Publisher Summary Studies of cytotoxicity by human lymphocytes revealed not only that both allogeneic and syngeneic tumor cells were lysed in a non-MHC-restricted fashion, but also that lymphocytes from normal donors were often cytotoxic. Lymphocytes from any healthy donor, as well as peripheral blood and spleen lymphocytes from several experimental animals, in the absence of known or deliberate sensitization, were found to be spontaneously cytotoxic in vitro for some normal fresh cells, most cultured cell lines, immature hematopoietic cells, and tumor cells. This type of nonadaptive, non-MHC-restricted cellmediated cytotoxicity was defined as “natural” cytotoxicity, and the effector cells mediating natural cytotoxicity were functionally defined as natural killer (NK) cells. The existence of NK cells has prompted a reinterpretation of both the studies of specific cytotoxicity against spontaneous human tumors and the theory of immune surveillance, at least in its most restrictive interpretation. Unlike cytotoxic T cells, NK cells cannot be demonstrated to have clonally distributed specificity, restriction for MHC products at the target cell surface, or immunological memory. NK cells cannot yet be formally assigned to a single lineage based on the definitive identification of a stem cell, a distinct anatomical location of maturation, or unique genotypic rearrangements.

Biology of natural killer cells.

The mechanism underlying the differentiation of CD4+ T cells into functionally distinct subsets (Th1 and Th2) is incompletely understood, and hitherto unidentified cytokines may be required for the functional maturation of these cells. Here we report the cloning of a recently identified IFN-gamma-inducing factor (IGIF) that augments natural killer (NK) activity in spleen cells. The gene encodes a precursor protein of 192 amino acids and a mature protein of 157 amino acids, which have no obvious similarities to any peptide in the databases. Messenger RNAs for IGIF and interleukin-12 (IL-12) are readily detected in Kupffer cells and activated macrophages. Recombinant IGIF induces IFN-gamma more potently than does IL-12, apparently through a separate pathway. Administration of anti-IGIF antibodies prevents liver damage in mice inoculated with Propionibacterium acnes and challenged with lipopolysaccharide, which induces toxic shock. IGIF may be involved in the development of Th1 cells and also in mechanisms of tissue injury in inflammatory reactions.

Cloning of a new cytokine that induces IFN-gamma production by T cells.

The brain and the immune system are the two major adaptive systems of the body During an immune response the brain and the immune system "talk to each other" and this process is essential for maintaining homeostasis Two major pathway systems are involved in this cross-talk: the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) This overview focuses on the role of SNS in neuroimmune interactions, an area that has received much less attention than the role of HPA axis Evidence accumulated over the last 20 years suggests that norepinephrine (NE) fulfills the criteria for neurotransmitter/neuromodulator in lymphoid organs Thus, primary and secondary lymphoid organs receive extensive sympathetic/noradrenergic innervation Under stimulation, NE is released from the sympathetic nerve terminals in these organs, and the target immune cells express adrenoreceptors Through stimulation of these receptors, locally released NE, or circulating catecholamines such as epinephrine, affect lymphocyte traffic, circulation, and proliferation, and modulate cytokine production and the functional activity of different lymphoid cells Although there exists substantial sympathetic innervation in the bone marrow, and particularly in the thymus and mucosal tissues, our knowledge about the effect of the sympathetic neural input on hematopoiesis, thymocyte development, and mucosal immunity is extremely modest In addition, recent evidence is discussed that NE and epinephrine, through stimulation of the beta(2)-adrenoreceptor-cAMP-protein kinase A pathway, inhibit the production of type 1/proinflammatory cytokines, such as interleukin (IL-12), tumor necrosis factor-alpha, and interferon-gamma by antigen-presenting cells and T helper (Th) 1 cells, whereas they stimulate the production of type 2/anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta Through this mechanism, systemically, endogenous catecholamines may cause a selective suppression of Th1 responses and cellular immunity, and a Th2 shift toward dominance of humoral immunity On the other hand, in certain local responses, and under certain conditions, catecholamines may actually boost regional immune responses, through induction of IL-1, tumor necrosis factor-alpha, and primarily IL-8 production Thus, the activation of SNS during an immune response might be aimed to localize the inflammatory response, through induction of neutrophil accumulation and stimulation of more specific humoral immune responses, although systemically it may suppress Th1 responses, and, thus protect the organism from the detrimental effects of proinflammatory cytokines and other products of activated macrophages The above-mentioned immunomodulatory effects of catecholamines and the role of SNS are also discussed in the context of their clinical implication in certain infections, major injury and sepsis, autoimmunity, chronic pain and fatigue syndromes, and tumor growth Finally, the pharmacological manipulation of the sympathetic-immune interface is reviewed with focus on new therapeutic strategies using selective alpha(2)- and beta(2)-adrenoreceptor agonists and antagonists and inhibitors of phosphodiesterase type IV in the treatment of experimental models of autoimmune diseases, fibromyalgia, and chronic fatigue syndrome

