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T-cell-mediated concomitant immunity to syngeneic tumors. I. Activated macrophages as the expressors of nonspecific immunity to unrelated tumors and bacterial parasites.

Progressive growth of the SA1 sarcoma was shown to result in the generation of a state of concomitant resistance to growth of a second implant of the same tumor. The responding lymph nodes of concomitantly immune mice were shown to contain theta-positive T cells that could specifically neutralize the growth of tumor cells in a normal test recipient. Nevertheless, the concomitantly immune host itself was capable to a limited extent of suppressing the growth of unrelated tumors. The generation of immunity, moreover, was associated with the generation of a powerful state of macrophage-mediated, nonspecific resistance to the bacterial parasite, Listeria monocytogenes. It was concluded that systemic macrophage activation was the consequence of the generation of T-cell-mediated immunity to the progressively growing tumor, and that this not only gave the host the capacity to inhibit the growth of unrelated tumors, but also to protect itself against microbial infection. The results gives credence to the view that macrophages play a central role in defense against microbial and neoplastic growth.

Animals↗

Type 2 immunity is controlled by IL-4/IL-13 expression in hematopoietic non-eosinophil cells of the innate immune system.

Nippostrongylus brasiliensis infection and ovalbumin-induced allergic lung pathology are highly interleukin (IL)-4/IL-13 dependent, but the contributions of IL-4/IL-13 from adaptive (T helper [Th]2 cells) and innate (eosinophil, basophils, and mast cells) immune cells remain unknown. Although required for immunoglobulin (Ig)E induction, IL-4/IL-13 from Th2 cells was not required for worm expulsion, tissue inflammation, or airway hyperreactivity. In contrast, innate hematopoietic cell-derived IL-4/IL-13 was dispensable for Th2 cell differentiation in lymph nodes but required for effector cell recruitment and tissue responses. Eosinophils were not required for primary immune responses. Thus, components of type 2 immunity mediated by IL-4/IL-13 are partitioned between T cell-dependent IgE and an innate non-eosinophil tissue component, suggesting new strategies for interventions in allergic immunity.

Animals↗

Human immunodeficiency virus type 1 Gag-specific vaginal immunity and protection after local immunizations with sindbis virus-based replicon particles.

The majority of human immunodeficiency virus (HIV) infections occur through vaginal and rectal transmission. In seeking a safe, nonreplicating gene-delivery vector that can induce mucosal and systemic immune responses and protection, Sindbis virus-based replicon particles expressing HIV-1 Gag (SIN-Gag) were developed. In mice, after nasal or intramuscular immunization with SIN-Gag and vaginal challenge with vaccinia virus (VV) expressing HIV-1 Gag (VV-Gag), CD8(+) T cell-mediated responses were detected locally, in the vaginal mucosa and in the draining iliac lymph nodes (ILNs), and systemically, in the spleen. However, the mice were not protected against VV-Gag replication in the ovaries. In contrast, after vaginal or rectal immunization with SIN-Gag and vaginal challenge with VV-Gag, despite lower local CD8(+) T cell-mediated responses in the vaginal mucosa and ILNs, the mice were protected against VV-Gag replication in the ovaries. Therefore, local immunization with SIN-Gag induced both local mucosal cell-mediated responses and protection.

AIDS Vaccines↗

Cluster survey evaluation of coverage and risk factors for failure to be immunized during the 1995 National Immunization Days in Egypt.

BACKGROUND: In 1995, Egypt continued to experience endemic wild poliovirus transmission despite achieving high routine immunization coverage with at least three doses of oral poliovirus vaccine (OPV3) and implementing National Immunization Days (NIDs) annually for several years. METHODS: Parents of 4188 children in 3216 households throughout Egypt were surveyed after the second round of the 1995 NIDs. RESULTS: Nationwide, 74% of children are estimated to have received both NID doses, 17% one NID dose, and 9% neither NID dose. Previously unimmunized (47%) or partially immunized (64%) children were less likely to receive two NID doses of OPV than were fully immunized children (76%) (P < 0.001). Other risk factors nationwide for failure to receive NID OPV included distance from residence to nearest NID site >10 minute walk (P < 0.001), not being informed about the NID at least one day in advance (P < 0.001), and residing in a household which does not watch television (P < 0.001). Based on these findings, subsequent NIDs in Egypt were modified to improve coverage, which has resulted in a marked decrease in the incidence of paralytic poliomyelitis in Egypt. CONCLUSIONS: In selected situations, surveys can provide important information that is useful for planning future NIDs.

