T lymphocytes mature into CD4- or CD8-expressing single positive cells in the thymus from where they become “peripheral T lymphocytes” which populate the secondary lymphoid organs. Upon interaction with antigen-presenting cells, peripheral T lymphocytes become activated, proliferate and expand to differentiate into effector and memory cells.
Until some years ago two functionally different CD4+ T helper (Th) cell types were known, i.e. “Th1 cells” which are induced by the action of IFN-gamma and IL-12 to protect against specific intracellular pathogens, and “Th2 cells” which are induced by IL-4 to encounter parasitic infections and also to participate in allergic reactions.
Additional CD4+ Th subtypes have been described meanwhile.
First the “Th17 effector T cell”, which produces IL-17 and IL-6 and which is generated by the action of IL-23. Th17 cells function to clear a range of pathogens distinct from Th1 and under pathologiocal conditions they are involved in autoimmune responses. The latter has sparked general interest for these cells as targets for immuno-modulatory and anti-inflammatory therapies.
“Treg cells” (CD4+, CD25+, FoxP3+) represent another variant of CD4+ effector T-cells with a pivotal role in the regulation of immune responses.
FOCUS Immunology provides state-of-the-art scientific support and services to study these cell types under GLP conditions. If you are interested in learning more about FOCUS Immunology’s experience and offers or if you want to discuss your specific experimental needs, please feel free to contact:
Dr. Eddy Bruyns, Head of FOCUS Immunology Laboratory via e-mail eddy.bruyns@focus-cdd.com or via telephone +49 6221 64935124.
Bettelli et al Nat Immunol 2007 8:345-350
Shevach Immunol Rev 2006 212: 60-73
Murphy Nat Rev Immunol 2002 2: 933-944
In a workshop hosted by the European Medicine Agency the possible role of in vitro cytokine release assays for prediction of unwanted side effects of novel (immuno-) therapeutics has been discussed. With respect to the latter the “cytokine release syndrome” and “cytokine storm” are severe and sometimes fatal adverse clinico-pathological events for which predictive assay systems are urgently needed.
In the workshop the central role of so-called “multiple cytokine secreting cells” in the pharmaco-dynamics of immuno-modulatory compounds and associated adverse events was pointed out.
As the name implies, these cells are characterized by the production of several cytokines in any single cell and thus contrast cells in which only one or two cytokines may be detected. In other words: “Multiple Cytokine Secretion” is a functional characteristic of a given cell and pretty much every T cell may become such a multiple cytokine secreting cell upon activation. Multiple cytokine secretion is a temporary state, only as long as the cell is being activated.
Physiological stimulation of T cells to multiple cytokine secretion is required for host defense and tissue remodeling. However, aberrant or un-intentional stimulation under pathological conditions or by (over-dosing of) immuno-modulatory compounds may result in severe pathologies, such as the above-mentioned “Cytokine Release Syndrome“.
The analysis of multiple cytokine secreting cells requires sophisticated multi-parameter assays, like multiplex immunological assays for measuring cytokine profiles in cellular secretions under various stimulation conditions. Ultimately, it requires multi-color intracellular cytokine staining by flow cytometry, which allows multiple cytokine determinations at the single level.
FOCUS Immunology is experienced in providing state-of-the-science analyses for multiple cytokine secreting cells under GLP conditions. If you are interested in learning more about FOCUS Immunology’s experience and offers or if you want to discuss your specific experimental needs, please feel free to contact
Dr. Eddy Bruyns, Head of FOCUS Immunology Laboratory via e-mail eddy.bruyns@focus-cdd.com or via telephone +49 6221 64935124.
EMEA workshop: “In vitro cytokine release assays to predict Cytokine Release Syndrome: the current-state-of-the science”
Zhang and colleagues explored the immunomodulatory activity of the cholesterol-lowering agent simvastatin. Their pharmaco-dynamic studies indicated that the immuno-modulatory activity of statins may involve two basic mechanisms. First, it may involve an increase in SOCS-3 and SOCS -7, i.e. members of the molecular family of “Suppressors of Cytokine Secretion”. And second, it may involve the inhibition of Interleukin-17 (IL-17), a central pro-inflammatory mediator.
