Kotschenreuther, Konstantin ORCID: 0000-0001-9455-2444 (2026). Influence of the Cannabinoids Anandamide and Cannabidiol on Cytokine Production by CD4+ T Cells and Th17 Differentiation in Patients with Rheumatoid Arthritis. PhD thesis, Universität zu Köln.

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Abstract

This work is based on investigations into the effects of cannabinoids such as cannabidiol (CBD) and anandamide (AEA) on phenotypic changes in cluster of differentiation 4-positive (CD4+) T cells from patients suffering from rheumatic autoimmune diseases, particularly rheumatoid arthritis (RA). Cannabinoids such as CBD are becoming increasingly prevalent in society and are often recommended for the treatment of various conditions, including RA. This is further underscored by the new German Cannabis Act (CanG), which regulates the handling of cannabis as of April 1, 2024, and, among other changes, eased access to medicinal cannabis. This is expected to further increase public acceptance and unsupervised use of cannabis and its derivatives. Additionally, the anticipated analgesic properties of CBD have led to increased use among RA patients seeking alternatives or supplements to their existing pain management plans. Given this growing prevalence of CBD use, often without medical supervision, it is clear that a better understanding of the full spectrum of CBD effects is necessary. Only in this way can patients be adequately informed about the benefits and risks associated with incorporating CBD into their existing medication plans. Alongside the increasing prevalence of cannabinoid use, our understanding of RA as a disease is also advancing. While the focus of RA research was initially on T helper 1 (Th1) cells, T helper 17 (Th17) cells and their interplay with regulatory T (Treg) cells are gaining importance as potential key players in the pathogenesis of RA. This enables a more precise investigation of potential therapeutics like CBD and their effects on RA-specific pathomechanisms. Our knowledge regarding the influence of CBD on Th17 cells and its significance in the context of RA is still incomplete. The aim of this work is to gain a deeper understanding of the effects of cannabinoids on Th17 differentiation and Interleukin-17A (IL-17A) positivity. With this objective, comprehensive in vitro studies were conducted to establish direct relationships between cannabinoid exposure and CD4+ T cell properties. Analysis of cannabinoid receptors 1 and 2 (CB1, CB2) showed no significant differences between RA patients and healthy controls, though a notable trend toward increased G-protein coupled receptor 55 (GPR55) expression was observed in RA and psoriatic arthritis patients. The results demonstrate that CBD significantly reduced CD4+ T cell viability while paradoxically increasing the proportion of IL-17A-positive cells, particularly in RA patients. This effect persisted even under Th17-polarizing conditions. Gene expression analysis revealed that CBD significantly upregulated serum glucocorticoid-regulated kinase 1 (SGK1) while downregulating colony stimulating factor 2 (CSF2) in RA patients, suggesting complex modulation of inflammation-related pathways. Despite increased cellular IL-17A positivity, ELISA analysis showed reduced secretion of IL-17A, interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α) in culture supernatants, potentially due to the substantial cytotoxic effects observed. Importantly, preliminary observational data from patients self-reporting non-standardized CBD use showed both increased IL-17A-positive CD4+ T cell percentages and elevated disease activity scores, aligning with our in vitro findings. Although CBD was able to reduce TNF-α- and IFN-γ-positive CD4+ T cells, our understanding of RA as an increasingly Th17 cell-mediated disease suggests that CBD use in RA patients could be detrimental from an autoimmunity perspective. This is primarily due to the finding that CBD led to an increased proportion of IL-17A-positive cells among CD4+ T cells, which should be taken into account when considering recommending CBD as a therapy supplement. However, further studies are required to understand the mechanism of action leading to the effects observed here. In vivo mouse studies should also be conducted to better understand the effects of CBD consumption in relation to the multiple and complex interactions within the body. It is also essential to analyze the extent to which the in vitro results presented here can be translated directly to patients given the high doses of CBD used in these experiments. So far, the data is not sufficient to unreservedly recommend CBD as a treatment approach for RA patients. Further studies are necessary to evaluate the potential and risks of cannabinoids in RA therapy and to make a recommendation for RA therapy.

