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PubMed2003

Critical role of the Th1/Tc1 circuit for the generation of tumor-specific CTL during tumor eradication in vivo by Th1-cell therapy.

Th1 and Th2 cells obtained from OVA-specific T cell receptor transgenic mice completely eradicated the tumor mass when transferred into mice bearing A20-OVA tumor cells expressing OVA as a model tumor antigen. To elucidate the role of Tc1 or Tc2 cells during tumor eradication by Th1- or Th2-cell therapy, spleen cells obtained from mice cured of tumor by the therapy were re-stimulated with the model tumor antigen (OVA) for 4 days. Spleen cells obtained from mice cured by Th1-cell therapy produced high levels of IFN-gamma, while spleen cells from mice cured by Th2-cell therapy produced high levels of IL-4. Intracellular staining analysis demonstrated that a high frequency of IFN-gamma-producing Tc1 cells was induced in mice given Th1-cell therapy. In contrast, IL-4-producing Tc2 cells were mainly induced in mice after Th2-cell therapy. Moreover, Tc1, but not Tc2, exhibited a tumor-specific cytotoxicity against A20-OVA but not against CMS-7 fibrosarcoma. Thus, immunological memory essential for CTL generation was induced by the Th1/Tc1 circuit, but not by the Th2/Tc2 circuit. We also demonstrated that Th1-cell therapy is greatly augmented by combination therapy with cyclophosphamide treatment. This finding indicated that adoptive chemoimmunotherapy using Th1 cells should be applicable as a novel tool to enhance the Th1/Tc1 circuit, which is beneficial for inducing tumor eradication in vivo.

Animals↗
PubMed1992

A theoretical framework for the immunoepidemiology of helminth infection.

Field studies of parasitic helminths in endemically infected human communities have provided quantitative information on the relationships between parasite burdens, immune responses and age. There are considerable difficulties in the interpretation of these immunoepidemiological data due to the complexities of the biological processes generating the observed patterns. In this paper simple mathematical models are used to explore the expected patterns of variation with host age in parasite burdens, the aggregation of parasites among hosts, levels of immune response, and the correlation between parasite burdens and immune responses. These relationships reflect rates of infection, rates of parasite mortality, the strength of the immune response, and the duration of immunological memory. The models generate some complex and counterintuitive patterns. The analysis suggests that some of these patterns might serve to (i) distinguish effects due to acquired immunity from effects due to age-dependent exposure, (ii) identify potentially protective immune responses, and (iii) identify the parasite stages important in the development of acquired immunity. The results imply that previous analyses of immunoepidemiological data may have been overly simplistic and, especially, that patterns believed to be inconsistent with protective immunity may have been incorrectly interpreted.

Adolescent↗
PubMed1994

A theoretical framework for the immunoepidemiology of blocking antibodies to helminth infection.

Epidemiological evidence is widely cited in support of the hypothesis that certain antibody responses to human helminth, especially schistosome, infection exhibit blocking activity. This evidence includes positive correlations between antibody levels and the rate of re-establishment of infection following chemotherapy, antibody levels which peak in younger and more susceptible age classes, lower ratios of blocking antibodies to others in older and less susceptible age classes. In this paper simple mathematical models are used to explore expected age-specific relationships between antibody levels, parasite burdens and re-establishment rates for different combinations of protective, neutral and blocking immune responses. In general, all the above cited patterns may be generated without invoking blocking activity, especially if the abilities to produce different antibody responses have different immunological memories, i.e. persist for different lengths of time in the absence of continued exposure to antigen. None of these patterns, including a positive correlation between antibody levels and rates of re-establishment following chemotherapy, offers unambiguous evidence for blocking activity. Blocking activity is also predicted to affect the shape of the age-intensity curve and the relationship between susceptibility to infection and age in ways which are not necessarily consistent with the epidemiological evidence. The importance of the blocking activity, which has been convincingly demonstrated in vitro, to population level immunoepidemiological patterns in the field therefore remains uncertain.

