Methotrexate preferentially affects Tc1 and Tc17 subset of CD8 T lymphocytes

Sandhu, Amit; Ahmad, Shabeer; Kaur, Prabhdeep; Bhatnagar, Archana; Dhawan, Veena; Dhir, Varun

doi:10.1007/s10067-018-4011-8

Cited by 13 publications

(14 citation statements)

References 30 publications

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“…We further evaluated the impact of GM on the function of T M cells in terms of cytokine production including IFNγ, TNFα, IL-2, and IL-17. First, we noticed that GM untreated patients and healthy controls had a similar cytokine expression profile, which might reflect a normalization effect exerted by MTX therapy in the GM untreated group (MTX use 74.28%, Table 1); In fact, previous studies have shown a decline in CD8 + IFNγ + cells (24) and a reduction in circulating Th17 subsets after MTX treatment (25). Moreover, long-term therapy with MTX in combination with low dose corticosteroids for RA influenced the predominance of type 1 cytokines toward normalization of the cytokine balance in both CD4 + and CD8 + T lymphocytes (26).…”

Section: Discussionmentioning

confidence: 73%

Restored and Enhanced Memory T Cell Immunity in Rheumatoid Arthritis After TNFα Blocker Treatment

et al. 2019

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TNFα inhibitors have shaped the landscape of rheumatoid arthritis (RA) therapy with high clinical efficiency. However, their impact on T cell recall responses is not well-elucidated. We aimed to analyze the immune profiles of memory T cells in RA patients undergoing TNFα inhibitor Golimumab (GM) treatment. Frequencies of peripheral T cell subsets and cytokine expression profiles in memory T cells (T M ) upon PMA/Ionomycine stimulation were determined by flow cytometry. Antigen-specific CD8 T cell immunity was analyzed through stimulating PBMCs with CMV-EBV-Flu (CEF) viral peptide pool and subsequent intracellular IFNγ staining. Both peripheral CD8 and CD4 T cells from GM treated patients had a shift pattern characterized by an enlarged effector T M and a reduced central T M cell population when compared to GM untreated group. An increase in the frequencies of TNFα + , IL-2 + , and IL-17 + CD8 T M cells was observed whereas only TNFα + CD4 T M cells increased in GM treated patients. Moreover, GM treated patients contained more peripheral IFNγ-producing CD8 T cells specific to CEF viral peptides. Together, these results show a distinct T cell subset pattern and enhanced memory T cell immunity upon GM treatment, suggesting an immunoregulatory effect of TNF inhibitor Golimumab on peripheral memory T cell responses.

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Section: Discussionmentioning

confidence: 73%

Restored and Enhanced Memory T Cell Immunity in Rheumatoid Arthritis After TNFα Blocker Treatment

et al. 2019

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“…These characteristics may also account, at least in part, for the extremely favorable clinical behavior of CD8+ cytotoxic T-cell lymphoma type after methotrexate cessation. Very recently, Snadhu et al [31]. reported that methotrexate preferentially affects subsets of CD8+ T lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

Methotrexate-associated lymphoproliferative disorders of T-cell phenotype: clinicopathological analysis of 28 cases

et al. 2019

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Methotrexate-associated lymphoproliferative disorders are categorized as "other immunodeficiency-associated lymphoproliferative disorders in the WHO classification. Methotrexate-associated lymphoproliferative disorder is mainly a B-cell lymphoproliferative disorders or Hodgkin lymphoma type, whereas T-cell lymphoproliferative disorders are relatively rare (4-8%). Only a small number of methotrexate-associated T-cell lymphoproliferative disorders have been detailed thus far. Because of the rarity, methotrexate-associated T-cell lymphoproliferative disorder has not been well studied and its clinicopathological characteristics are unknown. A total of 28 cases of methotrexate-associated T-cell lymphoproliferative disorders were retrospectively analyzed. Histologically and immunohistochemically, they were divided into three main types: angioimmunoblastic T-cell lymphoma (n = 19), peripheral T-cell lymphoma, NOS (n = 6), and CD8 + cytotoxic Tcell lymphoma (n = 3). Among the 28 cases, only one CD8 + cytotoxic T-cell lymphoma case was Epstein-Barr viruspositive. The other 27 cases were negative for Epstein-Barr virus on tumor cells, but scattered Epstein-Barr virus-infected Bcells were detected in 24 cases (89%), implying the reactivation of Epstein-Barr virus caused by immunodeficient status of the patients. After the diagnosis of methotrexate-associated T-cell lymphoproliferative disorder, methotrexate was immediately withdrawn in 26 cases. Twenty (77%) cases presented with spontaneous regression. Compared to methotrexateassociated B-cell lymphoproliferative disorder, patients with methotrexate-associated T-cell lymphoproliferative disorder had a significantly higher proportion of males (p = 0.035) and presence of B-symptoms (p = 0.036), and lower proportion of Epstein-Barr virus + tumor cells (p < 0.001). Although the difference was not significant, the methotrexate-associated T-cell lymphoproliferative disorder also had more frequent spontaneous regression (p = 0.061). In conclusion, methotrexateassociated T-cell lymphoproliferative disorder was divided into three main types: angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, NOS, and CD8 + cytotoxic T-cell lymphoma. Angioimmunoblastic T-cell lymphoma was the most common type. Methotrexate-associated T-cell lymphoproliferative disorder was characterized by a high rate of spontaneous regression after methotrexate cessation. Epstein-Barr virus positivity was relatively rare in methotrexateassociated T-cell lymphoproliferative disorder, significantly less frequent than methotrexate-associated B-cell lymphoproliferative disorder, suggesting different pathogenesis.

