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Studies on the immune response in chickens I. Effect of various immunization procedures on the primary and secondary antibody responses to bovine serum albumin.

Antibody response and generation of immunological memory in chickens after stimulation by bovine serum albumin (BSA) were investigated. A single intravenous injection of BSA induced a relatively high primary antibody response but failed to generate definite memory for the secondary antibody response. Variation in antigen dosage and the time interval between antigen injections did not affect significantly the levels of the primary and secondary antibody responses. The immunogenicity of deaggregated BSA in chickens was as potent as that of aggregated BSA. Soluble adjuvants such as the capsular polysaccharide of Klebsiella pneumoniae, cell wall lipopolysaccharide of Salmonella enteritidis and cell wall peptidoglycan of Staphylococcus epidermidis exhibited little enhancing effect on antibody response and memory. However, stimulation of chickens by BSA emulsified in Freund's adjuvant enhanced generation of memory. Repeated injection of BSA alone also showed a similar effect. It seems likely therefore that in chickens continous antigenic stimulation is required for generation of definite memory. From the present results it has been concluded that the characteristics of the immune response of chickens to BSA resemble those of mammals to T-independent antigens.

Animals↗

Mini-review: Regulation of cytotoxic T lymphocyte responses by dendritic cells: peaceful coexistence of cross-priming and direct priming?

Cross-priming is the process whereby professional APC, mainly dendritic cells (DC), prime T cells by presenting antigens processed from proteins of other cells such as tumor cells or virus-infected cells. It has been argued that the importance of cross-priming of CD8(+) CTL responses has been overemphasized, despite strong evidence that these mechanisms operate when infectious organisms, tumors or self antigens cannot efficiently access the biosynthetic MHC class I processing pathway of DC. Since DC are ideally equipped to capture exogenous antigen and also, particularly in the mature state, express costimulatory molecules, it is difficult to distinguish whether effects are due to cross-presentation, costimulation, or both. Whether cross-priming or cross-tolerance occurs depends on the maturation state of the DC, as well as the levels of MHC class I-bound peptides they present. Cross-presentation of tumor-derived antigens has been demonstrated but, importantly, requires adequate APC activation to prime CTL responses. Similarly, cross-presentation of antigens from infectious organisms appears to be common, and frequently leads to cross-priming. Interactions between cross-presenting DC, CD4(+) cells and CD8(+) T cells in the establishment of immunological memory are still not well defined. Experiments utilizing DC depletion are needed to further examine the role of processes such as cross-priming and costimulation in the immune response.

Animals↗

Competence and competition: the challenge of becoming a long-lived plasma cell.

Plasma cells provide humoral immunity. They have traditionally been viewed mainly as short-lived end-stage products of B-cell differentiation that deserve little interest. This view is changing, however, because we now know that plasma cells can survive for long periods in the appropriate survival niches and that they are an independent cellular component of immunological memory. Studies of the biology of plasma cells reveal a mechanism of intriguing simplicity and elegance that focuses memory provided by plasma cells on recently encountered pathogens while minimizing the 'fading' of memory for pathogens encountered in the distant past. This mechanism is based on competition for survival niches between newly generated plasmablasts and older plasma cells.

Animals↗

The dynamics of the cellular immune response to HIV infection: implications for vaccination.

Recent advances in measuring T-cell responses to viruses have led to new insights into how these T cells respond. In the acute infection there are massive CD8+ T-cell responses to both Epstein-Barr virus (EBV) and to human immunodeficiency virus (HIV). Many of these T cells are effector cells and only a minority appear to be capable of maintaining immunological memory. In persistent virus infections, high levels of antigen-specific effector cells persist. If virus does not persist, the effectors fade in number but memory is maintained and is primed to react rapidly to a new challenge. A vaccine that stimulates only T-cell responses may protect when these memory cells respond rapidly enough to generate high numbers of effectors before the infecting virus becomes established.

AIDS Vaccines↗

[The induction of an immune response to influenza virus antigens by anti-idiotypic antibodies].

The present investigation indicate that homologous polyclonal anti-idiotypic antibodies induce both humoral and cell-mediated immune response. Experiments on the exhaustion of immune sera with vaccine have revealed that anti-idiotypic antibodies induce not only specific antibodies to influenza virus antigens, but also antibodies to other epitopes of the globulin molecule of the anti-idiotype. Anti-idiotypic antibodies, when reintroduced into animals, induce the production of anti-influenza antibodies of the anamnestic type, but do not induce the formation of antihemagglutinins. The injection of influenza vaccine to animals, previously immunized with anti-idiotypic antibodies, induces the production of antihemagglutinins; an increase in the level of immune complexes and antibodies to anti-idiotype, i.e. anti-idiotypic antibodies, induces the development of immunological memory with respect to influenza virus antigens, including antihemagglutinins.

