Skip to main content
Erschienen in: Journal of Clinical Immunology 4/2011

01.08.2011

Combined Treatment of Etanercept and MTX Reverses Th1/Th2, Th17/Treg Imbalance in Patients with Rheumatoid Arthritis

verfasst von: Chen Lina, Wang Conghua, Leng Nan, Zhu Ping

Erschienen in: Journal of Clinical Immunology | Ausgabe 4/2011

Einloggen, um Zugang zu erhalten

Abstract

Objective

To explore the mechanism of Etanercept in the treatment of rheumatoid arthritis (RA), we investigated whether the Th1/Th2 and Th17/regulatory T cells (Treg) imbalance could be reversed by Etanercept and whether the reversal was related to the improvement of clinical indications.

Methods

We conducted a 12-week study in 40 active RA patients, of whom 20 were given a stable weekly dose of methotrexate (MTX) alone and the other ten received a combined therapy of Etanercept and MTX. Ten healthy donors were chosen as controls. Frequencies of Th1, Th2, Th17, and Treg were quantified using flow cytometry, and related serum cytokines were detected by enzyme-linked immunosorbent assay. The composite 28-joint count Disease Activity Score, erythrocyte sedimentation rate, and C-reactive protein were assessed at each visit.

Results

Percentages of IFN-γ+Th1 and IL-17+Th17 among CD4+ T cells were significantly higher, while CD4+CD25highFoxp3+ Treg were significantly lower in RA patients compared with those in healthy control. After 12 weeks of therapy of MTX single or combination of MTX and Etanercept, the circulating Th17/Treg ratio significantly decreased, while no significant difference was observed in Th1/Th2 ratio. In combined therapy group, the Th17/Treg ratio was positively correlated with the remittance of disease activity. IL-1β, TNF-α, IL-6, IL-17, and IL-23 were significantly decreased, while TGF-β was significantly elevated. The Th17/Treg ratio was positively related to TGF-β, but negatively correlated with IL-6.

