Zusammenfassung
□ T-Zell-Antwort
T-Lymphozyten besitzen eine Schlüsselstellung in der Koordination der Immunantwort. T-Helfer-Zellen tragen dazu über die Freisetzung von Zytokinen bei, zytotoxische T-Zellen eliminieren als fremd erkannte Zellen. Über ihren T-Zell-Rezeptor erkennt jede T-Zelle ein spezifisches Peptidantigen, das ihr im Falle der T-Helfer-Zellen von antigenpräsentierenden Zellen, im Fall der zytotoxischen T-Zellen von fast allen anderen Körperzellen im Kontext von Haupthistokompatibilitätsantigenen (MHC) präsentiert wird. Durch den Antigenkontakt wird über den T-Zell-Rezeptor ein Aktivierungssignal in die Zelle hinein vermittelt, das zur Proliferation, zur Produktion von Zytokinen oder zur effektiven Zytotoxizität führt.
□ Kostimulation
Zur vollen Aktivierung ist jedoch ein zweites Signal notwendig, das der kostimulatorische Rezeptor CD28 nach Bindung seiner spezifischen Liganden B7-1 (CD80) und B7-2 (CD86) bietet. Dieselben Liganden bindet auch der Rezeptor CTLA-4 (CD152), der jedoch erst nach zwei bis drei Tagen Aktivierung an der Oberfläche von T-Zellen erscheint und durch seine Interaktion mit den B7-Molekülen in der Lage ist, die Aktivierung von T-Lymphozyten wieder herabzuregulieren.
□ Immunsuppression durch CTLA-4Ig
Ein gentechnisch hergestelltes, lösliches Fusionsprotein (CTLA-4Ig), das aus der extrazellulären Domäne von CTLA-4 und dem Fc-Teil von Immunglobulinen besteht, kann die Interaktion von CD28 und CTLA-4 mit ihren Liganden unterbinden und so im Fall unerwünschter Aktivierung des Immunsystems wie Transplantatabstoßung oder Autoimmunerkrankungen die Aktivierung von T-Lymphozyten verhindern oder reduzieren.
□ Schlußfolgerung
Die Bedeutung des regulatorischen Systems CD28/CTLA-4/B7 und der Beeinflussung durch CTLA-4Ig konnte in den letzten Jahren in einer Vielzahl von Tiermodellen gezeigt werden und verspricht einen neuartigen Ansatz zur therapeutischen Immunmodulation auch beim Menschen.
Abstract
□ T cell response
T lymphocytes play a key role in the coordination of the immune response. T helper cells contribute primarily by means of cytokine release, whereas cytotoxic T cells eliminate cells bearing antigens recognized as foreign. Through its T cell receptor each T cell can recognize a specific peptide antigen, which is presented in the context of the major histocompatibility complex (MHC) to T helper cells by specialized antigen-presenting cells or to cytotoxic T cells by nearly all body cells. Upon contact with its specific antigen, the T cell receptor transduces an activation signal into the T cell, leading to proliferation, cytokine production, or efficient cytotoxicity.
□ Costimulation
However, a second costimulatory signal is necessary to achieve complete activation. This can be provided by the accessory T cell molecule CD28 upon binding to its respective ligands B7-1 (CD80) or B7-2 (CD86). The same ligands bind to CTLA-4 (CD152), a receptor expressed at the surface of T cells previously activated for 2 to 3 days and capable of downregulating activation.
□ Immunosuppression by CTLA-4Ig
A genetically engineered soluble fusion protein containing the extracellular domain of CTLA-4 and the Fc portion of an immunoglobulin heavy chain (CTLA-4Ig) prevents the interaction of CD28 and CTLA-4 with their B7 ligands, the subsequent activation of T cells and theraby eliminates or reduces unfavorable immune system activation in transplant rejection or autoimmunity.
□ Conclusion
The importance of the regulatory system comprising CD28, CTLA-4 and the B7 molecules and its modulation by CTLA-4Ig has been demonstrated in a substantial number of animal models in recent years and holds promise as a novel approach for therapeutic immunomodulation in humans.
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Nagel, T., Kalden, J.R. & Manger, B. Regulation der T-Zell-Aktivierung über CD28 und CTLA-4. Med Klin 93, 592–597 (1998). https://doi.org/10.1007/BF03042674
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DOI: https://doi.org/10.1007/BF03042674