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The immune response and the eye. TCR alpha-chain related molecules regulate the systemic immunity to antigen presented in the eye.

Injection of antigen into the anterior chamber (AC) of the eye results in the induction of immune deviation in which antibody production is activated and delayed-type hypersensitivity (DTH) is inhibited. This system is termed anterior chamber associated immune deviation (ACAID) and the model is used to examine certain aspects of the immunologic privilege of the eye. Recent studies have established that following antigen presentation in the eye, an 'ACAID-inducing' signal is produced that directly enters the blood. This signal then homes to the spleen where T cells that down-regulate DTH are activated. For many antigens this 'ACAID signal' is a soluble protein released within 2 days of AC injection. Although the presence of this molecule (or molecules) has been described using several antigens, the exact nature of the soluble mediator has escaped characterization. We have further explored the nature of this signal using HSV-1-induced immune deviation. Our results show the soluble 'signal' was released by T cells that encounter antigen in the ocular microenvironment. This mediator was antigen specific, contained TCR alpha-chain (but not the TCR beta-chain) determinants and had an apparent molecular weight of 46 kDa. These results show that the release of soluble TCR alpha-chain from sites of T cell interaction within the microenvironment of the eye can regulate systemic immune responses. These results have implications for the control of immune response that might be damaging to organs such as the eye.

Animals↗

Immunity to transplantable nitrosourea-induced neurogenic tumors. I. Potentiation of tumor immunity with Corynebacterium parvum.

Various injection schedules of C. parvum and tumor cells of the nitrosourea-induced malignant neurinoma, TR-481, were used to induce tumor immunity in syngeneic CDF rats. Although subcutaneous injection of the poorly immunogenic TR-481 cells alone or with C. parvum caused retardation of growth of 2 x 10(5) TR-481 cells injected 1-3 weeks later, no significant difference in tumor size or incidence was obtained, as judged by tumor growth at 8 weeks. In contrast, injection of TR-481 with C. parvum into C. parvum-presensitized rats caused a more significant degree of tumor immunity with complete inhibition of the challenge tumor growth in 17-33% of the animals. Repeated subcutaneous injection of gamma-irradiated TR-481 tumor cells mixed with C. parvum also proved effective, resulting in absence of tumor growth in 40% of the rats. Tumor immunity was specific, since growth of an unrelated tumor was unaffected. It is suggested that local immunological reactivity to C. parvum in the immunizing tumor promotes development of specific tumor immunity.

Adjuvants, Immunologic↗

Potentials for improving health department immunization rates: the relationships between service delivery factors and immunization completion.

The majority of children at risk for incomplete immunizations receive care in the public sector. A multivariate model of differing health department practices and policies was developed to assess their association with immunization completion rates among health department users in Georgia's 159 county health departments. Simulations based on the model tested the impact of several programmatic and policy options. Higher immunization rates were associated with no fees, more clinical sites, computerized tracking systems, fewer missed opportunities, younger age of initial immunizations, and greater per capita budgets. A combination of these health department factors could increase immunization rates by 18 percent.

Georgia↗

Nerve growth factor and the immune system: old and new concepts in the cross-talk between immune and resident cells during pathophysiological conditions.

PURPOSE OF REVIEW: This review provides an overview of nerve growth factor and its involvement in the immune system. Furthermore, recent data are provided revealing new important insights into the mechanisms of action of nerve growth factor in allergic reaction. RECENT FINDINGS: Recent studies on the effects of nerve growth factor on the immune cells involved allergic reaction, and on the potential role of nerve growth factor in tissue remodelling are presented. SUMMARY: Nerve growth factor has an extended function from the nervous system to a wide range of activities in the immune system. Several papers have highlighted the role of the factor in allergic inflammation. This review describes old and new concepts of nerve growth factor in the immune system: the relation between nerve growth factor and the main cells taking part in allergic inflammatory disorders, structural cells, mediators and cytokines/chemokines, as well as the mechanisms leading to nerve growth factor increase. Understanding these complex mechanisms will introduce new therapeutic approaches for nerve growth factor in the immune system, in addition to those already established in the nervous system.

Cell Communication↗

Mechanism of immunity to influenza: maternal and passive neonatal protection following immunization of adult ferrets with a live vaccinia-influenza virus haemagglutinin recombinant but not with recombinants containing other influenza virus proteins.

