Regulatory T cell frequencies in patients with rheumatoid arthritis are increased by conventional and biological DMARDs but not by JAK inhibitors

Meyer, Anja; Wittekind, Paula S.; Kotschenreuther, Konstantin; Schiller, Joanna; Tresckow, Julia von; Haak, Thomas H; Kofler, David M.

doi:10.1136/annrheumdis-2019-216576

Cited by 30 publications

(22 citation statements)

References 7 publications

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“…However, the role of IL-35-producing Bregs in RA is not clearly elucidated. Although the effect of several biologics used for the treatment of RA on regulatory cells has been investigated [13][14][15] , how abatacept treatment may regulate the levels of Bregs, conventional Tregs (cTregs) and unconventional Tregs (uTregs) is not largely known 16,17 . Thus, besides its direct role in suppressing T cells activation, it is crucial to assess the drug's ability to induce regulatory B and T cells as a CD28 independent mechanism of controlling chronic inflammation during RA.…”

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confidence: 99%

Abatacept enhances blood regulatory B cells of rheumatoid arthritis patients to a level that associates with disease remittance

Alenazy

Sharif-Askari

Omair

et al. 2021

Sci Rep

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Abatacept, an inhibitor of CD28 mediated T-cell activation, has been shown to be effective in controlling inflammation during rheumatoid arthritis (RA). However, its effects on immune regulatory B and T cells (Bregs and Tregs) has not been fully explored. Thirty-one RA patients treated with abatacept for ≥ 6 months along with 31 RA patients treated with other modalities as well as 30 healthy controls were recruited. Of these 62 RA patient, 49 (79%) were females with a mean age of 54 ± 12 years and disease duration of 10 ± 6 years. The blood levels of Tregs and Bregs and their production of immunosuppressive cytokines, were determined using FACS analysis and Luminex Multiplex assay. Treatment with abatacept significantly enhanced the blood level of IL-35+ IL-10+ Bregs (P = 0.0007). Their levels were higher in the blood of remitted patients (DAS28-CRP < 2.6) compared to the unremitted ones (P = 0.0173), 6 months following abatacept treatment initiation. Moreover, abatacept treatment significantly enhanced the blood levels of LAG3+ conventional and unconventional Tregs of RA patients. This increase in the blood levels of Bregs and Tregs was accompanied with an elevated serum level of IL-35 and IFN-β in abatacept-treated patients. Therefore, Abatacept efficiency to achieve remittance in RA could be attributed, in part, to its ability to enhance immune regulatory cells, especially IL-135+ IL-10+ Bregs.

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confidence: 99%

Abatacept enhances blood regulatory B cells of rheumatoid arthritis patients to a level that associates with disease remittance

Alenazy

Sharif-Askari

Omair

et al. 2021

Sci Rep

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“…In addition, Tofacitinib decreases expression levels of CD80/CD86 and thereby the T-cell stimulatory capacity of DCs through suppression of type I IFN signaling [ 209 ]. In contrast to effector T cells, Tregs appear less sensitive to Tofacitinib, as their numbers and suppressive activity are preserved upon treatment [ 206 , 210 , 211 ]. Similar to Ruxolitinib, B-cell numbers increase upon Tofacitinib treatment [ 194 , 205 , 207 ].…”

Section: The Effects Of Jakinibs On the Immune System: Focus On Cytotoxic Lymphocytesmentioning

confidence: 99%

Untwining Anti-Tumor and Immunosuppressive Effects of JAK Inhibitors—A Strategy for Hematological Malignancies?

