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PubMed2005

Susceptibility and resistance to monocytic ehrlichiosis in the mouse.

To address the role of cellular immunity during ehrlichia infection, we have utilized a model of monocytic ehrlichiosis that results from infection of mice by Ixodes ovatus ehrlichia (IOE). Although ehrlichiosis in humans is largely a disease of immunocompromised individuals, the use of the IOE model has allowed us to identify factors required for host defense in normal mice. Using a low-dose infection C57BL/6 mouse model, we have demonstrated that host defense requires immune mechanisms involving CD4 T cell-mediated, TNF-alpha-, IL-12-, and IFN-gamma-dependent, macrophage activation. We have also provided formal evidence that IFN-gamma produced by CD4 Th1 cells is sufficient for protective immunity. Our recent studies have demonstrated, in addition, an essential role for IL-10, which is probably important in inhibiting immunopathological responses, and for inducible nitric oxide synthase. The latter observation establishes an important role for reactive nitrogen intermediates in bacterial elimination in vivo. In contrast, evaluation of mice carrying wild-type and mutant alleles of Nramp1 revealed at most a modest role for this gene in resistance to fatal IOE infection. Other studies in low-dose infected mice have indicated that the generation of immunological memory may be impaired during low-dose IOE infection, possibly due to bacterial immune subversion. These studies highlight the utility of the IOE mouse model in identifying important parameters of the immune response during ehrlichiosis.

Animals↗

PubMed1978

[Erythrocyte antigen: isolation, biochemical and immunologic properties].

The authors suggest a simple method of obtaining erythrocytic antigen in considerable amounts. This antigen is of stromal origin, contains from 10 to 20% protein, and is relatively homogenous. With the concentration of from 1 to 50 microgram by protein the preparation represents a transparent solution; with greater concentrations the antigen is white, turbid, but is well dissolved and convenient for administration to the animals. In case of a single administration without any adjuvants the antigen is highly immunogenic in low doses by protein. To the optimal immunizing dose of erythrocytes (5 X 10(8)) correspond about 100 microgram of the antigen by protein. The primary response to the antigen is similar to the response to sheep red blood cells (SRBC). It is exceedingly effective for the formation of immunological memory. The level of secondary responses in the adoptive transfer to all the EAG doses always exceeded the secondary response to SRBC. By adding EAG into agar during the local hemolysis in gel test determined the avidity of the antibodies synthesized at various periods of the immune response to SRBC.

Animals↗

PubMed2006

Nonspecific desensitization, functional memory, and the characteristics of SHIP phosphorylation following IgE-mediated stimulation of human basophils.

Previous studies of secretion from basophils have demonstrated the phenomenon called nonspecific desensitization, the ability of one IgE-mediated stimulus to alter the cell's response to other non-cross-reacting IgE-mediated stimuli, and a process that would modify phosphatidylinositol 3,4,5-phosphate levels was speculated to be responsible for nonspecific desensitization. The current studies examined the changes and characteristics of SHIP1 phosphorylation as a measure of SHIP1 participation in the reaction. Based on the earlier studies, two predictions were made that were not observed. First, the kinetics of SHIP1 phosphorylation were similar to reaction kinetics of other early signals and returned to resting levels while nonspecific desensitization remained. Second, in contrast to an expected exaggerated SHIP phosphorylation, cells in a state of nonspecific desensitization showed reduced SHIP phosphorylation (compared with cells not previously exposed to a non-cross-reacting Ag). Discordant with expectations concerning partial recovery from nonspecific desensitization, treatment of cells with DNP-lysine to dissociate bound DNP-HSA, either enhanced or had no effect on SHIP phosphorylation following a second Ag. These experiments also showed a form of desensitization that persisted despite dissociation of the desensitizing Ag. Recent studies and the results of these studies suggest that loss of early signaling components like syk kinase may account for some of the effects of nonspecific desensitization and result in a form of immunological memory of prior stimulation. Taken together, the various characteristics of SHIP phosphorylation were not consistent with expectations for a signaling element involved in nonspecific desensitization, but instead one which itself undergoes nonspecific desensitization.

Antibodies, Anti-Idiotypic↗

PubMed1989

Adoptive immunity transferred by naive donor cells immunized in vitro.