Neonatal ferrets are protected against infection with influenza virus by milk-derived anti-influenza virus IgG after suckling on an immune mother. Live vaccines protect better than killed vaccines despite their stimulation of lower maternal haemagglutination-inhibiting antibody levels. This suggests that antibody to virus proteins other than the haemagglutinin may also be involved. To investigate this, adult ferrets were immunized intradermally with live vaccinia-influenza virus recombinants each expressing one of the 10 influenza virus polypeptides. Adult ferrets immunized with a recombinant expressing the H3 haemagglutinin were completely protected, and also passively protected their offspring, against a live challenge with clone 7a of the reassortant influenza virus A/Puerto Rico/8/34-A/England/939/69 (H3N2), immunity being mediated by IgG antibody. However, ferrets immunized similarly with recombinants expressing the H1 haemagglutinin, neuraminidase (N1 or N2), polymerases (PB1, PB2 or PAC), matrix protein (M1 or M2), nucleoprotein (NP) or non-structural proteins (NS1 or NS2) were completely susceptible to the influenza virus.

Animals↗

The probiotic bacterium Lactobacillus casei induces activation of the gut mucosal immune system through innate immunity.

The mechanisms by which probiotic bacteria affect the immune system are unknown yet, but many of them are attributed to an increase in the innate or in the acquired immune response. To study the influence of the probiotic bacterium Lactobacillus casei in the expression of receptors involved in the innate immune response, this bacterium was orally administered to BALB/c mice. After, they were sacrificed; the small intestine and intestinal fluids were collected to measure secretory immunoglobulin A (IgA) specific for L. casei. Mononuclear cells from Peyer's patches were isolated to determine the CD-206 and TLR-2 receptors. In histological slices we determined the number of IgA+, CD4+, CD8+, and CD3+ cells and two cytokines (interleulin-5 [IL-5] and IL-6). CD-206 and TLR-2 increased with respect to the untreated control. We did not observe an increase in the T population or in the IL-5-positive cells. IgA+ cells and IL-6-producing cells increased after 7 days of L. casei administration. We did not find specific antibodies against L. casei. The main immune cells activated after oral L. casei administration were those of the innate immune response, with an increase in the specific markers of these cells (CD-206 and TLR-2), with no modification in the number of T cells.

Administration, Oral↗

Plasmodium knowlesi: persistence of transmission blocking immunity in monkeys immunized with gamete antigens.

Eight rhesus monkeys immunized with a partially purified preparation of Plasmodium knowlesi gametes were monitored for over 6 years to determine the extent of transmission blocking immunity. Monkeys were challenged regularly, and anti-gamete antibodies were assayed by in vivo and in vitro mosquito feedings. Transmission blocking immunity persisted at high levels in most of the monkeys. In those animals in which protection waned between challenges, a challenge infection provided a sufficient booster effect to prevent infection of mosquitoes. Immunity to other stages of malaria (i.e., sporozoites and asexual erythrocyte forms) failed to induce immunity against gametes.

Animals↗

Cross-protective immune responses induced in rhesus macaques by immunization with attenuated macrophage-tropic simian immunodeficiency virus.

The simian immunodeficiency virus (SIV) macaque model of AIDS has provided a valuable system with which to investigate vaccine approaches for protection against human immunodeficiency virus type 1 (HIV-1) infection. In particular, the ability of macaques persistently infected with attenuated infectious molecular clones of SIV to resist challenge with the pathogenic parental swarm has conclusively demonstrated that protective immunity can be achieved by immunization prior to exposure. The breadth of these protective responses and the immunological correlates of protection, however, have not been identified. In addition, vaccine studies have mainly employed lymphocyte-tropic strains of HIV-1 and SIV. Recent studies have implicated macrophage-tropic strains in the transmission of HIV-1 and have suggested that these virus strains should be examined in vaccine strategies. Macrophage-tropic viruses may confer additional advantages in the induction of protective immunity by replication in antigen-presenting cells. In this study, the immune response of rhesus macaques inoculated with an attenuated macrophage-tropic recombinant of SIVmac239 (SIV/17E-Cl) was evaluated with respect to protective immunity by heterologous challenge at various times after infection. Vigorous type-specific neutralizing-antibody responses restricted to SIV/17E-Cl were evident by 2 weeks postinfection. By 7 months, however, cross-reactive neutralizing antibodies emerged which neutralized not only SIV/17E-Cl but also the heterologous primary isolate SIV/DeltaB670. Challenge of SIV/17E-Cl-infected monkeys with SIV/DeltaB670 at various times postinfection demonstrated that protective responses were associated with the appearance of cross-reactive neutralizing antibodies. Furthermore, passive transfer of sera from SIV/17E-Cl-infected animals passively protected two of four naive recipients.