Adolescent↗
PubMed1989

Studies on active immunization with self antigens. I. Production of antibody to unmodified proteins by neonatal immunization.

Newborn BALB/c mice were repeatedly injected either with syngeneic (BALB/c) or xenogeneic (bovine) myosin, albumin, or actin in sterile physiological saline. The serum antibody response was evaluated by enzyme immunoassay 1 and 2 months after birth and after two booster injections. At 1 month, higher antibody titres were found in the sera of mice injected with syngeneic than with xenogeneic antigens. At 2 months and after boosting, anti-syngeneic actin antibodies were present in equal or higher amounts, anti-syngeneic albumin antibodies were not detected, and anti-syngeneic myosin antibodies were considerably decreased. Antibodies produced after booster injections of syngeneic actin were found to be highly specific and to belong mainly to the IgG isotype. These results suggest that newborn mice are better able than adult mice to respond to stimulation with self antigens, and that administration of self proteins during neonatal life may lead to the induction of immunological memory. They also indicate that one of the primary functions of the immune system in newborn mice is the recognition of self antigens.

Actins↗
PubMed1991

Localization of circulating immune complexes from patients with rheumatoid arthritis in murine spleen germinal centres.

In previous studies we have demonstrated high levels of rheumatoid factor (RF) and large-size (greater than 22S) circulating immune complexes (CIC) in the serum of rheumatoid arthritis (RA) patients with extra-articular disease. These findings were paralleled by a concurrent increase in the level of RF-associated cross-reactive idiotypes (CRI) and an apparent diversification of the RF repertoire detected in the serum of the same patients. In the present study we examine the ability of CICs to activate the complement system in vivo, and its possible influence on expanding the RF repertoire in RA patients with extra-articular disease. Activation of complement by CICs is the key for germinal centre localization and long-term retention of such complexes on the surface of follicular dendritic cells (FDC), and so provides a source for the selection of cells with high affinity receptors for IgG and leads to the establishment of immunological memory. CICs containing different immunoglobulin isotypes and from different patients localized in mouse spleen germinal centres. However, intense localization was mainly seen for IgG-containing complexes from the serum of patients with large-size (greater than 22S) IgG-IgM RF complexes. The ability of these complexes to localize in mouse spleen germinal centres was related to activation of the complement system via the classical pathway in the patients' sera. Localization of IgG complexes was significantly (P less than 0.05) higher in sera from RA patients with extra-articular disease than those with articular disease alone. This study demonstrates the ability of large-size (greater than 22S) IgG-IgM RF complexes to activate complement, and suggests a possible role for such complexes in modulating the immune response to IgG in RA patients with extra-articular disease.

Animals↗
PubMed1994

Twenty-five years of germinal centre physiology: implications for tolerance in the secondary B cell repertoire.

Twenty-five years ago, when I delivered the inaugural lecture of the Scandinavian Society for Immunology, my mind was filled with germinal centres because of the extraordinary antigen-capturing mechanism there, which depended on follicular dendritic cells trapping the antigen and holding it in an extracellular location for long periods of time, following which the germinal centre reaction developed around the antigen depot. It was apparent that germinal centres had much to do with immunological memory, but few functional details of their role were known. In the intervening period, a great deal of knowledge has accumulated about germinal centres, which have become known as the sites of extensive B cell proliferation, immunoglobulin variable region gene hypermutation, and selection of better antigen-binding variants leading to affinity maturation in the antibody response. Our laboratory's interest was reawakened when we came to examine the hypothesis that B lymphocytes destined to develop into memory B cells might pass through a 'second window' of tolerance susceptibility if they encountered antigen in the absence of T-cell help. We have constructed a model of tolerance dependent on the injection of soluble deaggregated antigen before or even up to 6 days after T cell-dependent challenge immunization. The model was intended to mimic what might happen if a B cell, developing correctly in a germinal centre, fortuitously mutates to acquire cross-reactivity to a soluble self antigen. We have shown that the surrogate self-antigen can profoundly impair the germinal centre process and virtually stop the emergence of high affinity memory B cells.

