WordNet

(physiology) the effect of a stimulus (on nerves or organs etc.)
the act of arousing an organism to action
any stimulating information or event; acts to arouse action (同)stimulus, stimulant, input
major food fish of Arctic and cold-temperate waters (同)codfish
lean white flesh of important North Atlantic food fish; usually baked or poached (同)codfish
lettuce with long dark-green leaves in a loosely packed elongated head (同)cos_lettuce, romaine, romaine lettuce

PrepTutorEJDIC

刺激,興奮;激励
=codfish 1
〈人〉'を'ばかにする
cosine
=because
Colorado
cobaltの化学記号

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2018/01/17 11:59:07」(JST)

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During the activation of lymphocytes, co-stimulation is often crucial to the development of an effective immune response. Co-stimulation is required in addition to the antigen-specific signal from their antigen receptors.^[1]

T Cell Co-stimulation

T cells require two signals to become fully activated. A first signal, which is antigen-specific, is provided through the T cell receptor (TCR) which interacts with peptide-MHC molecules on the membrane of antigen presenting cells (APC). A second signal, the co-stimulatory signal, is antigen nonspecific and is provided by the interaction between co-stimulatory molecules expressed on the membrane of APC and the T cell.

One of the best characterized co-stimulatory molecules expressed by T cells is CD28, which interacts with CD80 (B7.1) and CD86 (B7.2) on the membrane of APC. Another costimulatory receptor expressed by T cells is ICOS ( Inducible Costimulator), which interacts with ICOS-L.

T cell co-stimulation is necessary for T cell proliferation, differentiation and survival. Activation of T cells without co-stimulation may lead to T cell anergy, T cell deletion or the development of immune tolerance.

B Cell Co-stimulation

B cell binds antigens with its BCR (a membrane-bound antibody), which transfers intracellular signals to the B cell as well as inducing the B cell to engulf the antigen, process it, and present it on the MHC II molecules.^[2] The latter case induces recognition by antigen-specific Th2 cells, leading to activation of the B cell through binding of TCR to the MHC-antigen complex. It is followed by synthesis and presentation of CD40L (CD154) on the Th2 cell, which binds to CD40 on the B cell, thus the Th2 cell can co-stimulate the B cell.^[3] Without this co-stimulation the B cell cannot proliferate further. ^[4]

Co-stimulation for B cells is provided alternatively by complement receptors. Microbes may activate the complement system directly and complement component C3b bind to microbes. After C3b is degraded into a fragment iC3b (inactive derivative of C3b), then cleaved to C3dg, and finally to C3d, which continue to bind to microbal surface, B cells express complement receptor CR2 (CD21) to bind to iC3b, C3dg, or C3d.^[5] This additional binding makes the B cells 100- to 10,000-fold more sensitive to antigen.^[6] CR2 on mature B cells forms a complex with CD19 and CD81. This complex is called the B cell coreceptor complex for such sensitivity enhancement to the antigen.^[7]

Applications

Abatacept (Orencia) is a T cell co-stimulation modulator approved for the treatment of rheumatoid arthritis. The cytokines secreted by activated T cells are thought to both initiate and propagate the immunologically driven inflammation associated with rheumatoid arthritis. Orencia, a soluble fusion protein, works by altering the co-stimulatory signal required for full T-cell activation. Belatacept is another novel molecule which is being tested for use in renal transplantation.

A new co-stimulatory superagonistic drug, TGN1412, was the subject of a clinical trial at Northwick Park Hospital, London. The trial became surrounded in controversy as the six volunteers became seriously ill within minutes of being given the drug.

In essence, the co-stimulatory molecules function as "flashing red lights" that interact with the T cell, communicating that the material being presented by the dendritic cell material indicates danger. Dendritic cells displaying co-stimulatory molecules while presenting antigen are able to activate T cells. In contrast, T cells that recognize antigen presented by a dendritic cell not displaying co-stimulatory molecules are generally driven to apoptosis, or may become unresponsive to future encounters with the antigen.