Animals↗

Immunization with a single major histocompatibility complex class I-restricted cytotoxic T-lymphocyte recognition epitope of herpes simplex virus type 2 confers protective immunity.

We have evaluated the potential of conferring protective immunity to herpes simplex virus type 2 (HSV-2) by selectively inducing an HSV-specific CD8(+) cytotoxic T-lymphocyte (CTL) response directed against a single major histocompatibility complex class I-restricted CTL recognition epitope. We generated a recombinant vaccinia virus (rVV-ES-gB498-505) which expresses the H-2Kb-restricted, HSV-1/2-cross-reactive CTL recognition epitope, HSV glycoprotein B residues 498 to 505 (SSIEFARL) (gB498-505), fused to the adenovirus type 5 E3/19K endoplasmic reticulum insertion sequence (ES). Mucosal immunization of C57BL/6 mice with this recombinant vaccinia virus induced both a primary CTL response in the draining lymph nodes and a splenic memory CTL response directed against HSV gB498-505. To determine the ability of the gB498-505-specific memory CTL response to provide protection from HSV infection, immunized mice were challenged with a lethal dose of HSV-2 strain 186 by the intranasal (i.n.) route. Development of the gB498-505-specific CTL response conferred resistance in 60 to 75% of mice challenged with a lethal dose of HSV-2 and significantly reduced the levels of infectious virus in the brains and trigeminal ganglia of challenged mice. Finally, i.n. immunization of C57BL/6 mice with either a recombinant influenza virus or a recombinant vaccinia virus expressing HSV gB498-505 without the ES was also demonstrated to induce an HSV-specific CTL response and provide protection from HSV infection. This finding confirms that the induction of an HSV-specific CTL response directed against a single epitope is sufficient for conferring protective immunity to HSV. Our findings support the role of CD8(+) T cells in the control of HSV infection of the central nervous system and suggest the potential importance of eliciting HSV-specific mucosal CD8(+) CTL in HSV vaccine design.

Amino Acid Sequence↗

Systemic immunity and mucosal immunity are induced against human immunodeficiency virus Gag protein in mice by a new hyperattenuated strain of Listeria monocytogenes.

Vaccines designed to control chronic infections by intracellular agents such as human immunodeficiency virus type 1 (HIV-1) require the induction of cell-mediated immune responses to rid the host of pathogen-infected cells. Listeria monocytogenes has characteristics that make it an attractive vaccine vector for use against such infections. Here we show that parenteral immunization with a new highly attenuated strain of this organism provided complete protection against systemic and mucosal challenges with a recombinant vaccinia virus expressing HIV-1 gag. Immunization also generated a strong, long-term memory cytotoxic-T-lymphocyte (CTL) response in spleen, mesenteric lymph nodes, and Peyer's patches directed against the gag protein. Oral immunization with this attenuated strain also produced complete, long-lasting protection against the recombinant virus but only against mucosal virus challenge. Curiously, oral immunization was associated with a transient CTL response in the three lymphoid tissues examined.

AIDS Vaccines↗

Humoral and cellular immune response to RNA immunization with flavivirus replicons derived from tick-borne encephalitis virus.