Animals↗

Immunological analysis of the rats with anterior hypothalamic lesions.

We have previously identified the suppression of lymphocyte blastogenesis and the acceleration of growth of subcutaneous tumors by bilateral anterior hypothalamic lesions in rats. The present study was performed to clarify the changes in lymphocyte subsets and natural killer (NK) activity after making the lesions. The influence on immunological memory was also studied. The CD4/CD8 ratio of peripheral blood lymphocytes and spleen cells, T cell receptor alpha beta-positive cells of the thymocytes and NK activity of the spleen cells decreased significantly. Major histocompatibility complex (MHC) antigen expression on RBL-1 cells injected intraperitoneally into pre-immunized rats was also suppressed. These results suggest that the anterior hypothalamus has some influences on the control of the cellular immunological functions at the peripheral level, on the maturation of T cells at the level of thymus and on the antigen recognition by T cell receptors and MHC antigens.

Animals↗

Recombinant murine interleukin-12 elicits potent antileukemic immune responses in a murine model of Philadelphia chromosome-positive acute lymphoblastic leukemia.

Despite the success of chemotherapy regimens in the treatment of acute lymphoblastic leukemia (ALL), certain subsets of patients have a high rate of induction failure and subsequent relapse. One of these subsets of patients carry a translocation between chromosomes 9 and 22, the so called Philadelphia chromosome (Ph+). The result of this translocation is the fusion oncogene, Bcr-Abl, which is uniquely expressed in the leukemia clone, and as such has the potential to initiate antileukemic immune responses against the leukemia blasts. We utilized a murine model of Ph+ ALL to look at the ability of systemic interleukin 12 (IL-12) treatments to initiate antileukemic immune responses, and studied the mechanisms by which it does so. We found that IL-12 was able to eliminate pre-established leukemia, and that this protection was mediated by CD4, CD8, and NK cells in combination. While IL-12 was able to eliminate pre-established leukemia, it did not elicit immunologic memory. Consistent with previous work, vaccination with irradiated leukemia cells transduced with immunomodulator genes was able to establish long-term memory, and, when used with IL-12, was able to eradicate pre-existing disease and induce resistance to subsequent leukemia challenge. These studies demonstrate the feasibility of an immunotherapeutic approach towards the treatment of Ph+ ALL.

Animals↗

Aging and the immune response to tetanus toxoid: diminished frequency and level of cellular immune reactivity to antigenic stimulation.

The period of efficacious immune reactivity afforded by tetanus immunization and the need for continuing some forms of tetanus vaccination programs have been the subjects of recent debates. Our studies demonstrate that the level of antitetanus immunity based on immunological memory (i.e., cellular immune responsiveness) varies dramatically as a function of age, with older individuals constituting a population which is increasingly susceptible to tetanus infection.

Adolescent↗

[Primary and secondary immune response in animals following spontaneous loss of tolerance].

Mice subjected to tolerogenic treatment by sheep red blood cells (SRBC) and cyclophosphamide were immunized at various intervals (from 1 to 8 weeks after treatment) either by a single injection of 5 X 10(8) SRBC or by a double-injection of 1 X 10(6) SRBC. In control mice both immunization methods proved to be equally successful. In the experimental animals the immunological memory formation and/or its realization was destroyed to a greater extent and was restored more slowly than the capacity to the primary response.

Animals↗

Controlling the generation and function of human CD8+ memory T cells in vitro with immunosuppressants.