Child, Preschool↗

Cross-reactive antigens: their potential for immunization-induced immunity to Gram-negative bacteria.

The involvement of multiple species and serologic types in gram-negative bacteremia prompted evaluation of immunization with shared, cross-reactive antigens of gram negative bacilli. Active and passive immunization with Re chemotype mutants of Salmonella minnesota afforded significant protection against heterologous gram-negative bacilli and were considerably more effective than immunization with smooth S. minnesota or its Ra, Rb, Rc, Rd1 and Rd2 mutants. Since the lipopolysaccharide of the Re mutant is composed solely of 2-keto-3-deoxycotonate (KDO) and lipid A, the protective activity of antibody to the Re mutant and lipid A was evaluated. Immunization with Re mutant protected granulocytopenic rabbits against lethal bacteremia and protected mice against lethal challenge with heterologous endotoxins, whereas antibody to lipid A had no protective activity. In concomitant clinical studies, high titers of antibody to the Re mutant at the onset of bacteremia were associated with a significant diminution in the frequency of shock and death, which was independent of any effect of O-specific antibody.

Animals↗

Immune mechanisms in chlamydial eye infection: cellular immune responses in chronic and acute disease.

The current studies detail cell-mediated immune responses to Chlamydia trachomatis antigen in both acute and chronically infected monkeys. Peripheral blood mononuclear leukocytes (PBMLs) from three groups of animals (immunized before infection, not immunized before infection, and chronically infected) were tested for the capacity to proliferate in response to C. trachomatis antigen in vitro. Only those animals that had been systemically immunized before acute ocular infection responded significantly. Coculturing macrophages from nonresponding animals with T cells from D-histocompatible responding animals showed that the ability to present antigen was unaffected in nonresponding animals. These studies also demonstrated that removal of suppressor T cells from PBMLs before culture resulted in increased proliferation in the chronically infected group and suggested that the nonresponsiveness seen in chronic ocular disease may be mediated by suppressor T cells.

Acute Disease↗

Persistence of cell-mediated and humoral immune responses in healthy children immunized with live attenuated varicella vaccine.

Two hundred fourteen healthy seronegative children immunized with various doses of Oka/Merck varicella vaccine were studied for persistence of varicella-zoster virus (VZV)-specific lymphocyte proliferation and antibodies to VZV as determined by a glycoprotein (gp) ELISA. Of the 140 vaccinees tested for VZV-specific lymphocyte proliferation, 94% had positive responses, with a mean stimulation index of 8.9 (range, 3.0-44.6). Of 214 tested by gpELISA, 95% were positive for up to 6 years after immunization; the geometric mean titer was 30.2 (range, 1.3-3510.0). Of 122 individuals tested both by ELISA and for VZV-specific lymphocyte proliferation, 91% had persistence of both responses. Persistence of cellular and humoral immune responses in a large percentage of vaccinees for up to 6 years after immunization with Oka/Merck varicella vaccine suggests that protection against severe varicella is likely to be similarly long-lasting.

Adolescent↗

Immunity to onchocerciasis: identification of a putatively immune population in a hyperendemic area of Ecuador.

The existence of immunity to Onchocerca volvulus (Ov) infection is suggested by the presence of uninfected persons in hyperendemic areas. A major barrier to the study of immunity has been the correct identification of putatively immune (PI) subjects. To identify a PI group in a hyperendemic area in Ecuador, clinical and epidemiologic information was combined with a polymerase chain reaction (PCR)-based assay identifying Ov DNA in skin snips and a recombinant antigen-based ELISA. Comparison of immune responses revealed that PI subjects had significantly lower levels of Ov-specific IgG, IgG subclasses, and IgE than infected (INF) subjects. Female subjects were significantly more likely to be PI than male subjects, and INF female subjects had significantly lower levels of Ov-specific IgG, IgG1, and IgG3 than INF male subjects. Thus, the use of molecular-based techniques has helped to define more precisely the PI state in onchocerciasis.

Adolescent↗

Interleukin-12 treatment during immunization elicits a T helper cell type 1-like immune response in mice challenged with respiratory syncytial virus and improves vaccine immunogenicity.