A new vaccination principle against flaviviruses, based on a tick-borne encephalitis virus (TBEV) self-replicating noninfectious RNA vaccine that produces subviral particles, has recently been introduced (R. M. Kofler, J. H. Aberle, S. W. Aberle, S. L. Allison, F. X. Heinz, and C. W. Mandl, Proc. Natl. Acad. Sci. USA 7:1951-1956, 2004). In this study, we evaluated the potential of the self-replicating RNA vaccine in mice in comparison to those of live, attenuated vaccines and a formalin-inactivated whole-virus vaccine (ImmunInject). For this purpose, mice were immunized using gene gun-mediated application of the RNA vaccine and tested for CD8+ T-cell responses, long-term duration, neutralizing capacity, and isotype profile of specific antibodies and protection against lethal virus challenge. We demonstrate that the self-replicating RNA vaccine induced a broad-based, humoral and cellular (Th1 and CD8+ T-cell response) immune response comparable to that induced by live vaccines and that it protected mice from challenge. Even a single immunization with 1 microg of the replicon induced a long-lasting antibody response, characterized by high neutralizing antibody titers, which were sustained for at least 1 year. Nevertheless, it was possible to boost this response further by a second injection with the RNA vaccine, even in the presence of a concomitant CD8+ T-cell response. In this way it was possible to induce a balanced humoral and cellular immune response, similar to infection-induced immunity but without the safety hazards of infectious agents. The results also demonstrate the value of TBEV replicon RNA for inducing protective long-lasting antiviral responses.

Animals↗

Rectal immunization with rotavirus virus-like particles induces systemic and mucosal humoral immune responses and protects mice against rotavirus infection.

To evaluate whether the rectal route of immunization may be used to provide appropriate protection against enteric pathogens such as rotaviruses (RV), we studied the antibody response and the protection induced by rectal immunization of mice with RV virus-like particles (VLP). For this purpose, 6-week-old BALBc mice were rectally immunized twice with RV 8-2/6/7-VLP derived from the bovine RV RF81 strain either alone or combined with various adjuvants including four toxins [cholera toxin (CT) and three attenuated Escherichia coli-derived heat-labile toxins (LTs), LT(R192G), LT(R72), and LT(K63)] and two Toll-like receptor-targeting adjuvants (CpG and resiquimod). Six weeks after the second immunization, mice were challenged with murine RV strain ECw. RV VLP administered alone were not immunogenic and did not protect mice against RV challenge. By contrast, RV VLP combined with any of the toxin adjuvants were immunogenic (mice developed significant titers of anti-RV immunoglobulin A [IgA] in both serum and feces and of anti-RV IgG in serum) and either efficiently induced complete protection of the mice (no detectable fecal virus shedding) or, for LT(K63), reduced the amount of fecal virus shedding after RV challenge. When combined with RV VLP, CpG and resiquimod failed to achieve protection, although CpG efficiently induced an antibody response to RV. These results support the consideration of the rectal route for the development of new immunization strategies against RV infection. Rectal delivery of a VLP-based vaccine might allow the use of adjuvants less toxic than, but as efficient as, CT.

Adjuvants, Immunologic↗

Tumor immunity in rats immunized with rat carcinoembryonic antigen.

Active immunization of rats with an emulsion consisting of Freund's complete adjuvant (FCA) and an extract of rat tumor containing carcinoembryonic antigen (CEA) induced clear-cut protection from growth of the syngeneic CEA-positive tumor, RCA-1. No protection was observed in rats treated with FCA alone nor was there protection against a tumor that no serologically detectable CEA. The results suggested that the tumor immunity exhibited by the immunized rats was mediated by an immune response specific for rat CEA. It was shown further that multiparous rats were more resistant to growth of RCA-1 tumor than nulliparous rats. This suggested that immunization against rat CEA, which is an oncofetal antigen, may occur during pregnancy.

Adenocarcinoma↗

Creating alternative immunization clinics to maintain and improve community immunization rates.

Immunization campaigns are among the most effective means for improving community health, yet underimmunized groups leave communities at risk for vaccine-preventable diseases. In 1993, the Childhood Immunization Initiative (CII) was implemented to address this risk. The goal of the CII, to achieve immunization coverage 90% or greater among 2-year-old children, was reached nationwide by 1996. However, individual states ranged from 81% to 99% for specific vaccines (Centers for Disease Control and Prevention, 1997b). The work of the CII is ongoing and was expanded in 1996 to address the immunization needs of adolescents. The purpose of this article is to present a model for providing immunization services in alternative sites, in which the community health nurse takes the service to the people. Building linkages with local communities, preparing the clinic site and supplies, arranging for staffing of an alternative clinic, and evaluation after service provision are key elements to a successful outreach clinic.

Community Health Centers↗

Hemagglutinin and neuraminidase specific cell-mediated immune responses to influenza A virus following immunization in guinea pigs.