References

^ Seda, V; Mraz, M (2014). "B cell receptor (BCR) signalling and its crosstalk with other pathways in normal and malignant cells". European Journal of Haematology. 94: 193–205. doi:10.1111/ejh.12427. PMID 25080849.
^ Seda, V; Mraz, M (2014). "B cell receptor (BCR) signalling and its crosstalk with other pathways in normal and malignant cells". European Journal of Haematology. 94: 193–205. doi:10.1111/ejh.12427. PMID 25080849.
^ Janeway CA, Travers P, Walport M, Shlomchik M (2001). Immunobiology 5 : The Immune System in Health and Disease, 5th ed. New York: Garland Pub., ISBN 0-8153-3642-X
^ Noelle, R. J.; Roy, M.; Shepherd, D. M.; Stamenkovic, I.; Ledbetter, J. A.; Aruffo, A. (1992). "A 39-kDa protein on activated helper T cells binds CD40 and transduces the signal for cognate activation of B cells". Proceedings of the National Academy of Sciences of the United States of America. 89 (14): 6550–6554. doi:10.1073/pnas.89.14.6550. PMC 49539 . PMID 1378631.
^ Frank K, Atkinson JP (2001). "Complement system." In Austen KF, Frank K, Atkinson JP, Cantor H. eds. Samter's Immunologic Diseases, 6th ed. Vol. 1, p. 281–298, Philadelphia: Lippincott Williams & Wilkins, ISBN 0-7817-2120-2
^ Dempsey, P. W.; Allison, M. E.; Akkaraju, S.; Goodnow, C. C.; Fearon, D. T. (1996). "C3d of complement as a molecular adjuvant: Bridging innate and acquired immunity". Science. 271 (5247): 348–350. doi:10.1126/science.271.5247.348. PMID 8553069.
^ Abbas AK, Lichtman AH (2003). Cellular and Molecular Immunology, 5th ed. Philadelphia: Saunders, ISBN 0-7216-0008-5.

UpToDate Contents

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English Journal

Pharmacokinetics, pharmacodynamics, and immunogenicity of belatacept in adult kidney transplant recipients.

Shen J, Townsend R, You X, Shen Y, Zhan P, Zhou Z, Geng D, Wu D, McGirr N, Soucek K, Proszynski E, Pursley J, Masson E.Author information Clinical Pharmacology and Pharmacometrics, Oncology-Immunology, Bristol-Myers Squibb, P.O. Box 4000, E1.409, Princeton, NJ 08543-4000, USA.AbstractBACKGROUND AND OBJECTIVES: Belatacept is a first-in-class, selective co-stimulation blocker recently approved for the prophylaxis of organ rejection in adult kidney transplant recipients. The objective of this study was to report the pharmacokinetics, pharmacodynamics, and immunogenicity of belatacept.
Clinical drug investigation.Clin Drug Investig.2014 Feb;34(2):117-26. doi: 10.1007/s40261-013-0153-2.
BACKGROUND AND OBJECTIVES: Belatacept is a first-in-class, selective co-stimulation blocker recently approved for the prophylaxis of organ rejection in adult kidney transplant recipients. The objective of this study was to report the pharmacokinetics, pharmacodynamics, and immunogenicity of belatace
PMID 24217983

CXC chemokine receptor 4 signaling upon co-activation with stromal cell-derived factor-1α and ubiquitin.

Tripathi A1, Davis JD1, Staren DM1, Volkman BF2, Majetschak M3.Author information 1Department of Surgery, Loyola University Chicago, Stritch School of Medicine, United States.2Department of Biochemistry, Medical College of Wisconsin, United States.3Department of Surgery, Loyola University Chicago, Stritch School of Medicine, United States; Department of Molecular Pharmacology & Therapeutics, Loyola University Chicago, Stritch School of Medicine, United States. Electronic address: mmajetschak@lumc.edu.AbstractRecently, we reported that extracellular ubiquitin functions as another agonist of CXC chemokine receptor (CXCR)4. Whereas the cognate CXCR4 ligand, stromal cell-derived factor (SDF)-1α, is also a CXCR7 agonist, ubiquitin does not bind to CXCR7. Because both ligands are present in the extracellular environment, co-activation of CXCR4 appears to be physiologically relevant. CXCR4 mediated effects of ubiquitin, however, are not well understood and consequences of co-activation of CXCR4 with both ligands are unknown. Utilizing proximity ligation assays and flow cytometry, we detected CXCR4, but not CXCR7, on the cell surface of THP-1 cells, which suggests that confounding effects of CXCR7 are unlikely. Time course and magnitude of reduction of cell surface CXCR4 expression were comparable after stimulation of THP-1 cells with both ligands. SDF-1α was more efficacious than ubiquitin to mobilize Ca(2+). Co-stimulation of THP-1 cells with both ligands resulted in synergistic effects on Ca(2+) fluxes at suboptimal ligand concentrations. Homologous desensitization of Ca(2+) fluxes was detectable with both ligands. SDF-1α pre-stimulation desensitized ubiquitin induced Ca(2+) fluxes, but not vice versa. Effects of SDF-1α and ubiquitin on cAMP levels, Akt and ERK1/2 phosphorylation and chemotactic responses were additive. The chemotactic activities of ubiquitin and SDF-1α were sensitive to AMD3100, pertussis toxin, U73122, LY94002 and U0126. These data suggest that CXCR4 activation with SDF-1α and ubiquitin results in partially synergistic effects on cellular signaling events and in differential effects on receptor desensitization. The ligand ratio that is present in the extracellular environment may contribute to the regulation of CXCR4 mediated functions.
Cytokine.Cytokine.2014 Feb;65(2):121-5. doi: 10.1016/j.cyto.2013.12.008. Epub 2013 Dec 24.
Recently, we reported that extracellular ubiquitin functions as another agonist of CXC chemokine receptor (CXCR)4. Whereas the cognate CXCR4 ligand, stromal cell-derived factor (SDF)-1α, is also a CXCR7 agonist, ubiquitin does not bind to CXCR7. Because both ligands are present in the extracellular
PMID 24373940