Adjuvant effects of exogenous interleukin (IL)-12 on induction of immune responses against respiratory syncytial virus (RSV) infection in mice were evaluated. Giving recombinant IL-12 at the time of immunization with a formalin-inactivated alum-precipitated RSV preparation resulted in significant reduction of virus replication in lungs 4 days after RSV challenge. Intraperitoneal or intramuscular IL-12 was effective when given at the time of immunization but not at the time of challenge. IL-12 treatment resulted in increased interferon-gamma mRNA in lungs, increased IgG2a RSV-specific antibody isotype utilization, and increased endogenous IL-12 p40 mRNA expression. IL-12 treatment did not significantly affect clinical outcome or cytotoxic T lymphocyte activity. These data demonstrate that IL-12 has potent adjuvant effects that may be due to induction of T helper cell type 1-like immune responses.

Adjuvants, Immunologic↗

Consumption of milk from cows immunized with intestinal bacteria influences age-related changes in immune competence in mice.

Milk was obtained from nonimmunized cows and cows immunized with a mixture of various human gut bacteria. Each milk was administered orally to 2-mo-old C57BL/6 mice at a dose of 150 g.kg-1.d-1 for either 6 or 16 mo. The study group had fewer enteric bacteria and a lower concentration of the serum antibodies against enteric bacteria compared with the control group at 8 and 18 mo of age. Furthermore, the study group at 18 mo old had a higher redirected cytotoxicity of intestinal intraepithelial lymphocytes, a higher proliferative response of mesenteric lymph nodes cells against mitogenic or alloantigenic stimulation and a greater ability of the spleen cells to produce anti-sheep erythrocytes IgG antibody after systemic immunization with sheep erythrocytes. A lower level of autoantibodies was observed at 8 mo and 18 mo of age in the study group compared with the control group. These results suggest that the senescence of the murine immune system may be delayed by consumption of milk from immunized cows.

Animals↗

Tuberculosis in Bacillus Calmette-Guérin-immunized and unimmunized children in Sweden: a ten-year evaluation following the cessation of general Bacillus Calmette-Guérin immunization of the newborn in 1975.

An analysis was made of childhood tuberculosis in Sweden between 1969 and 1984 which included the 6.25 years before and the 9.75 years after the cessation of general Bacillus Calmette-Guérin (BCG) immunization of the new-born on April 1, 1975. The annual incidence of tuberculosis per 100,000 children ages 0 to 4 years increased from an average of 1.1 cases in the period 1970 to 1974 to 1.3 cases in the period 1975 to 1979 and to 2.1 cases in the period 1980 to 1984, including both children born in Sweden and those born abroad. Among children born in Sweden after April 1, 1975, tuberculosis occurred in 58 (57 unimmunized and one BCG-immunized), or 1.3 cases per 100,000 person years up to and including 1984. Eighteen of the 58 children were asymptomatic. Minor symptoms were reported in 13 and clinical illness in 27 children, 2 of whom developed meningitis and 1 of whom died of miliary infection. The relative increase of tuberculosis in the mainly unimmunized cohorts born in Sweden after April 1, 1975, compared with the mainly BCG-immunized cohorts born in Sweden in the period 1969 to 1974 was, by the end of 1984, estimated at 6.0 (95% confidence interval, 2.3, 16.1). Tuberculosis was about 10 times more common in non-BCG-immunized children born in Sweden of foreign parents than in those born of Swedish parents.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

Differences in immune cells engaged in cell-mediated immunity after chemotherapy for far advanced pancreatic cancer.

OBJECTIVES: Little is known about the effects of chemotherapy on the immunity of cancer patient or the ideal timing for immunotherapy combined with chemotherapy. To address these questions, we evaluated the effect of gemcitabine and cisplatin combination chemotherapy on the immunity of pancreatic cancer patients. METHODS: Thirteen patients with far advanced pancreatic cancer were enrolled and 7 sex- and age-matched healthy volunteers were included as a control group. RESULTS: Compared with healthy controls, the amounts of peripheral blood mononuclear cells, dendritic cells (DCs), natural killer cells, CD4, and CD8 T cells were reduced. With this numerical suppression, NK cell cytotoxicity to K562 leukemia cells was also significantly impaired (7.7% +/- 4.9% versus 21.7% +/- 7.9% of DNA loss; P = 0.016). Serum concentrations of VEGF and interleukin-10 (IL-10) were higher than the control group (192.1 +/- 114.7 versus 50.8 +/- 39.5 pg/mL of vascular endothelial growth factor (VEGF) and 122 +/- 68.9 versus 111.4 +/- 37.4 pg/mL of IL-10). After 1 cycle of gemcitabine and cisplatin chemotherapy, the impaired immunity of patients with pancreatic cancer was restored. Specifically, the recovery of DCs occurred rapidly and exceeded the value of healthy controls. Levels of the immunosuppressive cytokines, IL-10 and VEGF, gradually decreased during chemotherapy. CONCLUSIONS: Systemic chemotherapy seems to be beneficial for restoring the impaired immunity of patients with pancreatic cancer, and one of the ideal times to collect DCs for immunotherapy is after completing each cycle of chemotherapy.