Item Type: Thesis (PhD thesis)
Translated abstract:
Abstract
Language
Diese Arbeit basiert auf Untersuchungen zu den Auswirkungen der Cannabinoide Cannabidiol (CBD) und Anandamid (AEA) auf phänotypische Veränderungen in Cluster of Differentiation 4-positiven (CD4+) T-Zellen von Patienten, die an rheumatischen Autoimmunerkrankungen, insbesondere rheumatoider Arthritis (RA), leiden. Cannabinoide wie CBD werden in der Gesellschaft immer präsenter und oft pauschal zur Behandlung verschiedener Erkrankungen, einschließlich der RA, empfohlen. Dies wird durch das neue Cannabisgesetz (CanG) unterstrichen, das zum 1. April 2024 den Umgang mit Cannabis in Deutschland neu regelte und unter anderem den Zugang zu medizinischem Cannabis erleichterte. Hierdurch ist eine weitere Zunahme der Akzeptanz und des Konsums von Cannabis und Cannabisderivaten ohne medizinische Aufsicht zu erwarten. Zusätzlich haben die erhofften analgetischen Eigenschaften von CBD zu einer vermehrten Nutzung unter RA-Patienten geführt, die nach Alternativen oder Ergänzungen zu ihrer bestehenden Schmerzmedikation suchen. Angesichts dieser zunehmenden Verbreitung der CBD-Nutzung, oft ohne medizinische Aufsicht, ist es klar, dass ein besseres Verständnis des gesamten Spektrums der CBD-Effekte notwendig ist. Nur so können Patienten ausreichend über die Vorteile und Risiken informiert werden, die mit der Aufnahme von CBD in ihre bestehenden Medikationspläne einhergehen. Neben der zunehmenden Verbreitung des Cannabinoidkonsums schreitet auch unser Verständnis der RA als Krankheit voran. Während der Schwerpunkt der RA-Forschung ursprünglich auf T-Helfer 1 (Th1)-Zellen lag, gewinnen T-Helfer 17 (Th17)-Zellen und ihr Zusammenspiel mit regulatorischen T (Treg)-Zellen als mögliche zentrale Akteure in der Pathogenese der RA an Bedeutung. Dies ermöglicht eine präzisere Untersuchung potenzieller Therapeutika wie CBD und deren Auswirkungen auf RA-spezifische Pathomechanismen. Unser Wissen über den Einfluss von CBD auf Th17-Zellen und dessen Bedeutung im Kontext der RA ist noch unvollständig. Ziel dieser Arbeit ist es, ein tieferes Verständnis der Auswirkungen von den Cannabinoiden CBD und AEA auf die Th17-Differenzierung und Interleukin-17A (IL-17A) Positivität zu erlangen. Mit diesem Ziel wurden umfassende in vitro Studien durchgeführt, um direkte Zusammenhänge zwischen Cannabinoidexposition und CD4+ T-Zell-Eigenschaften herzustellen. Die Analyse von Cannabinoid-Rezeptoren 1 und 2 (CB1, CB2) sowie des G-Protein-gekoppelten Rezeptors 55 (GPR55) zeigte keine signifikanten Unterschiede zwischen RA-Patienten und gesunden Kontrollen, obwohl eine bemerkenswerte Tendenz zu erhöhter GPR55 Expression bei RA- und Psoriasis-Arthritis-Patienten beobachtet wurde. Die Ergebnisse zeigen, dass CBD die Lebensfähigkeit von CD4+ T-Zellen signifikant reduzierte, während paradoxerweise der Anteil IL-17A-positiver Zellen, insbesondere bei RA-Patienten, erhöht wurde. Dieser Effekt blieb auch unter Th17-polarisierenden Bedingungen bestehen. Die Genexpressionsanalyse zeigte, dass CBD bei RA-Patienten Serum-Glucocorticoid-Kinase 1 (SGK1) signifikant hochregulierte und Kolonie-stimulierenden Faktor 2 (CSF2) herunterregulierte, was auf eine komplexe Modulation entzündungsbezogener Signalwege hindeutet. Trotz erhöhter zellulärer IL-17A-Positivität zeigte die ELISA-Analyse eine reduzierte Sekretion von IL-17A, Interferon-Gamma (IFN-γ) und Tumornekrosefaktor-alpha (TNF-α) im Zellkulturmedium, möglicherweise aufgrund der beobachteten erheblichen zytotoxischen Effekte. Vorläufige klinische Beobachtungen von Patienten, die über nicht-standardisierten eigenen CBD-Konsum berichteten, zeigten sowohl einen Anstieg des Anteils IL-17A-positiver CD4+ T-Zellen als auch erhöhte Krankheitsaktivitätswerte, was mit unseren in vitro Ergebnissen übereinstimmt. Obwohl CBD gleichzeitig den Anteil an TNF-α und IFN-γ positiven CD4+ Zellen reduzieren konnte, deutet unser erweitertes Verständnis der RA als eine überwiegend von Th17-Zellen vermittelte Erkrankung darauf hin, dass der Konsum von CBD bei RA-Patienten aus Sicht der Autoimmunität nachteilig sein könnte. Diese Vermutung ist hauptsächlich auf die Erkenntnis zurückzuführen, dass CBD zu einem erhöhten Anteil an IL-17A-positiver Zellen unter CD4+ T-Zellen geführt hat, was bei der Empfehlung von CBD als Therapieergänzung berücksichtigt werden sollte. Allerdings sind weitere Studien erforderlich, um den Wirkmechanismus, der zu den hier beobachteten Effekten führt, zu verstehen. Zusätzlich sollten In-vivo-Mäusestudien durchgeführt werden, um die Auswirkungen des CBD-Konsums im Hinblick auf die vielfältigen und komplexen Wechselwirkungen im Körper besser zu verstehen. Außerdem ist es wichtig zu analysieren, inwieweit sich die hier dargestellten in vitro Ergebnisse direkt auf Patienten übertragen lassen, da in diesen Experimenten hohe Dosen von CBD verwendet wurden. Bisher scheinen die Daten nicht ausreichend zu sein, um CBD uneingeschränkt als Behandlungsansatz für RA-Patienten zu empfehlen. In Zukunft sind weitere Studien notwendig, um das Potenzial und die Risiken von Cannabinoiden in der RA-Therapie zu bewerten und eine Empfehlung für die RA-Therapie auszusprechen.
German
Creators:
Creators
Email
ORCID
ORCID Put Code
Kotschenreuther, Konstantin
kkotsche1@gmail.com
https://orcid.org/0000-0001-9455-2444
UNSPECIFIED
URN: urn:nbn:de:hbz:38-791104
Date: 2026
Language: English
Faculty: Faculty of Medicine
Divisions: Faculty of Medicine > Innere Medizin > Klinik I für Innere Medizin - Hämatologie und Onkologie
Subjects: Medical sciences Medicine
Uncontrolled Keywords:
Keywords
Language
Rheumatoid Arthritis
English
Cannabinoids
English
Cannabidiol
English
Date of oral exam: 5 December 2025
Referee:
Name
Academic Title
Stripecke, R.
Universitätsprofessorin Dr. rer. nat. hab.
Kofler, D. M. G.
Professor Dr. med.
Related URLs:
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Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/79110

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