7 results
Search Results
2. A Generic Mechanism for Enhanced Cytokine Signaling via Cytokine-Neutralizing Antibodies.
- Author
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Shulgin, Boris, Helmlinger, Gabriel, and Kosinsky, Yuri
- Subjects
- *
CYTOKINES , *CELLULAR signal transduction , *IMMUNOGLOBULINS , *IMMUNE response , *DRUG efficacy - Abstract
Enhancement or inhibition of cytokine signaling and corresponding immune cells responses are critical factors in various disease treatments. Cytokine signaling may be inhibited by cytokine-neutralizing antibodies (CNAs), which prevents further activation of cytokine receptors. However, CNAs may result in enhanced—instead of inhibitory—cytokine signaling (an “agonistic effect”) in various in vitro and in vivo experiments. This may lead to lack of efficacy or adverse events for cytokine-inhibiting based medicines. Alternatively, cytokine-antibody complexes may produce stronger signaling vs. cytokine alone, thereby increasing the efficacy of stimulating cytokine-based drugs, at equal or lower cytokine doses. In this paper, the effect of cytokine signaling enhancement by a CNA was studied in a generic mathematical model of interleukin-4 (IL-4) driven T-cell proliferation. The occurrence of the agonistic effect depends upon the antibody-to-cytokine binding affinity and initial concentrations of antibody and cytokine. Model predictions were in agreement with experimental studies. When the cytokine receptor consists of multiple subunits with substantially differing affinities (e.g., IL-4 case), the choice of the receptor chain to be blocked by the antibody is critical, for the agonistic effect to appear. We propose a generic mechanism for the effect: initially, binding of the CNA to the cytokine reduces free cytokine concentration; yet, cytokine molecules bound within the cytokine-CNA complex—and released later and over time—are “rescued” from earlier clearance via cellular internalization. Hence, although free cytokine-dependent signalling may be less potent initially, it will also be more sustained over time; and given non-linear dynamics, it will lead ultimately to larger cellular effector responses, vs. the same amount of free cytokine in the absence of CNA. We suggest that the proposed mechanism is a generic property of {cytokine, CNA, receptor} triads, both in vitro and in vivo, and can occur in a predictable fashion for a variety of cytokines of the immune system. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
3. Enzymatic Strategies to Detoxify Gluten: Implications for Celiac Disease.
- Author
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Caputo, Ivana, Lepretti, Marilena, Martucciello, Stefania, and Esposito, Carla
- Subjects
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CELIAC disease , *GLUTEN , *T cells , *IMMUNE response , *POLYPEPTIDES , *AMINO acids , *APPETITE loss , *AUTOIMMUNE diseases , *IMMUNOGLOBULINS - Abstract
Celiac disease is a permanent intolerance to the gliadin fraction of wheat gluten and to similar barley and rye proteins that occurs in genetically susceptible subjects. After ingestion, degraded gluten proteins reach the small intestine and trigger an inappropriate T cell-mediated immune response, which can result in intestinal mucosal inflammation and extraintestinal manifestations. To date, no pharmacological treatment is available to gluten-intolerant patients, and a strict, life-long gluten-free diet is the only safe and efficient treatment available. Inevitably, this may produce considerable psychological, emotional, and economic stress. Therefore, the scientific community is very interested in establishing alternative or adjunctive treatments. Attractive and novel forms of therapy include strategies to eliminate detrimental gluten peptides from the celiac diet so that the immunogenic effect of the gluten epitopes can be neutralized, as well as strategies to block the gluten-induced inflammatory response. In the present paper, we review recent developments in the use of enzymes as additives or as processing aids in the food biotechnology industry to detoxify gluten. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
4. Immunological tolerance then and now: was the Medawar school right?
- Author
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Nossal, G. J. V.