Speedy restoration of immune responsiveness in bone marrow recipients has been the objective of studies in which the donor was immunized so that specific immunologic memory could be transferred adoptively and selectively. Using unrelated rabbits, matched for major histocompatibility antigens but mismatched for their immunoglobulin allotypes, it could be shown that recipients of lymphoid cells from naive donors became B cell chimeras but did not use donor-derived B cells for their antibody responses to test antigens. In contrast, cells from donors primed for such antigens dominated antibody production in recipients in response to specific challenge. Clonal restriction in such adoptive responses was demonstrated. We now show that the induction of effective memory in cells from naive donors can be achieved in vitro during the preparation of donor cells for transfer to the recipient. Early challenge of the recipient enhances expression of the transferred immune response quantitatively and also results in the establishment or preservation of a larger diversity of clones from the donor.

Animals↗

PubMed1986

[Immunosuppressor role of staphylococcal protein A].

The removal of protein A from the surface of staphylococci by means of proteolytic enzymes increases the immunogenic properties of staphylococci. Staphylococci containing protein A are less effective in mediating the immunological memory than those treated with proteolytic enzymes. The conjugation of protein A with staphylococci treated with proteolytic enzymes leads to the decrease of the immunogenic properties of staphylococci. Protein A not bound to staphylococci also suppresses antistaphylococcal immune response. The protective properties of corpuscular staphylococcal antigen are increased after the removal of protein A from the surface of staphylococci by proteolysis.

Animals↗

PubMed2004

Does malaria suffer from lack of memory?

It is widely perceived that immunity to malaria is, to an extent, defective and that one component of this defective immune response is the inability to induce or maintain long-term memory responses. If true, this is likely to pose problems for development of an effective vaccine against malaria. In this article, we critically review and challenge this interpretation of the epidemiological and experimental evidence. While evasion and modulation of host immune responses clearly occurs and naturally acquired immunity is far from optimal, mechanisms to control blood-stage parasites are acquired and maintained by individuals living in endemic areas, allowing parasite density to be kept below the threshold for induction of acute disease. Furthermore, protective immunity to severe pathology is achieved relatively rapidly and is maintained in the absence of boosting by re-infection. Nevertheless, there are significant challenges to overcome. The need for multiple infections to acquire immunity means that young children remain at risk of infection for far too long. Persistent or frequent exposure to antigen seems to be required to maintain anti-parasite immunity (premunition). Lastly, pre-erythrocytic and sexual stages of the life cycle are poorly immunogenic, and there is little evidence of effective pre-erythrocytic or transmission-blocking immunity at the population level. While these problems might theoretically be due to defective immunological memory, we suggest alternative explanations. Moreover, we question the extent to which these problems are malaria-specific rather than generic (i.e. result from inherent limitations of the vertebrate immune system).

Animals↗

PubMed1975

Kinetics of antibody formation and regulatory aspects of immunity.

This paper, which is to be read in conjunction with that of Dr. J.F.A.P. Miller earlier in this volume, addresses itself to the kinetics of antibody production and to the regulation of the immune response. It is divided into four main sections. The first examines the kinetics of antibody production to a single, strong challenge injection of antigen. The cellular events involved in the latent period and the subsequent exponential phase of antibody production are examined from the viewpoint of four key concepts: triggering, clonal expansion, IgM to IgG switch and affinity maturation. The second section examines the major regulatory influences and feedback loops in immunity. Antigen is discussed as an agent capable of causing tolerance as well as triggering. Antibody is considered an important regulator, and the mechanisms of IgM-positive feedback, IgG-negative feedback, and tolerance and blockade effects of immune complexes are outlined. Immunological memory, the opposite phenomenon to tolerance, is briefly described, as is the importance of genetic factors. The third sections looks at more complex models of the immune response, and in particular at the lessons to be learnt from tumour progression.

Animals↗

PubMed2005

Disruption of CD40/CD40-ligand interactions in a retinal autoimmunity model results in protection without tolerance.