Klein

Stoiber

Sexl

et al. 2021

Cancers

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The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway propagates signals from a variety of cytokines, contributing to cellular responses in health and disease. Gain of function mutations in JAKs or STATs are associated with malignancies, with JAK2V617F being the main driver mutation in myeloproliferative neoplasms (MPN). Therefore, inhibition of this pathway is an attractive therapeutic strategy for different types of cancer. Numerous JAK inhibitors (JAKinibs) have entered clinical trials, including the JAK1/2 inhibitor Ruxolitinib approved for the treatment of MPN. Importantly, loss of function mutations in JAK-STAT members are a cause of immune suppression or deficiencies. MPN patients undergoing Ruxolitinib treatment are more susceptible to infections and secondary malignancies. This highlights the suppressive effects of JAKinibs on immune responses, which renders them successful in the treatment of autoimmune diseases but potentially detrimental for cancer patients. Here, we review the current knowledge on the effects of JAKinibs on immune cells in the context of hematological malignancies. Furthermore, we discuss the potential use of JAKinibs for the treatment of diseases in which lymphocytes are the source of malignancies. In summary, this review underlines the necessity of a robust immune profiling to provide the best benefit for JAKinib-treated patients.

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“… 49 Similarly, Meyer et al report of a significant suppression of Th17 cell percentage following tofacitinib treatment in RA patients. 50 It seems that although some JAK inhibitors do not induce an increase in Treg frequency, they still exert a suppressive anti-inflammatory effect.…”

Section: Piks Are Involved In Autoimmune Diseases and Myeloproliferatmentioning

confidence: 99%

“… 50 It seems that although some JAK inhibitors do not induce an increase in Treg frequency, they still exert a suppressive anti-inflammatory effect.…”

Section: Piks Are Involved In Autoimmune Diseases and Myeloproliferatmentioning

confidence: 99%

The Binary Classification of Protein Kinases

Elkoshi¹

2021

JIR

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In an earlier publication a binary model for chronic diseases classification has been proposed. According to the model, chronic diseases were classified as “high Treg” or “low Treg” diseases, depending on whether the immune response is anti- or pro-inflammatory and assuming that regulatory T cells are major determinants of the response. It turned out that most cancers are “high Treg” diseases, while autoimmune diseases are “low Treg”. This paper proposes a molecular cause for this binary response. The mechanism proposed depends on the effect of protein kinases on the immune system. Thus, protein kinases are classified as anti- or pro-inflammatory kinases depending on whether they drive “high Treg” or “low Treg” diseases. Observations reported in the earlier publication can be described in terms of anti-inflammatory kinase (AIK) or pro-inflammatory kinase (PIK) activity. Analysis of literature data reveals that the two classes of kinases display distinctive properties relating to their interactions with pathogens and environmental factors. Pathogens that promote Treg activity (“high Treg” pathogens) activate AIKs, while pathogens that suppress Treg activity (“low Treg” pathogens) activate PIKs. Diseases driven by AIKs are associated with “high Treg” pathogens while those diseases driven by PIKs are associated with “low Treg” pathogens. By promoting the activity of AIKs, alcohol consumption increases the risk of “high Treg” cancers but decreases the risk of some “low Treg” autoimmune diseases. JAK1 gain-of-function mutations are observed at high frequencies in autoimmune diseases while JAK1 loss-of-function mutations are observed at high frequencies in cancers with high tumor-infiltrating Tregs. It should also be noted that the corresponding two classes of protein kinase inhibitors are mutually exclusive in terms of their approved therapeutic indications. There is no protein kinase inhibitor that is approved for the treatment of both autoimmune diseases and “high Treg” cancers. Although there are exceptions to the conclusions presented above, these conclusions are supported by the great bulk of published data. It therefore seems that the binary division of protein kinases is a useful tool for elucidating (at the molecular level) many distinctive properties of cancers and autoimmune diseases.

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Regulatory T cell frequencies in patients with rheumatoid arthritis are increased by conventional and biological DMARDs but not by JAK inhibitors

Cited by 30 publications

References 7 publications

Abatacept enhances blood regulatory B cells of rheumatoid arthritis patients to a level that associates with disease remittance

Abatacept enhances blood regulatory B cells of rheumatoid arthritis patients to a level that associates with disease remittance

Untwining Anti-Tumor and Immunosuppressive Effects of JAK Inhibitors—A Strategy for Hematological Malignancies?

The Binary Classification of Protein Kinases

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