Groups of guinea pigs were immunized with different inactivated recombinant influenza A viruses including H3ChN2Ch, Heq1N2Ch, H3ChNeq1 or uninfected allantoic fluid. Employing hemagglutination and neuraminidase inhibition tests, an in-vitro lymphocyte transformation (LTF) assay, and rosetting techniques for the separation of lymphocytes, influenza hemagglutinin (HA) and neuraminidase (NA) specific antibody and cell-mediated immune (CMI) responses were evaluated. Inactivated H3ChN2Ch, H3ChNeq1, HavN2Ch, and Heq1Neq1 recombinant influenza viruses were used as test antigens. Following immunization the CMI and antibody responses to influenza were characterized by the induction of specific LTF and antibody activity to homotypic HA or NA antigens but not to heterotypic HA or NA antigens. The temporal kinetics of the antibody response to influenza antigens was characterized by a prompt onset being initially detected at 1-2 weeks and reaching peak titers 3-4 weeks after immunization. Influenza specific LTF responses were first detected one week after immunization and declined to minimal responses at eight weeks. T-lymphocytes but not B-lymphocytes were capable of in-vitro recognition of the HA and NA antigens. After recognition the subsequent in-vitro lymphoproliferation was shown to involve both T and B lymphocytes.

Agglutinins↗

Enhanced CD8+ T cell immune responses and protection elicited against Plasmodium berghei malaria by prime boost immunization regimens using a novel attenuated fowlpox virus.

Sterile immunity can be provided against the pre-erythrocytic stages of malaria by IFN-gamma-secreting CD8(+) T cells that recognize parasite-infected hepatocytes. In this study, we have investigated the use of attenuated fowlpox virus (FPV) strains as recombinant vaccine vectors for eliciting CD8(+) T cells against Plasmodium berghei. The gene encoding the P. berghei circumsporozoite (PbCS) protein was inserted into an FPV vaccine strain licensed for use in chickens, Webster's FPV, and the novel FPV vaccine strain FP9 by homologous recombination. The novel FP9 strain proved more potent as a vaccine for eliciting CD8(+) T cell responses against the PbCS Ag. Sequential immunization with rFP9 and recombinant modified vaccinia virus Anakara (MVA) encoding the PbCS protein, administered by clinically acceptable routes, elicited potent CD8(+) T cell responses against the PbCS protein. This immunization regimen elicited substantial protection against a stringent liver-stage challenge with P. berghei and was more immunogenic and protective than DNA/MVA prime/boost immunization. However, further improvement was not achieved by sequential (triple) immunization with a DNA vaccine, FP9, and MVA.

Adjuvants, Immunologic↗

[Study of the immunodepressive effect of passive immunization on a model of adaptive immunity].

The effect of various doses of specific serum administered in passive immunization on the formation of primary and secondary adaptive immunity in mice of the CBA strain was studied. Primary and secondary response was more sensitive to passive immunization on a model of adaptive immunity than in vivo. Most sensitive to the immunodepressive action of specific antibodies IgM and IgG were plaque-forming cells, and most resistant -- rosette-forming cells and cells. This led to a supposition that antibodies administered in passive immunization depressed the development of the immunological response acting at the level of T- and B cells.

Animals↗

[Production of antirickettsial sera by immunizing horses. II. Obtaining and testing an immune serum to D. sibericus].

The authors present the results of immunization of horses-producers with a commercial antigen and the yolk culture of the living R. sibericus (strain K1) for the purpose of obtaining specific immune sera for many purposes. It was shown that the original combined scheme of immunization and reimmunization of horses, successfully approved in the preparation of immune sera to Rickettsia prowazeki also proved to be highly effective for obtaining the antisera to R. sibericus. Sera obtained after the primary immunization of horses could be successfully used as diagnostic sera, but they were of no use for the preparation of fluorescent antibodies and the highly active hemosensitin; as to the sera obtained after the remote reimmunization--they were universal raw material. Dry fluorescent antibodies to R. sibericus were prepared of the horse sera (their stain titre was 1 : 256--1 : 512) a highly active hemosensitin, and also dry commercial diagnostic sera for the IHT, CFR and the immunofluorescent reaction of microagglutination.

Agglutination Tests↗