Low-Dose Interleukin-2 Therapy Restores Regulatory T Cell Homeostasis in Patients with Chronic Graft-Versus-Host Disease

Matsuoka, Ken‐ichi; Koreth, John; Kim, Haesook T.; Bascug, O. Gregory; McDonough, Sean M.; Kawano, Yutaka; Murase, Kazuyuki; Cutler, Corey; Ho, Vincent T.; Alyea, Edwin P.; Armand, Philippe; Blazar, Bruce R.; Antin, Joseph H.; Soiffer, Robert J.; Ritz, Jérôme

doi:10.1126/scitranslmed.3005265

Cited by 411 publications

(387 citation statements)

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“…Treg homeostasis is altered in cGVHD and adoptive transfer or in vivo induction of Tregs may prevent or improve the symptoms of cGVHD. [2][3][4][5] Our understanding of the function of Bregs in this disease is limited. IL-10-producing B cells have been shown to inhibit CD4 T-cell proliferation, 6 TNF-a and IFN-g production, 21 and monocyte activation 7 in in vitro coculture experiments.…”

Section: Discussionmentioning

confidence: 99%

CD24hiCD27+ and plasmablast-like regulatory B cells in human chronic graft-versus-host disease

Masson

Bouaziz

Buanec

et al. 2015

Blood

146

119

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Key Points• Chronic graft-versus-host disease is associated with a global Breg defect.• This defect is particularly accentuated in the CD24 hi CD27 1 Breg compartment.Interleukin 10 (IL-10)-producing B cells (regulatory B cells [Bregs]) regulate autoimmunity in mice and humans, and a regulatory role of IL-10-producing plasma cells has been described in mice. Dysfunction of B cells that maintain homeostasis may play a role in the pathogenesis of chronic graft-versus-host disease (cGVHD) after allogeneic stem cell transplantation. Here, we found a relation between decreased Breg frequencies and cGVHD severity. An impaired ability of B cells to produce IL-10, possibly linked to poor signal transducer and activator of transcription 3 and extracellular signal-regulated kinase phosphorylation, was found in patients with active cGVHD. IL-10 production was not confined to a single B-cell subset, but enriched in both the CD24 hi CD27 1 and CD27 hi CD38 hi plasmablast B-cell compartments. In vitro plasmablast differentiation increased the frequency of IL-10-producing B cells. We confirmed that allogeneic transplant recipients had an impaired reconstitution of the memory B-cell pool. cGVHD patients had less CD24 hi CD27 1 B cells and IL-10-producing CD24 hi CD27 1 B cells. Patients with cGVHD had increased plasmablast frequencies but decreased IL-10-producing plasmablasts. These results suggest a role of CD24 hi CD27 1 B-cell and plasmablast-derived IL-10 in the regulation of human cGVHD. (Blood. 2015;125(11):1830-1839 IntroductionChronic graft-versus-host disease (cGVHD) is the leading cause of morbi-mortality after allogeneic hematopoietic stem cell transplantation (AHSCT). 1 GVHD prevention by means of adoptive transfer of regulatory T cells (Tregs) 2,3 and cGVHD treatment by in vivo induction of Tregs by low-dose interleukin 2 (IL-2) 4,5 may be effective. The exact role of IL-10-producing regulatory B cells (Bregs) in cGVHD is yet to be understood. Bregs have been shown to downmodulate adaptive 6 or innate immune responses 7 in mice and humans. In cGVHD, B cells are essentially recognized as positive regulators of inflammation. 1,8,9 Increased B-cell receptor responsiveness was found in cGVHD patients. 10 B-cell homeostatic defects were described in cGVHD, including elevated B-cell activating factor of the tumor necrosis factor (TNF) family (BAFF)/B-cell ratios, 11-15 expansion of CD21 lo B cells, 16 reduced CD5 1 B1-like cell numbers, 17 decreased CD27 1 memory B cells, and hypogammaglobulinemia. 18 BAFF concentrations correlated with increased circulating pre-germinal center (GC) B-cell and post-GC plasmablast cell counts in patients with cGVHD. 11 B-cell depletion with rituximab prevented cGVHD in humans. 19 Patients with cGVHD frequently have circulating antibodies reactive to recipient cells. 1,9,20 Besides their functions in antibody secretion, cytokine and chemokine production, and antigen presentation, B cells exhibit regulatory properties in several human autoimmune diseases including systemic lupus erythemat...

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Section: Discussionmentioning

confidence: 99%

CD24hiCD27+ and plasmablast-like regulatory B cells in human chronic graft-versus-host disease

Masson

Bouaziz

Buanec

et al. 2015

Blood

146

119

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“…This is consistent with the observed proliferative effect of in vivo low dose IL-2 on Tregs. 27 The IL2DT cohort demonstrated that lack of host Tregs is associated with improved in vivo donor NK-cell expansion and remission induction. However, in addition to IL2DT, cohort 3 also received products with higher NK cells doses, which may have contributed to the better clinical results.…”

