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Zytokinneutralisierung an spezifischen zellulären Quellen

Ein neues Therapiemodell?

Cytokine neutralization at specific cellular source

A new therapeutic paradigm? German Version

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Zusammenfassung

Hintergrund

Gegenwärtig basiert die Behandlung von Autoimmunerkrankungen auf der Beeinflussung allgemeiner Kontrollmechanismen, einschließlich derer, die durch immunregulatorische Zytokine vermittelt werden. Dieser Ansatz ist nicht kurativ und kann unerwünschte Nebenwirkungen haben, da die einzelnen Zytokine jeweils zahlreiche nutzbringende Funktionen haben, die nicht redundant sind, d. h., nicht von anderen Zytokinen übernommen werden können.

Methoden

Mithilfe von Verfahren der reversen Genetik, wie der gezielten konditionalen Genmodifikation, wurde die Rolle von zwei proinflammatorischen und immunmodulatorischen Zytokinen – dem Tumornekrosefaktor (TNF) und Interleukin-6 (IL-6) – bei verschiedenen Erkrankungszuständen untersucht.

Ergebnisse

Mehrere nichtredundante Funktionen von TNF aus unterschiedlichen zellulären Quellen wurden ermittelt. TNF aus myeloischen Zellen spielt eine pathogene Rolle bei verschiedenen Autoimmunerkrankungen, während TNF aus T‑Zellen bei experimenteller Arthritis und in einem Mycobacterium-tuberculosis-Infektionsmodell nichtredundante Schutzfunktionen hat. Um die Idee einer selektiven medikamentösen Hemmung von „schlechtem“ TNF aus myeloischen Zellen bei Bewahrung des „guten“ TNF aus T‑Lymphozyten zu testen, wurde ein myeloidspezifischer TNF-Inhibitor (MYSTI) hergestellt, ein rekombinanter Miniantikörper mit dualer Spezifität, der das Oberflächenmolekül F4/80 auf myeloischen Zellen und das Zytokin TNF binden kann. In-vitro-Experimente bestätigten, dass TNF an der Oberfläche von TNF-bildenden Zellen festgehalten wird. Wie In-vivo-Experimente zeigen, kann MYSTI Mäuse vor einer letalen TNF-vermittelten Hepatotoxizität schützen. Wirksam ist MYSTI auch bei experimenteller Arthritis.

Schlussfolgerung

Die vorgeschlagene Therapiestrategie könnte bei verschiedenen Autoimmunerkrankungen des Menschen wirksamer sein als eine systemische Antizytokintherapie, da sie die potenziell positiven Effekte desselben Zytokins aus anderen zellulären Quellen bewahren würde. Bispezifische Biologika wie MYSTI könnten zu einem interessanten Werkzeug für experimentelle Studien werden und letztlich auch Einzug in die Medikamentenentwicklung halten.

Abstract

Background

Currently, treatment of autoimmune diseases is based on manipulation of general control mechanisms, including those mediated by immunoregulatory cytokines. This approach is non-curative and may cause unwanted side effects due to numerous beneficial and non-redundant functions of a particular cytokine.

Methods

Techniques of reverse genetics, such as conditional gene targeting, were employed to uncover the contributions of two proinflammatory and immunomodulatory cytokines, tumour necrosis factor (TNF) and interleukin 6 (IL-6), in various disease states.

Results

Several non-redundant functions of TNF from distinct cellular sources were identified. TNF from myeloid cells is pathogenic in several autoimmune diseases, whereas TNF produced by T cells showed non-redundant protective functions in experimental arthritis and in a Mycobacterium tuberculosis infection model. To test the idea of selective pharmacological inhibition of “bad” TNF produced by myeloid cells while sparing “good” TNF produced by T lymphocytes, a myeloid-specific TNF inhibitor (MYSTI) was designed – a recombinant mini-antibody with dual specificity that can bind to the surface molecule F4/80 on myeloid cells and to TNF. In vitro experiments confirmed retention of TNF on the surface of TNF-producing cells and in vivo experiments indicated that MYSTI can protect mice from lethal TNF-mediated hepatotoxicity. MYSTI is also effective in experimental arthritis.

Conclusion

The proposed therapeutic strategy may be more effective than systemic anti-cytokine therapy in several human autoimmune diseases, as it would preserve the potentially beneficial effects of the same cytokine produced by other cell types. Such bispecific biological agents may become interesting tools for experimental studies and, eventually, drug development.

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Danksagung

Finanziell unterstützt von der Deutschen Forschungsgemeinschaft (Förderkennzeichen NE-14622/1) und der Russian Science Foundation (Förderkennzeichen #14-25-00160).

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Authors and Affiliations

  1. Institut der Leibniz-Gemeinschaft, Deutsches Rheuma-Forschungszentrum Berlin (DRFZ), Chariteplatz 1, 10117, Berlin, Deutschland

    A. A. Kruglov & S. A. Nedospasov

  2. Engelhardt Institute of Molecular Biology and Lomonosov Moscow State University, 119991, Moskau, Russland

    A. A. Kruglov & S. A. Nedospasov

Authors
  1. A. A. Kruglov
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  2. S. A. Nedospasov
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Correspondence to S. A. Nedospasov.

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Interessenkonflikt

A.A. Kruglov und S.A. Nedospasov geben an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.

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A. Radbruch, Berlin

H. Schulze-Koops, München

R.E. Schmidt, Hannover

U. Wagner, Leipzig

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Kruglov, A.A., Nedospasov, S.A. Zytokinneutralisierung an spezifischen zellulären Quellen. Z Rheumatol 76, 163–165 (2017). https://doi.org/10.1007/s00393-016-0244-6

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  • DOI: https://doi.org/10.1007/s00393-016-0244-6

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