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Results for “Immunologic Memory”

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PubMed2002

Humoral immunity and long-lived plasma cells.

A selected fraction of plasmablasts enters the compartment of nondividing, long-lived plasma cells to maintain humoral antibody memory. In accord with a current model for lymphocyte homeostasis, the lifetime of long-lived plasma cells is probably regulated by competition for a limited number of survival niches present in splenic red pulp, bone marrow and inflamed tissue. Plasma cells secreting autoantibodies specific for some, but not all, self-antigens are probably 'allowed' to enter the compartment of long-lived plasma cells and provide antibody-mediated 'autoimmune memory' that is resistant to conventional therapies.

Animals↗
PubMed2005

The bone marrow: a nest for migratory memory T cells.

It has been known for a long time that T-cell precursors generated in the bone marrow migrate to the thymus, where T-cell development occurs. However, a fact often neglected is that, under physiological conditions, mature CD4 and CD8 lymphocytes undergo extensive migration from the blood to the bone marrow and vice versa. Here, we first review several observations showing that the bone marrow can function as a secondary lymphoid organ for both CD4 and CD8 cells, as well as a preferential homing site for memory T cells. Second, we discuss evidence that, a long time after priming, memory CD8 cells proliferate more extensively in the bone marrow than they do in either secondary lymphoid or extra-lymphoid organs. Finally, we propose that the bone marrow is a central organ in mature T-cell traffic and contributes greatly to long-term cytotoxic memory, which has implications for adoptive immunotherapy and vaccine design.

Animals↗
PubMed1999

Do we need 3 doses of hepatitis B vaccine?

The hepatitis B virus (HBV) vaccine may provide protection through the clonal expansion of specific memory cells without necessarily having to produce high serum antibody levels. We develop a mathematical model which distinguishes between the accumulation of sensitive memory B and T-helper cells prior to a booster and the high circulating antibody levels present in an individual after a booster. We suggest this immune memory accumulates primarily in an antigen-independent fashion. These phenomena suggest individuals may be immune to infection six months after the priming vaccine dose(s) regardless of whether they receive a booster or not. This hypothesis is supported by immunogenicity data and by two independent vaccine efficacy trials comparing 0, 1 month schedules with 0, 1 and 6 month schedules.

Hepatitis B Vaccines↗
PubMed2002

Role of transfection in the priming of cytotoxic T-cells by DNA-mediated immunization.

DNA vaccination results in remarkably strong, broad-based immune responses to the encoded proteins and it is a simple and effective method of inducing cytotoxic T-lymphocyte (CTL) responses. Bone marrow-derived cells can take up and present exogenous antigenic protein liberated by transfected fibroblasts or myoblasts after the injection of such cells. In addition, dendritic cells can carry the injected plasmid DNA, supporting the hypothesis that dendritic cells can be directly transfected. It is, however, unclear from the current data what proportion of the cytotoxic immune response is initiated by the transfer of protein compared to that resulting from direct transfection of professional antigen presenting cells. This question is addressed here by using a matched series of plasmid DNA vectors expressing the wild-type or several mutant forms of HBsAg that are secretion-defective or severely truncated. The data indicate that neither HBsAg particle formation nor its secretion or liberation plays a significant role in the development of the cytotoxic immune response. The results argue that direct transfection of bone marrow-derived cells is the major, and possibly the only, mechanism used for priming of naive CTL precursors directed against the HBsAg.

Animals↗
PubMed2002

Effective therapeutic anticancer vaccines based on precision guiding of cytolytic T lymphocytes.