Conclusion

Etanercept in combination with MTX ameliorates RA activity by normalizing the distribution of Th17 and Treg, and their related cytokines, which may partly explain the mechanism of combined therapy of Etanercept plus MTX in RA treatment.
Literatur
1.
Zurück zum Zitat Weyand CM, Goronzy JJ. Pathogenesis of rheumatoid arthritis. Med Clin North Am. 1997;81:29–55.PubMedCrossRef Weyand CM, Goronzy JJ. Pathogenesis of rheumatoid arthritis. Med Clin North Am. 1997;81:29–55.PubMedCrossRef
2.
Zurück zum Zitat Hirota K, Hashimoto M, Yoshitomi H, Tanaka S, Nomura T, Yamaguchi T, et al. T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis. J Exp Med. 2007;204:41–7.PubMedCrossRef Hirota K, Hashimoto M, Yoshitomi H, Tanaka S, Nomura T, Yamaguchi T, et al. T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis. J Exp Med. 2007;204:41–7.PubMedCrossRef
3.
Zurück zum Zitat Nissinen R, Leirisalo-Repo M, Tiittanen M, Julkunen H, Hirvonen H, Palosuo T, et al. CCR3, CCR5, interleukin 4, and interferon-gamma expression on synovial and peripheral T cells and monocytes in patients with rheumatoid arthritis. J Rheumatol. 2003;30:1928–34.PubMed Nissinen R, Leirisalo-Repo M, Tiittanen M, Julkunen H, Hirvonen H, Palosuo T, et al. CCR3, CCR5, interleukin 4, and interferon-gamma expression on synovial and peripheral T cells and monocytes in patients with rheumatoid arthritis. J Rheumatol. 2003;30:1928–34.PubMed
4.
Zurück zum Zitat Boissier M-C, Assier E, Falgarone G, Bessis N. Shifting the imbalance from Th1/Th2 to Th17/treg: the changing rheumatoid arthritis paradigm. Joint Bone Spine. 2008;75:373–5.PubMedCrossRef Boissier M-C, Assier E, Falgarone G, Bessis N. Shifting the imbalance from Th1/Th2 to Th17/treg: the changing rheumatoid arthritis paradigm. Joint Bone Spine. 2008;75:373–5.PubMedCrossRef
5.
Zurück zum Zitat Sakaguchi S, Ono M, Setoguchi R, Yagi H, Hori S, Fehervari Z, et al. Foxp3 + CD25 + CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev. 2006;212:8–27.PubMedCrossRef Sakaguchi S, Ono M, Setoguchi R, Yagi H, Hori S, Fehervari Z, et al. Foxp3 + CD25 + CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev. 2006;212:8–27.PubMedCrossRef
6.
Zurück zum Zitat Bettelli E, Oukka M, Kuchroo VK. T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol. 2007;8:345–50.PubMedCrossRef Bettelli E, Oukka M, Kuchroo VK. T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol. 2007;8:345–50.PubMedCrossRef
7.
Zurück zum Zitat Afzali B, Lombardi G, Lechler RI, Lord GM. The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease. Clin Exp Immunol. 2007;148:32–46.PubMedCrossRef Afzali B, Lombardi G, Lechler RI, Lord GM. The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease. Clin Exp Immunol. 2007;148:32–46.PubMedCrossRef
8.
Zurück zum Zitat Carmona L, Gomez-Reino JJ. Survival of TNF antagonists in spondylarthritis is better than in rheumatoid arthritis. Arthritis Res Ther. 2006;8:R72.PubMedCrossRef Carmona L, Gomez-Reino JJ. Survival of TNF antagonists in spondylarthritis is better than in rheumatoid arthritis. Arthritis Res Ther. 2006;8:R72.PubMedCrossRef
9.
Zurück zum Zitat Nistala K, Wedderburn LR. Th17 and regulatory T cells: rebalancing pro- and anti-inflammatory forces in autoimmune arthritis. Rheumatology. 2009;10:1093–8. Nistala K, Wedderburn LR. Th17 and regulatory T cells: rebalancing pro- and anti-inflammatory forces in autoimmune arthritis. Rheumatology. 2009;10:1093–8.
10.
Zurück zum Zitat Ma HL, Napierate L, Stedman N. Tumor necrosis factor alpha blockade exacerbates murine psoriasis-like disease by enhancing Th17 function and decreasing expansion of Treg cells. Arthritis Rheum. 2010;62(2):430–40.PubMedCrossRef Ma HL, Napierate L, Stedman N. Tumor necrosis factor alpha blockade exacerbates murine psoriasis-like disease by enhancing Th17 function and decreasing expansion of Treg cells. Arthritis Rheum. 2010;62(2):430–40.PubMedCrossRef
11.
Zurück zum Zitat Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315–24.PubMedCrossRef Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315–24.PubMedCrossRef
12.
Zurück zum Zitat McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007;7:429–42.PubMedCrossRef McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007;7:429–42.PubMedCrossRef
13.
Zurück zum Zitat Steinman L. A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat Med. 2007;13:139–45.PubMedCrossRef Steinman L. A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nat Med. 2007;13:139–45.PubMedCrossRef
14.
Zurück zum Zitat Raza K, Falciani F, Curnow SJ, et al. Early rheumatoid arthritis is characerized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin. Arthritis Res Ther. 2005;7:R784–95.PubMedCrossRef Raza K, Falciani F, Curnow SJ, et al. Early rheumatoid arthritis is characerized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin. Arthritis Res Ther. 2005;7:R784–95.PubMedCrossRef
15.
Zurück zum Zitat Wilson NJ, Boniface K, Chan JR, et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol. 2007;8:950–7.PubMedCrossRef Wilson NJ, Boniface K, Chan JR, et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol. 2007;8:950–7.PubMedCrossRef
16.
Zurück zum Zitat Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, et al. Interleukins 1 beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol. 2007;8:942–9.PubMedCrossRef Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, et al. Interleukins 1 beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol. 2007;8:942–9.PubMedCrossRef
17.
Zurück zum Zitat Kageyama Y, Ichikawa T, Nagafusa T, Torikai E, Shimazu M, Nagano A. Etanercept reduces the serum levels of interleukin-23 and macrophage inflammatory protein-3 alpha in patients with rheumatoid arthritis. Rheumatol Int. 2007;28:137–43.PubMedCrossRef Kageyama Y, Ichikawa T, Nagafusa T, Torikai E, Shimazu M, Nagano A. Etanercept reduces the serum levels of interleukin-23 and macrophage inflammatory protein-3 alpha in patients with rheumatoid arthritis. Rheumatol Int. 2007;28:137–43.PubMedCrossRef