We examined the role of CD40/CD40L interactions on the development of experimental autoimmune uveoretinitis (EAU), a cell-mediated, Th1-driven autoimmune disease that serves as a model for autoimmune uveitis in humans. EAU-susceptible B10.RIII mice immunized with the retinal autoantigen interphotoreceptor retinoid binding protein in CFA and treated with anti-CD40L Ab (MR1) had reduced incidence and severity of disease. Real-time PCR analysis revealed that the innate and adaptive responses of protected mice were reduced, without an obvious shift toward a Th2 cytokine profile. In contrast to some other reports, no evidence was found for regulatory cells in adoptive transfer experiments. To determine whether CD40L blockade resulted in long-term tolerance, mice protected by treatment with MR1 Ab were rechallenged for uveitis after circulating MR1 Ab levels dropped below the detection limit of ELISA. MR1-treated mice developed severe EAU and strong cellular responses to interphotoreceptor retinoid binding protein, comparable to those of control mice. These responses were higher than in mice that had not received the primary immunization concurrently with anti-CD40L treatment. We conclude that 1) CD40/CD40L interaction is required for EAU and its disruption prevents disease development; 2) CD40L blockade inhibits the innate response to immunization and reduces priming, but does not result in immune deviation; and 3) protection is dependent on persistence of anti-CD40L Abs, and long-term tolerance is not induced. Furthermore, immunological memory develops under cover of CD40L blockade causing enhanced responses upon rechallenge. Taken together, our data suggest that ongoing CD40/CD40L blockade might be required to maintain a therapeutic effect against uveitis.

Adoptive Transfer↗

PubMed1993

Decreased expression of the memory marker CD26 on both CD4+ and CD8+ T lymphocytes of HIV-infected subjects.

Using a novel anti-CD26 (or anti-dipeptidyl peptidase IV) monoclonal antibody, we showed that the absolute numbers and the proportions of T4 and T8 cells expressing CD26 were significantly lower in HIV-infected persons than in controls. The absolute number of CD26+ T4 cells decreased according to disease progression, whereas the number of CD26+ T8 cells was low throughout all clinical stages. These trends were similar in CD26 dim and bright positive T-cell subsets. In both controls and HIV-positive subjects, the CD26 bright positive T cells were restricted to the CD45RO+ subset and preferentially co-expressed CD25 but largely lacked HLA-DR and CD38. Recall antigen-responsive cells from seronegative individuals were shown to co-express CD26 and CD45RO. The deficient CD26 expression on T8 cells from HIV-infected subjects could be normally upregulated after in vitro stimulation. In contrast to decreased T-cell-bound CD26, the enzymatic activity of plasma CD26/dipeptidyl peptidase IV was unchanged in HIV-infected patients compared with controls. We conclude that HIV infection leads to a deficient in vivo co-expression of CD26 bright and CD45RO on T cells. We speculate that this deficiency might play a part in the decrease of immunological memory during HIV infection.

ADP-ribosyl Cyclase↗

PubMed1976

5-Hydroxytryptophan effect on the development of the immune response: IgM and IgG antibodies and rosette formation in primary and secondary responses.

In animals immunized with bovine serum albumin, 5-hydroxytryptophan prolonged the latent period of the IgM and IgG primary responses, decreased response intensity, delayed the response peak and suppressed IgG immunological memory. In 5-hydroxytryptophan-treated mice, the number of rosette-forming cells (RFC) in the lymph node and spleen decreased during the primary and secondary responses. This effect was due to the decreased number of IgG RFC and to the later involvement of IgM RFC in the immune response. The absence of the secondary response was related to unprimed IgG memory cells. 5-hydroxytryptophan does not inhibit the primary and secondary responses after the connections between the hypothalamus and pituitary have been disrupted. The participation of the n.raphe-hypothalaminc-pituitary system in immuno-regulation and the putative mechanism underlying serotonin effect on the immune response are discussed.

5-Hydroxytryptophan↗

PubMed1996

Immunoregulation of the allergic reaction in the respiratory tract.