In natural immune responses CD4+ T helper (Th) cells, reactive with peptide antigens presented by major histocompatibility complex (MHC) class II molecules on dendritic cells (DC), can drive the maturation of DC that is required for induction of CD8+ cytolytic T-lymphocyte (CTL) immunity. Proper induction, expansion and maintenance of CTL responses are achieved through delicate interactions between CD4+ T cells, DC and CD8+ T cells involving several ligand-receptor pairs. Th cells to a large extent operate through up-regulation of CD40L, which then interacts with CD40 on DC to cause DC maturation. Subsequent CTL induction by activated DC requires CD80/CD86 on the DC to interact with the CD28 costimulatory receptor on CD8+ T cells. For maintenance and full expansion of CTL, interaction of the DC-expressed 4-1BB ligand with its receptor 4-1BB on CTL is also important. Alternative molecular triggers of DC activation that can support induction of powerful CTL responses include agonistic anti-CD40 antibody or ligands of Toll-like receptors (TLR) such as LPS (TLR4 ligand) or oligodeoxynucleotides containing CpG-motifs (TLR9 ligand). The combination of CpG adjuvant with a 35 amino acid long synthetic peptide comprising both tumor-specific CTL and Th epitopes proved to be a highly effective vaccine formulation capable of inducing therapeutic immunity against human papillomavirus-induced mouse tumors. The recently acquired insights into antigen presentation and costimulatory signals have made possible the development of a new generation of therapeutic anticancer vaccines.

Antigen Presentation↗
PubMed2003

Naive T cells are maintained by thymic output in early ages but by proliferation without phenotypic change after age twenty.

Analysing T-cell receptor excision circle numbers in healthy individuals we find a marked change in the source of naive T cells before and after 20 years of age. The bulk of the naive T cell pool is sustained primarily from thymic output for individuals younger than 20 years of age whereas proliferation within the naive phenotype is dominant for older individuals. Over 90% of phenotypically naive T cells in middle age are not of direct thymic origin. Moreover, this change in source of naive T cells is accompanied either by an increased death rate of T cells from the thymus or reduced thymic export. Modelling of these processes shows that new naive T cells of a thymic origin have a half-life of approximately 50 days before this change occurs, and that either the life-span of recent thymic emigrants (but not necessarily of all naive cells) decreases approximately threefold in middle age, or thymic production drops by this same amount. The decay rate of T-cell receptor excision circle levels for individuals over 20 years of age is consistent with the decay rate of the productive thymus. Our modelling suggests that at age 25, thymic export is responsible for 20% of naive T-cell production and that this percentage decreases with the 15.7 year half-life of the productive thymus so that by age 55 only 5% of naive production arises from thymic export.

Adolescent↗
PubMed1980

Cellular consequences in the suppression of antibody response by the antigen-specific T-cell factor.

Cellular events mediated by antigen-specific soluble factor extracted from carrier-primed suppressor T cells (TsF) in the suppressive interaction was studied. Keyhole limpet hemocyanin (KLH)-specific TsF directly acts on KLH-primed, I-J positive, nylon-wool-adherent T cells that have an acceptor site for TsF. The nylon-wool-adherent T cells, after accepting TsF in the presence of specific antigen, generate new suppressor T cells acting as an actual effector cell type. Antigen-specificity and syngeneity at I-J between TsF and acceptor T cells are both required for the induction of new suppressor T cells. Newly induced suppressor T cells, however, suppress both syngeneic and allogeneic responses in an antigen-nonspecific fashion.

Animals↗
PubMed2001

Molecular mechanisms regulating Th1 immune responses.

The T helper lymphocyte is responsible for orchestrating the appropriate immune response to a wide variety of pathogens. The recognition of the polarized T helper cell subsets Th1 and Th2 has led to an understanding of the role of these cells in coordinating a variety of immune responses, both in responses to pathogens and in autoimmune and allergic disease. Here, we discuss the mechanisms that control lineage commitment to the Th1 phenotype. What has recently emerged is a rich understanding of the cytokines, receptors, signal transduction pathways, and transcription factors involved in Th1 differentiation. Although the picture is still incomplete, the basic pathways leading to Th1 differentiation can now be understood in in vitro and a number of infection and disease models.

Animals↗
PubMed1987

2'Deoxycoformycin and deoxyadenosine affect IL 2 production and IL 2 receptor expression of human T cells.