18.
Zurück zum Zitat Ehrenstein MR, Evans JG, Singh A, Moore S, Warnes G, Isenberg DA, et al. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFα therapy. J Exp Med. 2004;200:277–85.PubMedCrossRef Ehrenstein MR, Evans JG, Singh A, Moore S, Warnes G, Isenberg DA, et al. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFα therapy. J Exp Med. 2004;200:277–85.PubMedCrossRef
19.
Zurück zum Zitat Valencia X, Stephens G, Goldbach-Mansky R, Wilson M, Shevach EM, Lipsky PE. TNF downmodulates the function of human CD4 + CD25high T-regulatory cells. Blood. 2006;108:253–61.PubMedCrossRef Valencia X, Stephens G, Goldbach-Mansky R, Wilson M, Shevach EM, Lipsky PE. TNF downmodulates the function of human CD4 + CD25high T-regulatory cells. Blood. 2006;108:253–61.PubMedCrossRef
20.
Zurück zum Zitat Cutolo M, Sulli A, Pizzorni C, Seriolo B, Straub RH. Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis. Ann Rheum Dis. 2001;60(8):729–35.PubMedCrossRef Cutolo M, Sulli A, Pizzorni C, Seriolo B, Straub RH. Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis. Ann Rheum Dis. 2001;60(8):729–35.PubMedCrossRef
21.
Zurück zum Zitat Papagoras C, Voulgari PV, Drosos AA. Strategies after the failure of the first anti-tumor necrosis factor alpha agent in rheumatoid arthritis. Autoimmun Rev. 2010;9:574–82.PubMedCrossRef Papagoras C, Voulgari PV, Drosos AA. Strategies after the failure of the first anti-tumor necrosis factor alpha agent in rheumatoid arthritis. Autoimmun Rev. 2010;9:574–82.PubMedCrossRef
22.
Zurück zum Zitat Pascual-Salcedo D, Plasencia C, Ramiro S, Nuño L, Bonilla G, Nagore D, Ruiz Del Agua A, Martínez A, Aarden L, Martín-Mola E, Balsa A.(2011) Influence of immunogenicity on the efficacy of long-term treatment with infliximab in rheumatoid arthritis. Rheumatology (Oxford) [in press]. Pascual-Salcedo D, Plasencia C, Ramiro S, Nuño L, Bonilla G, Nagore D, Ruiz Del Agua A, Martínez A, Aarden L, Martín-Mola E, Balsa A.(2011) Influence of immunogenicity on the efficacy of long-term treatment with infliximab in rheumatoid arthritis. Rheumatology (Oxford) [in press].
23.
Zurück zum Zitat Sarin A, Conan-Cibotti M, Henkart PA. Cyto-toxic effect of TNF and lymphotoxin on T lymphoblasts. J Immunol. 1995;155:3716–8.PubMed Sarin A, Conan-Cibotti M, Henkart PA. Cyto-toxic effect of TNF and lymphotoxin on T lymphoblasts. J Immunol. 1995;155:3716–8.PubMed
24.
Zurück zum Zitat Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006;126:1121–33.PubMedCrossRef Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006;126:1121–33.PubMedCrossRef
25.
Zurück zum Zitat Paradowska A, Maslinski W, Grzybowska-Kowalczyk A, Lacki J. The function of interleukin 17 in the pathogenesis of rheumatoid arthritis. Arch Immunol Ther Exp. 2007;55:329–34.CrossRef Paradowska A, Maslinski W, Grzybowska-Kowalczyk A, Lacki J. The function of interleukin 17 in the pathogenesis of rheumatoid arthritis. Arch Immunol Ther Exp. 2007;55:329–34.CrossRef
26.
Zurück zum Zitat Goldberg M, Nadiv O, Luknar-Gabor N, Agar G, Beer Y, Katz Y. Synergism between tumor necrosis factor alpha and interleukin-17 to induce IL-23 p19 expression in fibroblast-like synoviocytes. Mol Immunol. 2009;55:1854–9.CrossRef Goldberg M, Nadiv O, Luknar-Gabor N, Agar G, Beer Y, Katz Y. Synergism between tumor necrosis factor alpha and interleukin-17 to induce IL-23 p19 expression in fibroblast-like synoviocytes. Mol Immunol. 2009;55:1854–9.CrossRef
27.
Zurück zum Zitat Weischer M, Rocken M, Berneburg M. Calcineurin inhibitors and rapamycin: cancer protection or promotion? Exp Dermatol. 2007;16:385–93.PubMedCrossRef Weischer M, Rocken M, Berneburg M. Calcineurin inhibitors and rapamycin: cancer protection or promotion? Exp Dermatol. 2007;16:385–93.PubMedCrossRef
28.
Zurück zum Zitat Kehlen A, Pachnio A, Thiele K, Langner J. Gene expression induced by interleukin-17 in fibroblast-like synoviocytes of patients with rheumatoid arthritis: upregulation of hyaluronan-binding protein TSG-6. Arthritis Res Ther. 2003;5:R186–92.PubMedCrossRef Kehlen A, Pachnio A, Thiele K, Langner J. Gene expression induced by interleukin-17 in fibroblast-like synoviocytes of patients with rheumatoid arthritis: upregulation of hyaluronan-binding protein TSG-6. Arthritis Res Ther. 2003;5:R186–92.PubMedCrossRef
29.
Zurück zum Zitat Zhou L, Lopes JE, Chong MM, Ivanov II, Min R, Victora GD, et al. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature. 2008;453:236–40.PubMedCrossRef Zhou L, Lopes JE, Chong MM, Ivanov II, Min R, Victora GD, et al. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature. 2008;453:236–40.PubMedCrossRef
30.
Zurück zum Zitat Ichiyama K, Yoshida H, Wakabayashi Y, Chinen T, Saeki K, Nakaya M, et al. Foxp3 inhibits ROR{gamma}t-mediated IL-17A mRNA transcription through direct interaction with ROR{gamma}t. J Biol Chem. 2008;283:17003–8.PubMedCrossRef Ichiyama K, Yoshida H, Wakabayashi Y, Chinen T, Saeki K, Nakaya M, et al. Foxp3 inhibits ROR{gamma}t-mediated IL-17A mRNA transcription through direct interaction with ROR{gamma}t. J Biol Chem. 2008;283:17003–8.PubMedCrossRef
31.
Zurück zum Zitat Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441:235–8.PubMedCrossRef Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441:235–8.PubMedCrossRef
Metadaten
Titel
Combined Treatment of Etanercept and MTX Reverses Th1/Th2, Th17/Treg Imbalance in Patients with Rheumatoid Arthritis
verfasst von
Chen Lina
Wang Conghua
Leng Nan
Zhu Ping
Publikationsdatum
01.08.2011
Verlag
Springer US
Erschienen in
Journal of Clinical Immunology / Ausgabe 4/2011
Print ISSN: 0271-9142
Elektronische ISSN: 1573-2592
DOI
https://doi.org/10.1007/s10875-011-9542-6