Aged↗

Protective immunity against bovine leukaemia virus (BLV) induced in carrier sheep by inoculation with a vaccinia virus-BLV env recombinant: association with cell-mediated immunity.

The effects of vaccination of sheep with a recombinant vaccinia virus (rVV) expressing the bovine leukaemia virus (BLV) envelope glycoprotein (gp60) were studied by determining BLV titres in peripheral blood leukocytes after vaccination and challenge. The proliferation of BLV was suppressed markedly, not only when rVV was inoculated prior to challenge with BLV, but also when it was inoculated after challenge. These results indicate that vaccination with rVV induces protective immunity that can suppress the growth of BLV in carrier animals. Since rVV induced a strong anti-BLV delayed-type hypersensitivity response without producing detectable levels of binding or neutralizing antibodies, and there was no apparent correlation between the humoral immune response and BLV proliferation, a cell-mediated immune response was assumed to play a major role in protective immunity.

Animals↗

Immunization with recombinant class 1 outer-membrane protein from Neisseria meningitidis: influence of liposomes and adjuvants on antibody avidity, recognition of native protein and the induction of a bactericidal immune response against meningococci.

The porA gene from Neisseria meningitidis was cloned into the pRSETA vector and recombinant class 1 outer-membrane protein expressed at high levels in Escherichia coli. The protein was readily purified by affinity chromatography on a Ni2+ matrix and used for immunization of mice with conventional AI(OH)3 adjuvant, with experimental adjuvants which have the potential for human use, and with liposomes. The resulting sera were analysed for the magnitude, subclass distribution and antigenic specificity of the immune response. In addition, surface plasmon resonance (SPR) was used to quantify antibody avidity by analysis of the kinetics of binding to native class 1 protein. Immunization with conventional and experimental adjuvants induced antibodies of low avidity that did not recognize native class 1 protein. In contrast, immunization with recombinant protein in liposomes induced antibodies of high avidity which recognized native class 1 protein, as measured by their ability to label meningococcal cells in immunofluorescence assays and to inhibit the binding of a protective mAb. These properties were associated with the presence in sera of high levels of antibodies with the ability to induce complement-mediated killing of meningococci. These data show that liposomes containing recombinant class 1 protein represent a potential basis of future vaccines, of defined composition, designed for the prevention of group B meningococcal infections.

Adjuvants, Immunologic↗

Induction of mucosal and systemic immune response by single-dose oral immunization with biodegradable microparticles containing DNA encoding HBsAg.

The purpose of this work was to assess the ability of plasmid DNA encoding hepatitis B virus (HBV) HBsAg encapsulated in poly(DL-lactide-co-glycolic acid) (PLGA) microparticles to induce local and systemic HBsAg-specific immunity following a single dose of oral immunization. RT-PCR analysis demonstrated prolonged transcription of plasmid DNA, consistent with the sustained expression and presentation of target antigen observed by confocal laser scanning microscopy, in gut-associated lymphocyte tissue (GALT) from mice immunized orally with plasmid DNA encapsulated into PLGA microparticles. Oral administration of PLGA-DNA microparticles induced a long-lasting and stable antigen-specific antibody response, both serum total antibody and intestinal IgA, in BALB/c mice. Mice immunized orally exhibited antigen-specific gamma interferon production and cytotoxic T lymphocyte responses in spleen and GALT after restimulation in vitro with HBsAg or tumour cells stably expressing HBsAg. In contrast, naked DNA vaccines given by intramuscular injection induced only systemic cellular and humoral responses to HBsAg, which were much lower than the responses elicited by oral DNA encapsulated in PLGA microparticles at equivalent doses. The results are encouraging with regard to obtaining good compliance and vaccination coverage with candidate plasmid DNA vaccines, especially in developing countries.

