Low-dose, but not high-dose, cyclosporin A promotes regulatory T-cell induction, expansion, or both

Baumgrass, Ria; Brandt, Claudia; Wegner, Fanny; Abdollahnia, Mandana; Worm, Margitta

doi:10.1016/j.jaci.2010.04.032

Cited by 23 publications

(22 citation statements)

References 7 publications

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“…1). Recent studies of cyclosporine A treatment for AD found that the responses were primarily due to activation of adaptive immune responses and, in particular, subsets of regulatory T cells [1,7,19]. Furthermore, other recent work has shown that single nucleotide polymorphisms in a promoter of the IL-18 gene [30] and particular IL-18 gene haplotypes [16] are associated with the likelihood of developing AD.…”

Section: Discussionmentioning

confidence: 99%

Association of serum interleukin-18 and other biomarkers with disease severity in adults with atopic dermatitis

et al. 2011

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Atopic dermatitis (AD) is a chronic inflammatory disease of the skin for which there are no reliable biomarkers to assess clinical severity. Serum interleukin-18 (IL-18) levels may be associated with AD severity. To identify putative biomarkers associated with clinical severity in adult AD patients, we enrolled 121 adult AD patients (mean age 35.7 years) and 50 healthy controls (mean age 31.7 years). We compared these groups for blood eosinophils and serum levels of IL-18, thymus and activation-regulated chemokine (TARC), total IgE, and lactate dehydrogenase (LDH). We also determined S. aureus enterotoxin B (SEB) specific IgE levels and the SCORingAD (SCORAD) scores for AD patients. For AD patients, stepwise logistic regression was used to estimate odds ratios (OR) for each biomarker for the likelihood of having AD, and multiple linear regression was used to identify biomarkers associated with SCORAD scores. Compared with healthy controls, adult AD patients had higher levels of IL-18, TARC, total IgE, eosinophils, and LDH. TARC levels had the highest OR for AD occurrence, while the OR for IL-18 was insignificant. Also, IL-18 was not related to the presence of SEB-IgE. Notably, IL-18 levels were significantly associated with SCORAD scores, as were TARC, total IgE, and LDH levels. A panel of biomarkers (IL-18, TARC, total IgE, and LDH) may be more useful to accurately assess clinical severity in adult AD patients.

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Section: Discussionmentioning

confidence: 99%

Association of serum interleukin-18 and other biomarkers with disease severity in adults with atopic dermatitis

et al. 2011

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“…Several studies have shown the suppressive effects of CsA on Treg numbers [26,27]. However, in patients with atopic dermatitis, low-dose CsA treatment (2 mg/kg/ day) results in an increase in the number of peripheral Tregs without affecting the CD3 + , CD4 + , and CD8 + cell populations [28,29]. Similarly, a lower dose of CsA has been shown to promote Treg development in a rat cardiac allograft model [30].…”

Section: Foxp3mentioning

confidence: 99%

“…2d and 4b). Blood trough levels of CsA ranging 50-100 ng/ml can be achieved by the administration of 2-3 mg/kg of CsA [28]. A recent study by Philippe et al demonstrated that an optimal CsA trough blood concentration for the treatment of SAA was 100 ng/ml [39].…”

Section: Foxp3mentioning

confidence: 99%

Cyclosporine restores hematopoietic function by compensating for decreased Tregs in patients with pure red cell aplasia and acquired aplastic anemia