Section: Foxp3mentioning

confidence: 99%

Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein

Bachanová¹,

Cooley²,

DeFor

et al. 2014

Blood

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362

333

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Key Points• Depletion of host regulatory T cells with IL2DT improves efficacy of haploidentical NK cell therapy for refractory acute myeloid leukemia.• Depletion of Treg and persistence of NK cells for $7 days after NK cell adoptive transfer predicts beneficial clinical responses.Haploidentical natural killer (NK) cell infusions can induce remissions in some patients with acute myeloid leukemia (AML) but regulatory T-cell (Treg) suppression may reduce efficacy. We treated 57 refractory AML patients with lymphodepleting cyclophosphamide and fludarabine followed by NK cell infusion and interleukin (IL)-2 administration. In 42 patients, donor NK cell expansion was detected in 10%, whereas in 15 patients receiving host Treg depletion with the IL-2-diphtheria fusion protein (IL2DT), the rate was 27%, with a median absolute count of 1000 NK cells/mL blood. IL2DT was associated with improved complete remission rates at day 28 (53% vs 21%; P 5 .02) and disease-free survival at 6 months (33% vs 5%; P < .01). In the IL2DT cohort, NK cell expansion correlated with higher postchemotherapy serum IL-15 levels (P 5 .002), effective peripheral blood Treg depletion (<5%) at day 7 (P < .01), and decreased IL-35 levels at day 14 (P 5 .02). In vitro assays demonstrated that Tregs cocultured with NK cells inhibit their proliferation by competition for IL-2 but not for IL-15. Together with our clinical observations, this supports the need to optimize the in vivo cytokine milieu where adoptively transferred NK cells compete with other lymphocytes to improve clinical efficacy in patients with refractory AML. This study is registered at clinicaltrials.gov, identifiers: NCT00274846 and NCT01106950. (Blood. 2014;123(25):3855-3863)

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“…To restore Treg homeostasis at chronic phase (that is, "maintenance phase" in Fig. 3), a phase 1 dose-escalation study aimed at exploring the maximum tolerated dose of daily low-dose subcutaneous IL-2 in patients with steroid-refractory chronic GVHD was conducted at Dana-Farber Cancer Institute [18,19]. Twenty-nine patients were included, and the maximum tolerated dose of IL-2 was 1 × 10 6 IU/m 2 .…”

Section: Therapeutic Intervention In Treg Homeostasis By Low-dose Il-2mentioning

confidence: 99%

“…12 of 23 evaluable patients achieved an objective partial response during the 8 weeks of IL-2 treatment. IL-2 therapy induced a series of changes in Treg homeostasis, including increased proliferation, increased thymic export, and enhanced resistance to apoptosis [19]. Based on these promising results, a Phase 2 study with low-dose (1 × 10 6 IU/m 2 /day) IL-2 was conducted and elucidated that clinical responders initiated IL-2 significantly earlier (508 versus 917 days after HSCT) and Treg:Tcon ratios ≥ 0.07 at baseline and ≥ 0.2 at week 1 also predicted clinical response [31,32].…”

Section: Therapeutic Intervention In Treg Homeostasis By Low-dose Il-2mentioning

confidence: 99%

“…In contrast, murine and clinical studies demonstrated that low-dose IL-2 administration was able to selectively stimulate Treg, since Treg possess the high-affinity IL-2 receptor, resulting in the induction of immune tolerance [12,[15][16][17]. The new therapeutic indication of IL-2 has been started in the field of HSCT and is spreading to the other fields including the treatment for autoimmune diseases [18,19]. In this review, we will first show our current understanding of the polymorphic process of Treg reconstitution after HSCT and then discuss the appropriate intervention in the altered Treg homeostasis in each distinct reconstituting phase by low-dose IL-2 for better outcomes of patients after HSCT.…”

Section: Introductionmentioning

confidence: 99%

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Low-dose interleukin-2 as a modulator of Treg homeostasis after HSCT: current understanding and future perspectives

Matsuoka

2017

Int J Hematol

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CD4 + CD25 + Foxp3 + Treg is a functionally distinct subset of mature T cells with broad suppressive activity and has been shown to play an important role in the establishment of immune tolerance after HSCT. Altered cytokine environment in post-HSCT lymphopenia with a relative functional deficiency of IL-2 could hamper the reconstitution of Treg, leading to refractory GVHD. Based on the theory of low-dose IL-2 in which Treg can be selectively stimulated through the high-affinity IL-2 receptor, clinical studies have been conducted and demonstrated that low-dose IL-2 administration can restore Treg homeostasis and promote the expansion of this subset on the polymorphic processes of Treg reconstitution after HSCT. The new therapeutic indication of IL-2 for immune tolerance has launched in the field of HSCT and is spreading to the other fields including the treatment for autoimmune diseases. To further extend the indication of low-dose IL-2 to more patients with various immunological problems, the optimization of the timing and dosing of IL-2 intervention and the concomitant immune suppressive therapy according to each patient-based assessment are to be desired in the near future. Further prospective studies may facilitate the development of novel therapeutic algorithms for the effective and safe induction of immune tolerance after HSCT.

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Low-Dose Interleukin-2 Therapy Restores Regulatory T Cell Homeostasis in Patients with Chronic Graft-Versus-Host Disease

Cited by 411 publications

References 48 publications

CD24hiCD27+ and plasmablast-like regulatory B cells in human chronic graft-versus-host disease

CD24hiCD27+ and plasmablast-like regulatory B cells in human chronic graft-versus-host disease

Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein

Low-dose interleukin-2 as a modulator of Treg homeostasis after HSCT: current understanding and future perspectives

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