The members of the SOCS family of molecules are important negative feedback regulators in adaptive and innate immune responses, while IL-17 producing CD4+ cells, the so-called “Th17 cells”, play a central role in the development of autoimmune diseases.
From their findings the authors conclude as follows: “Based on the described immunomodulatory mechanisms, good safety profile and oral biovailabalility, statins represent a promising therapeutic approach for multiple sclerosis and other chronic inflammatory diseases.”
Along the lines of this study by Zhang and colleagues, FOCUS Immunology is prepared to provide state-of-the-art services for pharmacodynamic (PD) analyses of immuno-modulatory compounds under GLP conditions.
If you are interested in learning more or in discussing your specific experimental needs, please feel free to contact Dr. Eddy Bruyns, Head of FOCUS Immunology Laboratory via e-mail eddy.bruyns@focus-cdd.com or via telephone +49 6221 64935124.
Source
Zhang et al.
Simvastatin Inhibits IL-17 Secretion by Targeting Multiple IL-17-Regulatory Cytokines and by Inhibiting the Expression of IL-17 Transcription Factor RORC in CD4+ Lymphocytes
The Journal of Immunology 2008; 180; 6988-6996
Hyperactivation of the immune system can lead to tissue destruction and auto-immunity. Therefore, the amplitude and duration of immune responses after antigenic and cytokine signaling are regulated in a feedback manner.
So-called “Suppressors of Cytokine Signaling (SOCS)” are important molecular players in this negative feedback regulation. 7 members of the SOCS molecular family have been described so-far. The SOCS family members 1 and 3 are of particular importance, since they are involved in adaptive and innate immune responses.
SOCS-1 and -3 are induced by LPS stimulation via the Toll-like Receptor-4 (TLR-4). While SOCS-1 directly targets the downstream signaling molecules of TLR4, SOCS-3 regulates the secondary effects of many LPS-induced cytokines. E.g. IL-1R signalling pathways are negatively regulated by SOCS-3.
In adaptive immune responses SOCS-1 and -3 play a role in the regulation of T cell activation, proliferation and diferentiation.
Recently, SOCS molecules were found to be central elements in the pharmacodynamics of the immuno-modulatory compound simvastatin and probiotic lactobacilli.
FOCUS Immunology is prepared to provide state-of-the-art services for pharmacodynamic (PD) studies for immunomodulatory compounds under GLP conditions. This includes studies on the regulation of intra- and extracellular mediators of inflammationand immunity.
If you are interested in learning more about FOCUS Immunology’s experience and offers or if you want to discuss your specific experimental needs, please feel free to contact Dr. Eddy Bruyns, Head of FOCUS Immunology Laboratory via e-mail eddy.bruyns@focus-cdd.com or via telephone +49 6221 64935124.
Source
Dimitriou et al.
Putting out the fire: coordinated suppression of the innate and adaptive immune systems by SOCS1 and SOCS3 proteins
Immunological reviews 2008, Vol. 224: 265-283
More information on SOCS1: Wikipedia on SOCS1
More information on SOCS3: Wikipedia on SOCS3
Modern flow cytometric methods allow the simultaneous detection of more than one fluorescent dye, this is termed “Multicolor flow cytometry”.
Thus, multicolor flow cytometry is a technology platform to gather detailed information on specific cells within a mixed population or on different parameters at the single cell level. This is especially relevant to maximize data generation from small or limited samples.
FOCUS Biomarker offers Multicolor Flow Cytometry to analyse immune cell parameters in clinical trials under GLP conditions. Together with our expertise in standardized cell sample generation and transportation as well as GLP-compliant assay development we offer this interesting technology for biomarker determination. This will enhance the assessment of PD aspects in early and late clinical trials with immuno-modulatory or anti-inflammatory drugs.
FOCUS Immunology laboratory is part of the Clinical Research Organisation (CRO) FOCUS-CDD GmbH. FOCUS Immunology provides immunological biomarker services under GLP and non-GLP conditions for the development of novel medicines.
Tuesday, August 10, 2010
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