BACKGROUND: Memory T cells play a pivotal role in acute and chronic rejection of transplanted organs. Novel therapies such as alemtuzumab and the identification of heterologous memory have highlighted their importance following transplantation. Unlike naive T cells, the influence of immunosuppressive agents on the de novo generation of memory T cells and on the function of pre-existing memory T cells is poorly understood. METHOD: CD8 effector memory T cells (Tem, CD45RA, CCR7) were generated by stimulating peripheral blood mononuclear cells for five days with anti-CD3 and anti-CD28 monoclonal antibodies, followed by nine days of rest. The influence of immunosuppression on this was assessed by flow cytometry. Tem that had been naturally formed in vivo were used to study the influence of the same agents on the function (intracellular interferon-gamma production) of Tem cells. RESULTS: Whereas all the immunosuppressive agents tested inhibited the expansion of CD8 Tem population by influencing their proliferation and apoptosis, the calcineurin inhibitors were better at controlling their function. Furthermore, Tem generated despite the presence of tacrolimus were functional and did not exhibit drug resistance. CONCLUSIONS: Immunosuppressive agents differ in their ability to control the generation and function of CD8 Tem; the calcineurin inhibitors being the most efficacious. This may be of importance when tailoring immunosuppressants for transplant recipients, particularly in those where there is pre-existing immunological memory or in those receiving T-cell depleting therapies, which skews the immune repertoire towards memory.

Antigens, CD↗

Clinical relevance of lower Hib response in DTPa-based combination vaccines.

Combination vaccines are essential to enable administration of all the required antigens in routine infant immunisation schedules at any single visit. Some combinations of diphtheria-tetanus-acellular pertussis (DTPa) with Haemophilus influenzae type b (Hib) conjugate vaccines have been shown to result in lower Hib titres than when Hib is administered separately. While confirming that a primary series with a DTPa-HBV-IPV/Hib combination gives lower antibody levels than separate Hib conjugates, we show that the nature (isotype and IgG subclasses) and function (avidity and opsonic activity) of the antibodies are the same, and immunologic memory is induced. It is likely therefore that the DTPa-HBV-IPV/Hib combination will be efficacious against Hib disease.

Antibodies, Bacterial↗

Burst-enhancing role of the IgG membrane tail as a molecular determinant of memory.

The basis of immune memory leading to heightened secondary antibody responses is a longstanding unanswered issue. Here we show that a single irreversible molecular change in the B cell antigen receptor, which is brought about by immunoglobulin M (IgM) to IgG isotype switching, is sufficient to greatly increase the extrafollicular proliferative burst of antigen-specific B cells. The unique membrane-spanning regions of IgG do not alter the T cell-dependent activation and proliferation of antigen-specific B cells in vivo, but markedly increase the number of progeny cells and plasmablasts that accumulate. These results establish a key molecular determinant of immunological memory and define an unexpected cellular basis by which it enhances the magnitude of secondary antibody responses.

Amino Acid Sequence↗

An alphabeta T-cell-independent immunoprotective response towards gut coccidia is supported by gammadelta cells.

Although gammadelta cells are commonly hypothesized to provide a 'first line of defence', gammadelta-cell-deficient mice are generally only marginally more susceptible to pathogens. Because gammadelta cells are enriched within epithelia, it is important to resolve whether immunoprotective capacity towards epithelial-tropic pathogens is absent from the gammadelta-cell compartment, or whether such activity is present but simply redundant with that of alphabeta T cells. In this work, following infection of the intestinal epithelium of alphabeta T-cell-deficient mice with the coccidian parasite, Eimeria vermiformis, gammadelta cells were shown to support the rapid activation of other lymphoid cells and to confer a transferable antipathogen effect that could be eradicated by neutralization of interferon-gamma. However, unlike alphabeta T cells, these effects of gammadelta cells showed no evidence of functional immunological memory. These results are directly relevant to coccidiosis, an economically significant disease of livestock, and should have general relevance to infections involving alphabeta T-cell deficiencies, e.g. cryptosporidiosis in patients with acquired immune deficiency syndrome (AIDS).

Adoptive Transfer↗

Tracking the dynamics of T-cell activation in response to Salmonella infection.

Despite the current availability of Salmonella vaccines, typhoid fever remains a significant public health problem in developing countries. A greater understanding of T-cell activation and the development of immunological memory during Salmonella infection should lead to the development of more effective prophylactic intervention. Here, we review recent literature on the initiation, expansion and memory development of T-cell responses using the mouse model of typhoid. We pay particular attention to strategies for tracking T-cell responses in vivo and ex vivo, and suggest models to integrate some these studies.

Animals↗

[Substitution of T-cell function by poly-4-vinypyridine in the formation of the primary and secondary immune response].

The influence of poly-4-vinylpiridine (P-4-VP) on the production of antibody forming cells (AFC) has been studied. P-4-VP induces helper activity in lymphoid organs of B-mice. P-4-VP injected into mice substitutes T cell function in the development of immunological memory. The possibility of substitution by P-4-VP of various functions or of different subpopulations of T cells in T cell-deprived mice is discussed.