Mechanism of pathogenesis of imiquimod-induced skin inflammation in the mouse: A role for interferon-alpha in dendritic cell activation by imiquimod.

Ueyama A, Yamamoto M, Tsujii K, Furue Y, Imura C, Shichijo M, Yasui K.Author information Medicinal Research Laboratories, Shionogi, Toyonaka, Japan.AbstractTopical application of imiquimod (IMQ), a Toll-like receptor (TLR)7 ligand, can induce and exacerbate psoriasis, a chronic inflammatory skin disorder. In a mouse model of IMQ-induced psoriasis-like skin inflammation, T-helper (Th)17 cells and interleukin (IL)-17/IL-22-producing γδ-T cells have been shown to play a pivotal role. However, the mechanisms of induction of the Th17 pathway and development of psoriasis-like skin inflammation by IMQ treatment remain unclear. In this study, we investigated pathogenic mechanisms of IMQ-induced psoriasis-like skin inflammation in mice. We first confirmed that, together with an increase in IL-17 and IL-22 production, application of IMQ to mouse skin induced the expression of cytokines required for activation of the Th17 pathway, and pro-inflammatory mediators involved in the pathology of psoriasis. Analysis of Tlr7(-/-) mice demonstrated that most of the in vivo effects of IMQ were mediated via TLR7. In an in vitro study using plasmacytoid dendritic cells (DCs), IMQ induced production of interferon (IFN)-α, IL-23, IL-6 and tumor necrosis factor (TNF)-α. Furthermore, when we analyzed in vitro-generated bone marrow-derived DCs with features similar to TNF-α and inducible nitric oxide synthase (iNOS)-producing DCs, IL-23, IL-6, IL-1β, TNF-α and iNOS/NO production was weakly induced by IMQ alone and further enhanced after co-stimulation with IMQ and IFN-α. These in vitro effects of IMQ were also mediated via TLR7 and the synergistic effect of IMQ, and IFN-α was suggested to be caused by upregulation of TLR7 expression by IFN-α. These results demonstrate part of the mechanism by which the Th17 pathway and psoriasis-like skin inflammation are induced by IMQ and IFN-α in a mouse model.
The Journal of dermatology.J Dermatol.2014 Feb;41(2):135-43. doi: 10.1111/1346-8138.12367. Epub 2014 Jan 3.
Topical application of imiquimod (IMQ), a Toll-like receptor (TLR)7 ligand, can induce and exacerbate psoriasis, a chronic inflammatory skin disorder. In a mouse model of IMQ-induced psoriasis-like skin inflammation, T-helper (Th)17 cells and interleukin (IL)-17/IL-22-producing γδ-T cells have bee
PMID 24387343

Japanese Journal

Cathelicidin antimicrobial peptide LL-37 augments interferon-beta expression and antiviral activity induced by double-stranded RNA in keratinocytes

British Journal of Dermatology 171(3), 492-498, 2014-09
NAID 120005526626

ISP-8-6 Significantly associated with favorable endometrium pattern in women aged>40 years by ovarian co-stimulation with growth hormone(Group 8 Reproduction 2,IS Poster,International Session)

日本産科婦人科學會雜誌 65(2), 1004, 2013-02-01
NAID 110009639746

Allergen Immunotherapy and Tolerance

Allergology International 62(4), 403-413, 2013
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