- Subjects
- *
IMMUNOLOGICAL tolerance , *IMMUNOLOGY , *T cells , *IMMUNE response , *B cells , *IMMUNOGLOBULINS , *BONE marrow , *ANTIGENS , *GENETIC mutation - Abstract
As perhaps the staunchest advocates of repertoire purging as the central mechanism of immunological tolerance, we note with satisfaction a spate of recent, elegant papers which suggest an intrathymic clonal abortion model as the explanation for at least some examples of T-cell tolerance. This view agrees with the classical formulation of the Billingham-Brent-Medawar school of tolerance as a specific, central failure of immune responsiveness. Repertoire purging within the B-lymphocyte compartment remains much more controversial. There is no doubt that experimental models exist where the B cell is the reversible target of tolerance induction. The question is, in view of the ease of inducing autoantibody formation both in vivo and in vitro, just how relevant are such clonal anergy mechanisms to authentic self-tolerance? Arguments are presented that there must be two windows of tolerance susceptibility in the ontogeny of the B cell; one while it is maturing in the bone marrow, to prevent autoreactivity of high affinity to important accessible self-antigens; and a second soon after activation of pre-memory cells by exogenous antigen, to prevent fortuitous mutations towards high-affinity anti-self-reactivity establishing a forbidden clone. [ABSTRACT FROM AUTHOR]
- Published
- 1989
5. HLA-linked immune suppression in humans.
- Author
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Sasazuki, T., Kikuchi, I., Hirayama, K., Matsushita, S., Ohta, N., and Nishimura, Y.
- Subjects
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HLA histocompatibility antigens , *IMMUNOSUPPRESSION , *IMMUNOGLOBULINS , *T cells , *ANTIGENS , *IMMUNE response - Abstract
There is no doubt that HLA-DR molecules are acting as the products of HLA-linked immune response genes (Ir-genes), because (i) HLA-DR molecules are the restriction elements in the interaction between CD4+ helper T cells and antigen-presenting cells (APC) to respond to many antigens such as streptococcal cell wall antigen (SCW) (Nishimura & Sasazuki, 1983; Sone et al., 1985; Hizayama et al., 1986), schistosomal antigen (Sj) (Hirayama et al., 1987), Mycobacterium leprae antigen (ML) (Kikuchi et al., 1986) and so on; and (ii) anti-HLA-DR monoclonal antibodies completely abolish the immune response to those antigens (Nishimura & Sasazuki, 1983; Sone et al., 1985). However, genetic analysis of the immune response to those antigens in families or populations revealed that responsiveness is recessive and non-responsiveness to those antigens is a dominant genetic trait that is tightly linked to HLA (Sasazuki et al., 1980a, 1983; Watanabe et al., 1988). This is completely opposite to the situation under the Ir-gene control where responsiveness is dominant and non-responsiveness is recessive. In this paper, we report evidence of how we came across the concept of HLA-linked immune suppression genes (Is-genes) besides Ir-genes, and show evidence for the epistatic interaction between HLA-DR and DQ to determine the immune response to several antigens in humans. [ABSTRACT FROM AUTHOR]
- Published
- 1989
6. A Fine Romance: T Follicular Helper Cells and B Cells
- Author
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King, Cecile
- Subjects
- *
T cells , *B cells , *IMMUNOGLOBULINS , *CELLULAR immunity , *IMMUNE response , *ANTIGENS - Abstract
T follicular helper (Tfh) cells help B cells to generate affinity-matured antibodies. Three papers in this issue of Immunity () provide information about the reciprocal relationship between B cells and Tfh cells. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
7. Beta Glucan: Supplement or Drug? From Laboratory to Clinical Trials.
- Author
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Vetvicka, Vaclav, Vannucci, Luca, Sima, Petr, and Richter, Josef
- Subjects
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IMMUNE response , *CLINICAL trials , *RANDOMIZED controlled trials , *IMMUNOGLOBULINS , *T cells - Abstract
Glucans are part of a group of biologically active natural molecules and are steadily gaining strong attention not only as an important food supplement, but also as an immunostimulant and potential drug. This paper represents an up-to-date review of glucans (β-1,3-glucans) and their role in various immune reactions and the treatment of cancer. With more than 80 clinical trials evaluating their biological effects, the question is not if glucans will move from food supplement to widely accepted drug, but how soon. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
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