The Sympathetic Nerve—An Integrative Interface between Two Supersystems: The Brain and the Immune System

Design activities are central to most applied disciplines. Research in design has a long history in many fields including architecture, engineering, education, psychology, and the fine arts (Cross 2001). The computing and information technology (CIT) field since its advent in the late 1940s has appropriated many of the ideas, concepts, and methods of design science that have originated in these other disciplines. However, information systems (IS) as composed of inherently mutable and adaptable hardware, software, and human interfaces provide many unique and challenging design problems that call for new and creative ideas.

/pdf/design-science-research-in-information-systems-1dq1e7v3c1.pdf

Design Science Research in Information Systems

Elimination of CD25+ T cells, which constitute 5-10% of peripheral CD4+ T cells in normal naive mice, leads to spontaneous development of various autoimmune diseases. These immunoregulatory CD25+CD4+ T cells are naturally unresponsive (anergic) in vitro to TCR stimulation, and, upon stimulation, suppress proliferation of CD25-CD4+ T cells and CD8+ T cells. The antigen concentration required for stimulating CD25+CD4+ T cells to exert suppression is much lower than that required for stimulating CD25-CD4+ T cells to proliferate. The suppression, which results in reduced IL-2 production by CD25-CD4+ T cells, is dependent on cellular interactions on antigen-presenting cells (and not mediated by far-reaching or long-lasting humoral factors or apoptosis-inducing signals) and antigen non-specific in its effector phase. Addition of high doses of IL-2 or anti-CD28 antibody to the in vitro T cell stimulation culture not only breaks the anergic state of CD25+CD4+ T cells, but also abrogates their suppressive activity simultaneously. Importantly, the anergic/suppressive state of CD25+CD4+ T cells appeared to be their basal default condition, since removal of IL-2 or anti-CD28 antibody from the culture milieu allows them to revert to the original anergic/suppressive state. Furthermore, transfer of such anergy/suppression-broken T cells from normal mice produces various autoimmune diseases in syngeneic athymic nude mice. These results taken together indicate that one aspect of immunologic self-tolerance is maintained by this unique CD25+CD4+ naturally anergic/suppressive T cell population and its functional abnormality directly leads to the development of autoimmune disease.

/pdf/immunologic-self-tolerance-maintained-by-cd25-cd4-naturally-3ztss0lfuo.pdf

Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state.

Homocytotropic antibody formation against dinitrophenylated Ascaris extracts (DNP-As) was selectively suppressed by the passive administration of homologous antibody against the same antigen. Unrelated antiserum or cross-reacting antibodies against haptenic group or carrier determinants had no suppressing effect. The suppression was preferentially directed to the homocytotropic antibody response, while the hemagglutinating γM antibody formation was unaffected. The effect was most significant when the antibody was administered simultaneously with, or a few days after, the initial antigen injection, whereas previous administration was less effective. The synthesis of homocytotropic antibody was terminated by the passive administration of antibody at the time when the PCA titer was at the maximum. The suppressive activity was detected in the 7S γG fraction of hyperimmune antiserum, while the early 19S or intermediate fractions had little activity. Heterologous antibody to the same antigen showed a similar inhibitory effect, but about twice as much antibody was required for the same degree of suppression. The results indicate the presence of so-called “feed-back” regulation in the homocytotropic antibody response. The possible mechanisms and biologic significances of this regulation are discussed.