Weitere Artikel der Ausgabe 4/2011

Journal of Clinical Immunology 4/2011 Zur Ausgabe

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Echinokokkose medikamentös behandeln oder operieren?

06.05.2024 DCK 2024 Kongressbericht

Die Therapie von Echinokokkosen sollte immer in spezialisierten Zentren erfolgen. Eine symptomlose Echinokokkose kann – egal ob von Hunde- oder Fuchsbandwurm ausgelöst – konservativ erfolgen. Wenn eine Op. nötig ist, kann es sinnvoll sein, vorher Zysten zu leeren und zu desinfizieren. 

Umsetzung der POMGAT-Leitlinie läuft

03.05.2024 DCK 2024 Kongressbericht

Seit November 2023 gibt es evidenzbasierte Empfehlungen zum perioperativen Management bei gastrointestinalen Tumoren (POMGAT) auf S3-Niveau. Vieles wird schon entsprechend der Empfehlungen durchgeführt. Wo es im Alltag noch hapert, zeigt eine Umfrage in einem Klinikverbund.

Proximale Humerusfraktur: Auch 100-Jährige operieren?

01.05.2024 DCK 2024 Kongressbericht

Mit dem demographischen Wandel versorgt auch die Chirurgie immer mehr betagte Menschen. Von Entwicklungen wie Fast-Track können auch ältere Menschen profitieren und bei proximaler Humerusfraktur können selbst manche 100-Jährige noch sicher operiert werden.

Die „Zehn Gebote“ des Endokarditis-Managements

30.04.2024 Endokarditis Leitlinie kompakt

Worauf kommt es beim Management von Personen mit infektiöser Endokarditis an? Eine Kardiologin und ein Kardiologe fassen die zehn wichtigsten Punkte der neuen ESC-Leitlinie zusammen.

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.