The nature of host responsiveness to inhaled antigens is now believed to be a direct reflection of the type of T-cell which dominates specific immunological "memory"; a predominantly Th2-like response potentially leading to allergic reactivity, versus apparent "unresponsiveness" if the memory pool is dominated by Th1 cells. The animal model literature suggests that potentially life-long dominance of immune responses to individual allergens is established at or around the time of first exposure, and involves an antigen-driven T-cell selection process. In humans, this process is likely to occur for most inhalant allergens, during early childhood. The outcome of these initial responses can be influenced by a variety of factors, including the nature and competence of the antigen presenting cells involved, the functional maturity of the CD4+ T-cell population at the time of exposure, and the presence of inflammatory or infectious stimuli at the level of the airway mucosa, which can effect the cellular and/or cytokine milieu within local draining lymph nodes. Recent studies from the animal models additionally indicate that the cytokine products from allergen-responsive major histocompatibility (MHC) class I restricted CD8+ T-cells, and also from allergen-responsive T-cell receptor 1 (TcR1) (gamma/delta) T-cells, play an important role in shaping emerging CD4 T-cell responses, via the creation of an interferon-gamma (IFN-gamma)-rich milieu which selects against Th2 cells. The key finding from these studies is that these regulatory mechanism(s) function optimally in the relatively early stages of immune responses, and are considerably less effective in deviating established (memory) responses. It is argued below that the potential exists for exploitation of this information for the development of novel immunoprophylactic strategies to prevent primary allergic sensitization in humans at a stage when allergen-specific immune responses are theoretically most susceptible to regulation i.e. during early childhood.

Animals↗

PubMed2003

Bone marrow as a priming site for T-cell responses to blood-borne antigen.

Although bone marrow is known as a primary lymphoid organ, its potential to serve as a secondary immune organ has hardly been explored. Here we demonstrate that naive, antigen-specific T cells home to bone marrow, where they can be primed. Antigen presentation to T cells in bone marrow is mediated via resident CD11c+ dendritic cells. They are highly efficient in taking up exogenous blood-borne antigen and processing it via major histocompatibility complex class I and class II pathways. T-cell activation correlates with dendritic cell-T cell clustering in bone marrow stroma. Primary CD4+ and CD8+ T-cell responses generated in bone marrow occur in the absence of secondary lymphoid organs. The responses are not tolerogenic and result in generation of cytotoxic T cells, protective anti-tumor immunity and immunological memory. These findings highlight the uniqueness of bone marrow as an organ important for hemato- and lymphopoiesis and for systemic T cell-mediated immunity.

Animals↗

PubMed1983

Cellular and humoral IgA responses after single and multiple local injections of antigen.

IgA responses in submandibular salivary glands, cervical lymph nodes, and saliva of rats were studied. Immunoglobulin-containing cells of the IgA isotype were examined by immunofluorescence of mononuclear cells isolated from the submandibular salivary glands and cervical lymph nodes after primary and multiple local injections of Streptococcus mutans. Also, salivary and serum antibodies to S. mutans were determined using an ELISA. The results support immunologic memory for the secretory (salivary) IgA system at both the cellular and humoral levels. Comparison of the dynamics of the IgAICC responses among the tissues and secretions after the injection regimes suggests that the cervical lymph nodes may provide an enriched tissue source for secretory IgA responses in the oral cavity.

Animals↗

PubMed1995

Kinetics of the local and systemic antibody response to primary and secondary infection with S48 Toxoplasma gondii in sheep.

Vaccination of sheep with live tachyzoites of Toxoplasma gondii, strain S48, affords protection against subsequent challenge with the parasite, but the mechanisms of immunity have not been fully determined. To understand better the nature of the antibody response the kinetics of both local and systemic antibody production were monitored in vaccinated sheep by means of an enzyme-linked immunosorbent assay and Western blotting. Local specific IgG production was analysed in efferent lymph obtained from the cannulated pre-femoral lymph node draining the site of infection. Antibody in efferent lymph plasma and peripheral blood serum from animals vaccinated with S48 tachyzoites was monitored and compared with IgG production in vaccinated sheep given a secondary tachyzoite challenge. Secondary challenge resulted in a clear immunological memory response, antibody being detected in the lymph 3 to 4 days after infection as compared with 7 to 8 days after a primary infection. IgG production was dominated by antibody recognizing a protein with an apparent molecular weight of 30 kDa, but other antigens (32, 24 and 11 kDa) were also readily detected.

Animals↗

PubMed2000

A repetitive sequence of Epstein-Barr virus nuclear antigen 6 comprises overlapping T cell epitopes which induce HLA-DR-restricted CD4(+) T lymphocytes.