Animals↗

Immune response to acute otitis media in children III. Implications of viral antibody in middle ear fluid.

With the technique of radioimmunodiffusion and indirect FA staining, IgA antibody to measles, mumps, rubella, and polio-1 were determined in serum and middle ear fluid (MEF) of 103 patients with otitis media. The occurrence of IgA viral antibody in MEF and its absence in simultaneously drawn serum was used as an indicator of local antibody production. Of the 401 assays performed, 41 instances of IgA antibody exclusively in MEF were found. Only four of these occurred in specimens from unimmunized patients and were directed against rubella virus. Of the 37 remaining cases, 16 each were directed against measles and polio-1 and four and one, respectively, for mumps and rubella viruses. The mean specific IgA titers were from 8- to 17-fold higher in MEF from immunized individuals than in the unimmunized and persisted for at least 9 to 19 months after immunization. The data thus indicate 1) specific immunologic sensitization of the middle ear mucosa can be achieved by parenteral as well as oral routes of immunization, and 2) specific immunologic memory exists in the middle ear mucosa. These two factors are crucial to feasibility of immunization against acute otitis media.

Antibodies, Viral↗

An Escherichia coli CS31A fibrillum chimera capable of inducing memory antibodies in outbred mice following booster immunization with the entero-pathogenic coronavirus transmissible gastroenteritis virus.

CS31A fibrillae are thin, flexible, heteropolymeric proteinaceous appendages exposed as a capsule-like material around the cell surface of certain Escherichia coli strains. Two antigenic peptides of the S spike glycoprotein (TGEV-S) amino acids (aa) 363-371 and 521-531 of the transmissible gastroenteritis virus (TGEV) were tandemly introduced in the loop-structured, variable region aa 202-218 of the major ClpG subunit protein composing the bulk of CS31A. The resulting hybrid fibrillae with a 25 aa heterologous peptide were produced at the cell surface. Using a monoclonal antibody (Mab) specific for the TGEV epitopes, purified hybrid fibrillae were analysed in Western blotting under native conditions, which showed that the two viral epitopes were recognized immunologically as an integral part of the hybrid fibrillae, and therefore that they were antigenically active. The immunogenicity of the fusion construct was evaluated with live recombinant bacteria, purified hybrid ClpG monomers, and purified chimeric CS31A polymers. Whatever the form of hybrid used as antigen, intraperitoneally immunized outbred mice elicited serum anti-TGEV peptides antibodies (Abs) with significant titres and capable of recognizing native TGEV particles, indicating that the epitopes are exposed in an immunogenic conformation in all cases. However, virus neutralization titres were only obtained after immunization with either purified polymers or monomers. Furthermore, 4 months after an ultimate immunization with 20 micrograms of hybrid fibrillae mice developed a strong anamnestic Ab response against the two TGEV peptides following booster inoculation with virions. We conclude that CS31A fibrillae carrying a combination of TGEV epitopes as insert can induce an immunological memory in outbred animals infected with TGEV, and therefore that hybrid CS31A fibrillae may prove efficient as components of a subunit vaccine.

Adhesins, Escherichia coli↗

A specific role for B cells in the generation of CD8 T cell memory by recombinant Listeria monocytogenes.

In this study, we investigated whether B cells play a role in the induction and maintenance of CD8 T cell memory after immunization with an intracellular bacterium, Listeria monocytogenes. Our results show that B cells play a minimal role in the initial activation and Ag-driven expansion of CD8 T lymphocytes. However, absence of B cells results in increased death of activated CD8 T cells during the contraction phase, leading to a lower level of Ag-specific CD8 T cell memory. Once memory is established, B cells are no longer required for the long-term maintenance and rapid recall response of memory CD8 T cells. Increased contraction of Ag-specific CD8 T cells in B cell-deficient mice is not due to impaired CD4 T cell responses since priming of epitope-specific CD4 T cell responses is normal in B cell-deficient mice following L. monocytogenes infection. Furthermore, no exaggerated contraction of Ag-specific CD8 T cells is evident in CD4 knockout mice. Thus, B cells play a specific role in modulating the contraction of CD8 T cell responses following immunization. Elucidation of factors that regulate the death phase may allow us to manipulate this process to increase the level of immunological memory and thus, vaccine efficacy.

Animals↗