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“…83 Dividing cytokine production into CD4 + IFN-c + (T h 1), CD4 + IL4 + (T h 2) and CD4 + IL17 + (T h 17) cells, and CD8 + IFN-c + (T c 1), CD8 + IL4 + (T c 2) and CD8 + IL17 + (T c 17) cells, MTX (up to 25 mg/week) significantly decreased the T c 1 subset and increased the T c 17 subset after 24 weeks of treatment in rheumatoid arthritis. 84 Frequencies were not altered in other subsets. Folic acid status also affects cellmediated immunity by reducing circulating T cells.…”

Section: Fae-induced Lymphopenia Linked To Infection and Influencing mentioning

confidence: 83%

“…While MTX induces apoptosis of in vitro activated T cells, it only slightly increased the risk of leukopenia in randomized controlled trials (RCTs) . Dividing cytokine production into CD4 + IFN‐γ + (T h 1), CD4 + IL4 + (T h 2) and CD4 + IL17 + (T h 17) cells, and CD8 + IFN‐γ + (T c 1), CD8 + IL4 + (T c 2) and CD8 + IL17 + (T c 17) cells, MTX (up to 25 mg/week) significantly decreased the T c 1 subset and increased the T c 17 subset after 24 weeks of treatment in rheumatoid arthritis . Frequencies were not altered in other subsets.…”

Section: Discussionmentioning

confidence: 99%

Fumaric acid ester‐induced T‐cell lymphopenia in the real‐life treatment of psoriasis

Brückner

Höxtermann

Dickel³

et al. 2019

Acad Dermatol Venereol

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Background Fumaric acid esters ( FAE s) are used to treat psoriasis and are known to cause lymphopenia in roughly 60% of the patients. Much remains to be elucidated about the biological effects of FAE s on lymphocytes. Objective To evaluate the influence of long‐term FAE (Fumaderm ® ) treatment on peripheral blood CD 4 + and CD 8 + T cells, CD 19 + B cells and CD 56 + natural killer ( NK ) cells in psoriasis. Methods In this single‐centre retrospective observational subcohort study, we obtained leucocyte and lymphocyte subset counts before initiating FAE therapy in 371 psoriasis patients (mean age, 47.8 years; 63.3% males) and monitored them during treatment (mean treatment duration, 2.9 years). Multiparametric flow cytometry was used for immunophenotyping. Results FAE s significantly reduced the numbers of CD 4 + T, CD 8 + T, CD 19 + B and CD 56 + NK cells. Among lymphocyte subsets, the mean percentage reduction from baseline was always highest for CD 8 + T cells, with a peak of 55.7% after 2 years of therapy. The risk of T‐cell lymphopenia increased significantly with the age of the psoriasis patients at the time that FAE therapy was initiated. It was significantly decreased for the combination therapy with methotrexate and folic acid (vitamin B9) supplementation. Supporting evidence was found suggesting that T‐cell lymphopenia enhances the effectiveness of FAE therapy. Conclusions Monitoring distinct T‐cell subsets rather than just absolute lymphocyte counts may provide more meaningful insights into both the FAE treatment safety and efficacy. We therefore suggest optimizing pharmacovigilance by additionally monitoring CD 4 + and CD 8 + T‐cell counts at regular intervals, especially in patients of middle to older age. Thus, further prospective studies are needed to establish evidence‐based recommendations to guide dermatologists in the management of psoriasis patients who are taking FAE s and who develop low absolute T‐cell counts.

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Methotrexate preferentially affects Tc1 and Tc17 subset of CD8 T lymphocytes

Cited by 13 publications

References 30 publications

Restored and Enhanced Memory T Cell Immunity in Rheumatoid Arthritis After TNFα Blocker Treatment

Restored and Enhanced Memory T Cell Immunity in Rheumatoid Arthritis After TNFα Blocker Treatment

Methotrexate-associated lymphoproliferative disorders of T-cell phenotype: clinicopathological analysis of 28 cases

Fumaric acid ester‐induced T‐cell lymphopenia in the real‐life treatment of psoriasis

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