et al. 2016

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Most patients with acquired pure red cell aplasia (PRCA) and some with acquired aplastic anemia (AA) respond well to cyclosporine (CsA), but thereafter often show CsA dependency. The mechanism underlying this dependency remains unknown. We established a reliable method for measuring the regulatory T cell (Treg) count using FoxP3 and Helios expression as markers and determined the balance between Tregs and other helper T cell subsets in 16 PRCA and 29 AA patients. The ratios of interferon-γ-producing CD4 + (Th1) T cells to Tregs in untreated patients and CsAdependent patients were significantly higher (PRCA 5.77 ± 1.47 and 7.38 ± 2.58; AA 6.18 ± 2.35 and 8.94 ± 4.06) than in healthy volunteers (HVs; 3.33 ± 0.90) due to the profound decrease in the percentage of Tregs. In contrast, the ratios were comparable to HVs in convalescent CsA-treated AA patients (4.74 ± 2.10) and AA patients in remission after the cessation of CsA treatment (4.24 ± 1.67). Low-dose CsA (100 ng/ml) inhibited the proliferation of conventional T cells (Tconv) to a similar degree to the inhibition by Tregs in a co-culture with a 1:1 Treg/Tconv ratio. The data suggest that CsA may reverse the hematopoietic suppression in PRCA and AA patients by compensating for the inadequate immune regulatory function that occurs due to a profound decrease in the Treg count.

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“…Several mechanisms, 13,[25][26][27][28][29][30][31][32][33][34] such as clonal deletion and anergy, veto effects, [35][36][37][38][39] Th2 polarization, regulatory T-cell (CD4 þ CD25 þ Foxp3 þ T cells, Tregs)-mediated suppression [40][41][42] and natural killer (NK) cell alloreactivity, 14,43,44 have been implicated in inducing immune tolerance ( Table 1). The mechanisms relevant to haploidentical SCT include: (1) alloreactive TCD and/or B-cell depletion as well as T-cell anergy; (2) veto activity of 'mega-dose CD34 þ cells', 12 which can suppress CTL precursor cells directed against their own Ags, but not those directed against third-party Ags; 45 (3) polarization of T cells from Th1 to Th2 phenotype, the Th2 cells can ameliorate severe GVHD via IL-4 and IL-10 production and potentially via IL-2 consumption and APC modulation.…”

Section: Mechanisms Relevant To Haploidentical Sctmentioning

confidence: 99%

“…5,6 STRATEGIES USED TO OVERCOME HLA BARRIERS Several strategies, such as ex vivo TCD, treatment of healthy donors with G-CSF, post transplant CY (PT/CY) and pharmacological agents, such as ATG and CsA, have been implicated in crossing HLA barriers (Table 1). [35][36][37][38] EX VIVO TCD The Perugia group pioneered an approach for graft TCD via the positive selection of CD34 þ stem cells. However, NK cells, monocytes and DCs that contribute to immune reconstitution after transplantation were simultaneously depleted in this approach.…”

Section: Mechanisms Relevant To Haploidentical Sctmentioning

confidence: 99%

Haploidentical SCT: the mechanisms underlying the crossing of HLA barriers

Huang

2014

Bone Marrow Transplant

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Research on the different mechanisms for crossing HLA barriers has progressed over the past 10 years. General outlines have come into view for a solution to this issue and are often presented as 'haploidentical SCT' immunology. In this review, we discuss several mechanisms that have recently been described in ex vivo and in vivo settings that can either avoid GVHD or promote hematopoietic reconstitution in haploidentical settings. The host and donor T-cell responses to allogeneic HLA molecules are a fundamental obstacle to the successful application of haploidentical transplantation, which results in unacceptably high incidences of GVHD and graft rejection. Thus, the T-cell response is a central factor in the establishment of a novel haploidentical transplant protocol with superior outcomes.

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Low-dose, but not high-dose, cyclosporin A promotes regulatory T-cell induction, expansion, or both

Cited by 23 publications

References 7 publications

Association of serum interleukin-18 and other biomarkers with disease severity in adults with atopic dermatitis

Association of serum interleukin-18 and other biomarkers with disease severity in adults with atopic dermatitis

Cyclosporine restores hematopoietic function by compensating for decreased Tregs in patients with pure red cell aplasia and acquired aplastic anemia

Haploidentical SCT: the mechanisms underlying the crossing of HLA barriers

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