody responses, including immunologic memory amplification and switch from IgM to IgG antibody production. One subject showed a high normal pattern, and one subject had a low normal pattern. The control subjects from Macquarie Island also had normal immune responses to bacteriophage phi X-174. CONCLUSIONS: These data do not support the hypothesis that de novo specific antibody responses of subjects become defective during the conditions of the Antarctic winter-over. Because the Antarctic winter-over model of spaceflight lacks the important factors of microgravity and solar radiation, caution must be used in interpreting these data to anticipate normal antibody responses in long-term spaceflight.

Adult↗
PubMed2004

T cell immunity using transgenic B lymphocytes.

Adaptive immunity exists in all vertebrates and plays a defense role against microbial pathogens and tumors. T cell responses begin when precursor T cells recognize antigen on specialized antigen-presenting cells and differentiate into effector cells. Currently, dendritic cells are considered the only cells capable of stimulating T lymphocytes. Here, we show that mature naïve B lymphocytes can be genetically programmed by using nonviral DNA and turned into powerful antigen-presenting cells with a dual capacity of synthesis and presentation of antigen to T cells in vivo. A single i.v. injection of transgenic lymphocytes activates T cell responses reproducibly and specifically even at very low cell doses (approximately 10(2)). We also demonstrate that T cell priming can occur in the absence of dendritic cells and results in immunological memory with protective effector functions. These findings disclose aspects in the regulation of adaptive immunity and indicate possibilities for vaccination against viruses and cancer in humans.

Animals↗
PubMed2004

A mucosally targeted subunit vaccine candidate eliciting HIV-1 transcytosis-blocking Abs.

A vaccine that would engage the mucosal immune system against a broad range of HIV-1 subtypes and prevent epithelial transmission is highly desirable. Here we report fusing the mucosal targeting B subunit of cholera toxin to the conserved galactosylceramide-binding domain (including the ELDKWA-neutralizing epitope) of the HIV-1 gp41 envelope protein, which mediates the transcytosis of HIV-1 across the mucosal epithelia. Chimeric protein expressed in bacteria or plants assembled into oligomers that were capable of binding galactosyl-ceramide and G(M1) gangliosides. Mucosal (intranasal) administration in mice of the purified chimeric protein followed by an i.p. boost resulted in transcytosis-neutralizing serum IgG and mucosal IgA responses and induced immunological memory. Plant production of mucosally targeted immunogens could be particularly useful for immunization programs in developing countries, where desirable product traits include low cost of manufacture, heat stability, and needle-free delivery.

AIDS Vaccines↗