Animals↗
PubMed1995

Characterization of the antibody response to a Haemophilus influenzae type b conjugate vaccine in children with recurrent lower respiratory tract infection.

Children with recurrent lower respiratory tract infection (RLRI) may respond poorly to polysaccharide antigens. To examine how such children respond to a polysaccharide coupled to a protein carrier, we immunized 15 children with RLRI aged 8-69 months and 15 carefully age-matched healthy controls once with a Haemophilus influenzae type b (Hib) conjugate vaccine. Total IgG subclasses, total antipolysaccharide Hib antibodies, and antipolysaccharide Hib antibodies of IgM, IgG, IgA, and IgG1-4 specificity were determined by ELISA. There were no significant differences between the two groups in any single total IgG subclass, but total IgG measured as the sum of all four subclasses was significantly lower in the children with RLRI than in the controls (P = 0.036). Before vaccination, the children with RLRI had significantly less IgG antipolysaccharide Hib antibody than the controls (P = 0.005), whereas 1 month later they had significantly more IgM antibody (P = 0.038). No other significant differences were found between the groups before or after immunization with respect to antipolysaccharide Hib antibodies. Since naturally occurring IgG antibodies are thought to be acquired partly as a consequence of antigenic stimulation on mucosal surfaces, we hypothesize that the low level of specific IgG found before immunization, as well as the low total IgG in the children with RLRI, may reflect an impaired ability to prime through mucosal surfaces. This is supported by our finding of an increased IgM response to Hib conjugate vaccine in these children, since this isotype predominates in the primary immune response, i.e., in the absence of immunologic memory.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies↗
PubMed1986

An electron microscopical and histochemical study on ferric nitrilotriacetate-induced "F1 amyloidosis".

Of a total of 80 offspring obtained by reciprocal crossing of ICR/JCL strain of mice of both sexes receiving 84-140 injections of Fe-NTA over 98-163 days before crossing, 52 (65%) showed severe generalized amyloidosis after 93-502 injections of Fe-NTA over 115-522 days, but not "hemochromatosis", which was a striking contrast to the findings of "hemochromatosis" without amyloidosis observed in the parent mice. Electron microscopic examinations revealed numerous bundles of non-branching, well-oriented amyloid fibrils radiated outward from the surface of cytoplasmic invaginations of the Kupffer cells or splenic reticuloendothelial cells of the F1 mice with amyloidosis, and close contact frequently observed between "amyloid-forming cells" and adjacent lymphocytes in the amyloid-laden liver and spleen of the F1 mice. Since the above findings in the F1 mice were not found in the parent mice treated with multiple Fe-NTA injections, the present authors assumed that the immunological memory for the Fe-NTA conjugate transmitted via the placenta to the fetus from the mother that received multiple Fe-NTA injections might be involved in the development of generalized amyloidosis in the F1 mice, although the possible mechanism by which Fe-NTA-induced "F1 amyloidosis" has been developed remains yet undetermined.

Amyloidosis↗
PubMed2005

New approaches in vaccine development for parasitic infections.

Vaccines have had a tremendous impact on the control of infectious diseases. Not only are vaccines potentially the least expensive mechanism to combat infectious diseases, under optimal conditions, widespread vaccination can result in disease eradication - as in the case of smallpox. Despite this great potential, vaccines have had little impact on human parasitic infections. The reasons for this are many - these eukaryotic pathogens are genetically and biologically complex organisms, some with elaborate life cycles and well-honed immune evasion mechanisms. Additionally, our understanding of the mechanisms of immune control of many parasitic infections -- of what constitutes an effective immune response and of how to induce high-quality immunological memory -- is not fully developed. This review attempts to highlight recent advances that could impact vaccine discovery and development in parasitic infections and proposes areas where future studies may lead to breakthroughs in vaccines for the agents of parasitic diseases. There are several other recent reviews highlighting the results of vaccine trials, specifically in the malaria field.