Regulation of Homocytotropic Antibody Formation in the Rat: I. Feed-Back Regulation by Passively Administered Antibody

CD69, an 'activation marker' that is rapidly induced on mature T cells after stimulation through the T cell antigen receptor (TCR) was found to be expressed on approximately 10% of normal thymocytes. All of these CD69+ thymocytes express alpha beta TCR, and they include both TCRlowCD4+CD8+ and TCRhighCD4+CD8- or CD4-CD8+ thymocytes. The CD69+ cells can be further segregated into heat-stable antigen (HSA)+TCRlow, HSA+TCRhigh and HSA-TCRhigh thymocyte populations. None of CD69+ cells express the mature T cell marker Qa-2. Thus CD69+ cells present in vivo appear phenotypically to represent transitional cell populations between immature TCRlowHSA+Qa-2-double-positive cells and mature TCRhighHSA-QA-2+ single-positive cells. In addition, TCR engagement by MHC molecules is required for CD69 expression in the thymus. Taken together, the CD69+ thymocytes appear to represent the cells auditioning in positive selection process or they are the cells that have been positively selected recently. Analysis of a TCR transgenic mouse model revealed an increased number of CD69+ thymocytes in a positively selecting thymus, whereas no CD69+ transgenic TCR+ thymocytes were observed in the non-selecting thymus. Based on the results of this study, we suggest that the surface expression of CD69 serves as a useful marker to identify and trace those thymocytes that are engaged in the TCR-mediated positive selection process in the thymus.

CD69 cell surface expression identifies developing thymocytes which audition for T cell antigen receptor-mediated positive selection

An enhanced and sustained production of homocytotropic antibody (HTA) was induced in rats that received 400 R of whole body x-irradiation and simultaneously were immunized with dinitrophenylated Ascaris suum extract (DNP-As) and Bordetella pertussis vaccine. The donor rats were hyperimmunized by repeated injections of DNP-As, As (unconjugated carrier) or DNP-BSA (hapten coupled to a different carrier) in complete Freund9s adjuvant. Suspensions of 10 8 to 10 9 thymocytes or spleen cells from hyperimmunized donors were passively transferred to recipient rats that were producing high titers of HTA. The production of HTA against DNP-As in the recipients was drastically reduced within 2 days after the transfer of thymocytes or spleen cells from donors hyperimmunized with DNP-As or As, whereas cells from the donors immunized with DNP-BSA showed no inhibitory effect. The results indicate that carrier-specific thymus-derived lymphocytes negatively regulate the HTA formation that is virtually hapten-specific.

Regulation of Homocytotropic Antibody Formation in the Rat VI. Inhibitory Effect of Thymocytes on the Homocytotropic Antibody Response

Adult rats about 3 months old were splenectomized or thymectomized and then immunized with dinitrophenylated Ascaris suum extracts (DNP-As) plus Bordetella pertussis 3 to 10 days after the operation. Homocytotropic antibody (HTA) formation against DNP-As was examined by passive cutaneous anaphylaxis (PCA) over a period of 45 days. HTA formation was found to be greatly enhanced and prolonged by splenectomy and thymectomy. Virtually no termination of HTA formation occurred. Combined extirpation of the spleen and thymus in adult rats had the same enhancing effect. Passive hemagglutination tests with sera treated or untreated with 2-mercaptoethanol showed that the production of γG and γM antibodies was unchanged. In contrast to adult thymectomy, neonatal thymectomy caused a loss, or at least a marked reduction, of the ability to produce HTA. The results suggest that adult splenectomy and thymectomy cause regulatory disturbances of HTA formation in the rat.

Regulation of homocytotropic antibody formation in the rat. 3. Effect of thymectomy and splenectomy.

An antigen-specific suppressive T-cell factor was extracted from physically disrupted thymocytes and spleen cells of mice that had been immunized with soluble protein antigens. The factor, when inoculated into syngeneic normal mice, could induce a significant suppression of IgG antibody response against a hapten coupled to the carrier protein by which the donor of the suppressor factor was immunized. The suppressor factor was found only effective in suppressing the antibody response of syngeneic or H-2 histocompatible recipients. The suppressive T-cell factor was removed by absorption with immunoadsorbent composed of the relevant antigen, but not with any of those of anti-immunoglobulin antibodies. The factor was successfully removed by alloantibodies with specificity for the K end (H-2K, I-A and I-B) of the H-2 complex of the donor strain, but not by those for the D end (I-C, SsSlp, and H-2D). The activity was removed by absorption with a heterologous antithymocyte serum. The mol wt of the suppression T-cell factor was between 35,000 and 60,000 as determined by Sephadex G-200 gel filtration. The suppressive T-cell factor was found to be a heat-liable protein.

/pdf/properties-of-antigen-specific-suppressive-t-cell-factor-in-2mjores8o1.pdf

Properties of antigen-specific suppressive T-cell factor in the regulation of antibody response of the mouse. I. In vivo activity and immunochemical characterization.

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