Most human adults carry the Epstein-Barr virus (EBV) and develop immunological memory against the structural and the virus-encoded cellular proteins. The EBV nuclear antigen 6 (EBNA6) elicits cytotoxic T cell responses and it also maintains a persistent antibody response. The majority of sera from EBV-seropositive individuals reacts with a synthetic peptide, p63, comprising 21 amino acids of a repetitive region of EBNA6. CD4(+) T lymphocytes, with specificity for p63, could be recalled from the T cell repertoire of EBV carriers that expressed certain HLA-DR allotypes which were identified as good binders of p63 by an in vitro flow cytometric assay. Analysis of the HLA-DR/p63 interaction by molecular mechanics calculations indicated the presence of multiple overlapping epitopes which were predicted to bind in a HLA-DRB1 allo- and subtype-specific manner. Specific activation of p63-selected long-term CD4(+) T cell cultures resulted in a proliferative response, in the production of IL-2 and in the secretion of high levels of tumor necrosis factor as measured by bioassays. Proliferation and cytokine production of p63-specific T cells could be induced by p63-loaded HLA-DR-matched antigen-presenting cells and by B cells co-expressing relevant HLA-DR molecules and EBNA6. Our results show that peptides of an EBNA6 repeat region induce CD4(+) T cells which can react with EBNA6-carrying cells in many individuals. We suggest that these T(h) cells may be important in conditioning dendritic cells for initiation potent virus-specific immune responses, provide help for EBV-specific B cells, drive IgG isotype switch and support the sustained effector function of memory cytotoxic T lymphocytes.

Adult↗

PubMed1978

Response of anamnestic IgA-producing cells in the mouse gut after repeated intragastric immunization.

1) Repeated intragastric immunization after a 90-day interval results in a local immunologic memory. 2) Repeated intragastric immunization does not induce the same circulation of gut lymphocytes as does the initial oral immunization. 3) Measurement of circulating antibodies is a poor criterion for gauging the local immune status. 4) A gastric intubation dose of 4 X 10(9) SRBC given daily for 4 days appears to be suboptimal for the induction of a local immune response.

Animals↗

PubMed2001

Type i interferons potently enhance humoral immunity and can promote isotype switching by stimulating dendritic cells in vivo.

Type I interferons (IFN-I) are rapidly induced following infection and play a key role in nonspecific inhibition of virus replication. Here we have investigated the effects of IFN-I on the generation of antigen-specific antibody responses. The data show that IFN-I potently enhance the primary antibody response to a soluble protein, stimulating the production of all subclasses of IgG, and induce long-lived antibody production and immunological memory. In addition, endogenous production of IFN-I was shown to be essential for the adjuvant activity of CFA. Finally, IFN-I enhanced the antibody response and induced isotype switching when dendritic cells were the only cell type responding to IFN-I. The data reveal the potent adjuvant activity of IFN-I and their important role in linking innate and adaptive immunity.

Adjuvants, Immunologic↗

PubMed2001

Ectopic expression of retinoic acid early inducible-1 gene (RAE-1) permits natural killer cell-mediated rejection of a MHC class I-bearing tumor in vivo.

In 1986, Kärre and colleagues reported that natural killer (NK) cells rejected an MHC class I-deficient tumor cell line (RMA-S) but they did not reject the same cell line if it expressed MHC class I (RMA). Based on this observation, they proposed the concept that NK cells provide immune surveillance for "missing self," e.g., they eliminate cells that have lost class I MHC antigens. This seminal observation predicted the existence of inhibitory NK cell receptors for MHC class I. Here, we present evidence that NK cells are able to reject tumors expressing MHC class I if the tumor expresses a ligand for NKG2D. Mock-transfected RMA cells resulted in tumor formation. In contrast, when RMA cells were transfected with the retinoic acid early inducible gene-1 gamma or delta (RAE-1), ligands for the activating receptor NKG2D, the tumors were rejected. The tumor rejection was mediated by NK cells, and not by CD1-restricted NK1.1(+) T cells. No T cell-mediated immunological memory against the parental tumor was generated in the animals that had rejected the RAE-1 transfected tumors, which succumbed to rechallenge with the parental RMA tumor. Therefore, NK cells are able to reject a tumor expressing RAE-1 molecules, despite expression of self MHC class I on the tumor, demonstrating the potential for NK cells to participate in immunity against class I-bearing malignancies.

Animals↗