Animals↗
PubMed2006

How to kill a mocking bug?

All metazoans have evolved means to protect themselves from threats present in the environment: injuries, viruses, fungi, bacteria and other parasites. Insect protection includes innate physical barriers and both cellular and humoral responses. The insect innate immune response, best characterized in Drosophila melanogaster, is a rapid broad response, triggered by pathogen-associated molecular patterns (PAMPs) recognition, which produces a limited range of effectors that does not alter upon continued pathogen exposure and lacks immunological memory. The Drosophila response, particularly its humoral response, has been investigated by both low and high-throughput methods. Three signalling pathways conserved between insects and mammals have been implicated in this response: Toll (equivalent to mammalian TLR), Imd (equivalent to TNFalpha) and Hop (equivalent to JAK/STAT). This review provides an entry point to the insect immune system literature outlining the main themes in D. melanogaster bacterial pathogen detection and humoral and cellular immune responses. The Drosophila immune response is compared with other insects and the mammalian immune system.

Animals↗
PubMed1997

Therapy with cultured T cells: principles revisited.

In animals and in humans, T-cell therapy can cure advanced disseminated leukemia that would otherwise be fatal. The therapeutic effect of immune T cells is quantitative. As the dose of effector T cells is increased, survival is proportionately increased. Therefore, effective T-cell therapy is predicated on the ability to procure large numbers of immune effector T cells. By using cultured T cells, the number of immune T cells can be increased in vivo substantially above the level achievable by vaccination. The survival of cultured T cells in vivo is dependent upon both the culture conditions used and the therapeutic regimens employed. Under appropriate conditions, cultured T cells can proliferate in vivo in response to stimulation by antigen, distribute widely and survive long term to provide effector function and immunologic memory. Given that T cells recognize peptides, the need for immunization with tumor can be circumvented by immunization with peptide. Peptide-specific T cells and the progeny of single T-cell clones can provide the necessary cellular functions to eradicate disseminated murine leukemia. The ability of cloned T cells to similarly provide substantial measurable immunity in humans has been validated in clinical trials. By priming with peptides and by using established culture conditions, T-cell therapy can now be directed against virtually any antigen within the host T-cell repertoire. The major remaining question to be answered is which proteins and which peptides are the most suitable targets for T-cell therapy trials.

Animals↗
PubMed1999

Cell-based vaccines for the stimulation of immunity to metastatic cancers.

We are developing vaccines for inducing immunity to metastatic cancers. Although primary tumors are frequently cured by surgery, chemotherapy, or radiation therapy, metastatic lesions often do not respond to these treatments or proliferate after conventional therapy is terminated. Vaccine therapy for established metastases as well as prophylactic vaccine treatment to prevent outgrowth of latent metastatic tumor cells would therefore be beneficial. Our goal is to activate CD4+ and CD8+ T lymphocytes; however, we have focused on activating tumor-specific CD4+ T-helper lymphocytes because of their pivotal role as regulatory cells and in the generation of long-term immunological memory. The vaccines are based on the premise that tumor cells express potentially immunogenic antigens that could be targeted for T-cell activation, and that if appropriately genetically modified, tumor cells could be antigen presenting cells for these antigens. To facilitate direct antigen presentation to CD4+ T cells, tumor cells have been transfected with syngeneic major histocompatibility complex class II, co-stimulatory molecule, and/or superantigen genes. In vivo studies in three mouse tumor models demonstrate that vaccination protects against future challenge with wild-type tumor, cures some solid primary tumors, reduces established metastatic disease, and extends mean survival time. Antigen presentation studies demonstrate that in vivo vaccine efficacy is directly related to in vitro antigen presentation activity. The relevance of antigen presentation activity of the vaccines is further confirmed by in vivo studies demonstrating that during the immunization process, the vaccines directly present tumor-encoded antigens to CD4+ T lymphocytes. Adaptation of these vaccines for the treatment of human metastatic cancers is discussed.