Congenital deficiency of the enzyme adenosine deaminase (ADA) leads to severe combined immunodeficiency. 2'Deoxycoformycin (dCF), a tightly binding inhibitor of ADA, can induce the metabolic state of ADA deficiency. In vivo, the drug causes specific impairment of lymphocyte function and shows strong immunosuppressive properties. However, to decide whether inhibition of the enzyme ADA offers an attractive approach for immunosuppressive therapy, more information is needed about the immunologic mechanisms affected. In human T cells, we investigated the effect of dCF and deoxyadenosine (AdR) on cell activation, interleukin 2 (IL 2) production, and IL 2 receptor induction after allogeneic and lectin-induced stimulation. After allogeneic stimulation, dCF and AdR affected several events in T cellular immune response. Early events in T cell activation showed to be most sensitive to the drugs. Primary MLC was completely inhibited by concentrations as low as 1 microM dCF and 1 microM AdR. The addition of human recombinant IL 2 (rIL 2) could not abrogate the inhibitory effect of the drugs. Apart from activation of T cells, the drugs interfered with proliferation of activated T cells. Two events in activated T cells were affected: IL 2 production and IL 2 receptor expression. In secondary MLC, IL 2 production was markedly reduced in the presence of 9 microM dCF and 60 microM AdR. These concentrations appeared also to affect IL 2 receptor expression in 12-day primary MLC cells stimulated with rIL 2. Lectin stimulation was also affected by the drugs. In phytohemagglutinin (PHA)-stimulated cultures, 9 microM dCF and 60 microM AdR resulted in inhibition of proliferation and IL 2 receptor expression, whereas IL 2 production was normal. It is concluded that dCF and AdR interfere with several events in T cellular immune response such as cell activation, IL 2 production, and IL 2 receptor expression. According to these results, inhibition of the enzyme ADA seems an attractive approach to immunosuppressive therapy.

Animals↗
PubMed1994

Anti-CD2 mAbs suppress cytotoxic lymphocyte activity by the generation of Th2 suppressor cells and receptor blockade.

The mechanism by which anti-CD2 mAbs inhibit hapten-specific and alloantigen specific CTL was explored. In vivo administration of alpha-CD2 mAbs resulted in 80 to 100% inhibition of alloantigen specific CTLs. Mixing cells from control animals with cells from alpha-CD2-treated groups demonstrated transferable suppression of CTL (40-67% suppression). These suppressor cells were CD4+CD8- and associated with increased IL-4 and TGF-beta in culture as compared with controls. Anti-CD2 mAbs added at the initiation of culture resulted in 60 to 72% inhibition of trinitrophenyl-CTL, whereas mAbs added at the time of assay resulted in less than 50% inhibition of trinitrophenyl-CTLs. F(ab')2 and Fab alpha-CD2 produced inhibition similar to intact mAbs when added at the time of the lytic assay, whereas both produced only modest inhibition in vivo or when added at the initiation of culture. Alloantigen-specific CTLs were not affected by Ab addition to either culture or assay. The immunosuppressive effects were generalizable because a panel of alpha-CD2 mAbs were all comparably effective in suppressing hapten-specific CTLs when administered in vivo. The results demonstrate that the inhibitory effects are the result of blockade of receptor adhesion function during Ag priming or target recognition, Fc-related effects, and the generation of a negative regulatory, CD4+CD8-, IL-4- and TGF-beta-producing TH2 suppressor T cell.

Animals↗
PubMed2006

Optimisation and parallelisation strategies for Monte Carlo simulation of HIV infection.

In recent years, the study of immune response behaviour through mathematical and computational models has attracted considerable efforts. The dynamics of key cell types, and their interactions, has been a primary focus in terms of building a picture of how the immune system responds to a threat. Discrete methods, based on lattice Monte-Carlo (MC) models, with their flexibility and relative simplicity have previously been used to model the immune system behaviour. However, due to speed and memory constraints, large-scale simulations cannot be done on a single computer. Key issues in the reduction of simulation time are code optimisation and code parallelisation. In this paper, optimisation and parallelisation solutions are discussed, with reference to existing MC simulation code for dynamics of HIV infection.

Antibodies, Viral↗