Administration, Oral↗

Prevention of immunization to D+ red blood cells with red blood cell exchange and intravenous Rh immune globulin.

BACKGROUND: Although young women who are D- occasionally receive unintentional transfusions with D+ red blood cells (RBCs), there are little data to assist with management of such an event. Two cases of D- girls transfused with D+ RBCs are reported. In an effort to prevent formation of anti-D, RBC exchange followed by administration of intravenous (IV) Rh immune globulin (RhIg) was used. CASE REPORTS: Patient 1, a 56-kg, 16-year-old D- girl, was involved in a motor vehicle crash. She received 4 units of Group O uncrossmatched D+ RBCs. Thirty-six hours after admission, she underwent RBC exchange with 10 units of D- RBCs, followed by a total of 2718 microg of IV RhIg over 32 hours. Six months later, her antibody screen was negative. Patient 2, a 39-kg, 10-year-old D- girl with aplastic anemia, received 1 unit of D+ RBCs. She underwent RBC exchange on the same day with 5 units of D- RBCs, followed by a total of 900 microg of IV RhIg over 8 hours. Six months later her antibody screen was negative. CONCLUSION: RBC exchange followed by a calculated dose of IV RhIg was successful in preventing allo-immunization to D. Several small studies suggest that both trauma and hematology patients may be less capable of becoming immunized with the transfusion of D+ blood components. Until these findings are more clearly defined, there will be times when prevention of immunization of any D- girl is desired. RBC exchange followed by RhIg appears to be one way to achieve this goal.

Adolescent↗

Immune thrombocytopenic purpura: autoimmune or immune complex disease?

To assess the pathogenic role of circulating immune complexes (CIC) in idiopathic thrombocytopenic purpura (ITP), 39 patients with ITP were compared to 17 patients with other forms of thrombocytopenia (hypersplenism (N = 12), impaired thrombopoiesis (3), thrombocytopenia of unknown origin (2)) and six nonthrombocytopenic subjects. In all patients, platelet mean life span (MLS), platelet associated IgG (PAIgG), as well as circulating anti-platelet antibodies and C1q binding activities were determined. In most cases, immune complex solubilization capacity (ICSC) and immune complex precipitation inhibition capacity (ICPIC) of sera were also assessed. All patients with ITP had a reduced platelet MLS, but PAIgG was elevated in only 16 out of 24 patients with chronic ITP, in six out of 10 patients with acute ITP and in four out of five patients with secondary ITP. In the group of patients with thrombocytopenia due to splenomegaly, seven out of 12 patients had elevated PAIgG while the platelet MLS was only slightly reduced. Of the 39 patients with ITP only one with secondary ITP had C1q binding material in his serum, as opposed to six out of 12 thrombocytopenic patients with splenomegaly. Whereas only three patients with ITP had abnormal immune-complex modulating capacities, such deviations were found in seven out of 12 patients with thrombocytopenia due to splenomegaly. We conclude that our data render the role of CIC in the pathogenesis of ITP very questionable.

Adolescent↗

T lymphocyte interferon-gamma production induced by Plasmodium falciparum antigen is high in recently infected non-immune and low in immune subjects.

Interferon (IFN) alpha and gamma were measured by radio-immunoassays in supernatants from cultures of peripheral blood mononuclear cells (PBMC) or purified T cell subsets incubated with either Plasmodium falciparum schizont-enriched malaria antigen (mAg), uninfected red blood cells (RBC) or pokeweed mitogen (PWM). Cell donors were 24 clinically immune, healthy African adult native residents of a P. falciparum-endemic region, Haut-Ogooué, Gabon, and seven non-immune, European temporary residents with a history of a single to a few malaria infections during the previous 1 to 9 months. When PBMC were cultured in medium alone or with RBC antigen no or low titres of IFN-gamma were detected. PBMC proliferation and IFN-gamma production observed in the presence of mAg were dose dependent and significantly correlated. When cultured with mAg, PBMC from non-immune Europeans produced significantly higher levels of IFN-gamma than did PBMC from clinically immune Africans. No such difference was found when PBMC were cultured with PWM. The mAg-induced IFN-gamma production was due mainly to CD4+ T cells and was not enhanced by CD8+ T cell depletion. No IFN-alpha was detected in culture supernatants. Thus, P. falciparum antigens are able to induce in vitro production of IFN-gamma by CD4+ T cells; however, in this sample, individuals considered to be clinically resistant to malaria were low producers of IFN-gamma.

Animals↗