Animals↗
PubMed1998

Distribution of interferon-gamma mRNA-positive cells in oral lichen planus lesions.

The present study investigated the potential involvement of interferon-gamma (IFN-gamma)-producing cells in the pathogenesis of oral lichen planus (OLP). On biopsies from 10 OLP patients, an in situ hybridization technique was employed to determine the topographical distribution of cells expressing IFN-gamma mRNA. It was estimated that approximately 1% or fewer lesional cells were IFN-gamma mRNA-positive. These cells were mainly encountered lining the basal membrane in a majority of the patients, or were in a few cases circumscribing the infiltrate, but were more seldom localized to the center of the lesion. A slightly higher, but not statistically significant, number of phytohemagglutinin (PHA)-induced IFN-gamma-producing cells, in vitro, was found in blood from 11 other OLP patients compared with blood from matched controls. Equal concentrations of IFN-gamma in supernatants from PHA-stimulated blood cells were detected in the two groups. Similarly, the IFN-gamma response towards C. albicans was alike in OLP and in healthy control (HC) blood cells, indicating normal immunological memory function in the OLP patients. A small set of cells with spontaneous IFN-gamma production was found in OLP and in HC peripheral blood. The data suggest that T-lymphocyte activation and cytokine production act locally and are not reflected in peripheral blood. The localization of the IFN-gamma mRNA-positive cells indicates that the antigenic peptides are presented at the periphery of the mononuclear cell infiltrate. Furthermore, the low frequency of IFN-gamma mRNA-positive cells in the lesions suggests that the disease is maintained by a small number of antigen-specific T cells.

Adult↗
PubMedDate not supplied

B-cell responses to lipopolysaccharide epitopes: Who sees what first - does it matter?

PROBLEM: Cholera is the paradigm for waterborne bacterial diseases. For over a 100 years, scientists have tried to develop a universally effective vaccine for cholera. We are hampered in our efforts because we do not know the details of the basic immune response to Vibrio cholerae antigens. What are the most proactive antigens? What special needs for immunization are engendered by previous exposure to cholera or the age of the individual? How long does immunity last, and is this immunity a classic immunologic memory or re-exposure and continual boosting? METHOD OF STUDY: Immunization with synthetic derivatives of the carbohydrate moieties of V. cholerae lipopolysaccharide (LPS) coupled to different carrier proteins (neoglycoconjugates, NGC) has allowed dissection of the response to the disaccharide array of perosamine that represent either the Inaba or the Ogawa serotype. Studying serum anti-LPS endpoint titers and the serum vibriocidal response to NGC provides insight into the importance of LPS serotype-specific B-cell epitopes and how antibody response are influenced by the form of the LPS immunogen. RESULTS: We found that murine serum antibody responses to V. cholerae LPS are dynamic. The magnitude of serum anti-LPS antibody titers and the capacity to induced vibriocidal antibodies (immunoglobulin M) are influenced by the initial immunizing serotype of LPS, the structure of the LPS immunogen (native LPS versus NGC), and the order of serotype immunization in a prime boost immunization strategy. The dynamic of the immune response to LPS immunogens is typified by the fact that the host species can affect the immunization response. We found mice do not make vibriocidal antibody to Inaba NGC but rabbits do. This is in contrast to the Ogawa NGC that induced vibriocidal antibody in mice. CONCLUSION: The results suggest that the host's B-cell repertoire can influence the immunization efficacy; therefore, the development of the new generation of NGC V. cholerae vaccines should focus on human volunteers and their ability to mount protective responses.

Animals↗
PubMed2002

Immunological responses are not abnormal in symptomatic Gulf War veterans.

The underlying etiology and pathogenesis of Gulf War veterans' illnesses continue to be under intense investigation. Reports have suggested the basis for these illnesses may be an altered immune system, but compelling evidence is lacking. We sought to determine whether in vitro immune responses were abnormal in symptomatic Gulf War veterans relative to matched controls. A randomized case-control study was conducted by blinded comparison of laboratory measures of in vitro immune responses in blood samples obtained from veterans in an outpatient facility of a Veterans Affairs medical center. Symptomatic Gulf War veterans with otherwise undefined illnesses (52 symptomatic subjects), asymptomatic Gulf War veterans (31 asymptomatic controls), and veterans who had applied for disability compensation and had not participated in the Gulf War (21 disability controls) represented the volunteer sample. In vitro cellular and humoral immune responses were measured to detect functional abnormalities in antigen presenting cells (autologous mixed leukocyte reactions and expression of interleukin (IL)-1beta, IL-6, IL-10, and tumor necrosis factor-alpha); T cells (lymphocyte proliferation using the polyclonal T-cell activators phytohemagglutinin and Concanavalin A; primary immune responses in allogeneic mixed leukocyte reactions; secondary immune response using the recall antigens tetanus toxoid, Candida albicans, and anthrax vaccine; and soluble IL-2 receptor expression); type-1 T-helper cells (gamma interferon expression); type-2 T-helper cells (IL-4 and IL-10 expression); and B cells (polyclonal B-cell activator pokeweed mitogen-induced immunoglobulin production). In general, immune response measures did not differ significantly between groups. Heightened responses observed in the disability control group (sporadically greater responses to one mitogen and two antigens) and the Gulf War participation control group (greater recall responses to anthrax vaccine) did not suggest impaired immune cell function in symptomatic veterans when compared with controls. We conclude that in vitro immunological responses are not abnormal in symptomatic Gulf War veterans.

Adult↗
PubMed1970

Radioresistance of cooperative function of carrier-specific lymphocytes in antihapten antibody responses.

Transfer of lymphoid cells from strain-2 guinea pigs immunized to bovine gamma globulin into syngeneic recipients immunized with dinitrophenyl ovalbumin markedly enhances the secondary antidinitrophenyl response of the recipient to challenge with dinitrophenyl-bovine gamma globulin. This function of the carrier bovine gamma globulin-specific cells is resistant to irradiation with up to 5000 rads, although the capacity of the irradiated cell population to transfer immunologic memory for bovine gamma globulins or to be stimulated by antigen to synthesize DNA in vitro is abolished by this treatment.

Animals↗
PubMed2006

Understanding the immune responses to the meningococcal strain-specific vaccine MeNZB measured in studies of infants.

Vaccine trials with infants enrolled between 6 and 10 weeks of age (young infants) and 6 and 8 months of age (older infants) provided an opportunity to evaluate immunoglobulin G (IgG) isotype distribution and avidity maturation as indicators of antibody function and immunologic memory. Following vaccination with a strain-specific outer membrane vaccine, MeNZB, pre- and postvaccination sera were used to determine IgG isotype responses and avidity indices (AI) in subsets of vaccinated subjects. Measurements of IgG isotypes involved 100 infants from each trial. AI were measured in 50 infants from the young infant trial who received a fourth vaccine dose and in 40 older infants from whom serum was collected 7 months after the primary vaccination course. IgG1 and IgG3 dominated the responses to the vaccine. A modest linear correlation (P < 0.001) occurred between serum bactericidal antibody (SBAb) titers and the total IgG or the IgG1 antibody units in older infants. The young infants showed a modest linear correlation between SBAb and total IgG (P = 0.005) and a weak linear correlation between SBAb and IgG1 (P = 0.003). Increased avidity with age was demonstrated in both groups. The AI in the young infants increased from 51.5% (95% confidence interval [CI], 47.7 to 54.7) postvaccination to 68.7% (95% CI, 65.5 to 71.9%) following the fourth dose of vaccine (P < 0.001). The mean avidity of the older infants increased significantly (P = 0.00012) from 42.4% (95% CI, 39.1 to 45.3%) postvaccination to 50.4% (95% CI, 47.2 to 53.6%) 4 months later. A fourth dose of MeNZB is now being given to young infants at 10 months of age.

Antibodies, Bacterial↗