Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation

Ianni, Mauro Di; Falzetti, Franca; Carotti, Alessandra; Terenzi, Adelmo; Castellino, Flora; Bonifacio, Elisabetta; Papa, Beatrice Del; Zei, Tiziana; Ostini, Roberta Iacucci; Cecchini, Debora; Aloisi, Teresa; Perruccio, Katia; Ruggeri, Loredana; Balucani, Chiara; Pierini, Antonio; Sportoletti, Paolo; Aristei, Cynthia; Falini, Brunangelo; Reisner, Yaīr; Velardi, Andrea; Aversa, Franco; Martelli, Massimo F.

doi:10.1182/blood-2010-10-311894

Cited by 947 publications

(831 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%

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

Masson

Bouaziz

Buanec

et al. 2015

Blood

143

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%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Masson

Bouaziz

Buanec

et al. 2015

Blood

143

119

View full text Add to dashboard Cite

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“…A number of other cell subsets have been suggested as treatment for GVHD, for example, CD4 þ regulatory T cells, 91 myeloid-derived suppressor cells 92 and CD8 þ regulatory T cells 93 ( Table 5). The target of these cell types is the suppression of alloreactivity, while MSCs and cells isolated from the placenta may also have regenerative abilities.…”

Section: Alternate Sources Of Cells For Acute Gvhdmentioning

confidence: 99%

Stromal cells–are they really useful for GVHD?

Kaipe

Erkers

Sadeghi

et al. 2014

Bone Marrow Transplant

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Mesenchymal stromal cells (MSCs) have immunomodulatory effects and are increasingly being used for the treatment of acute and chronic GVHD. Although they seem immuno-privileged, they induce alloresponses, but the risk of immunization is poorly characterized. After infusion, they first reach the lungs, liver and spleen, and are then difficult to trace. Several mechanisms are involved in stromal cells suppressing alloreactivity, such as induction of regulatory T cells, but whether or not this will also affect leukemic relapse or increase infections is not known. Although several encouraging pilot studies have been published, there have been few prospective randomized trials. There may be a bias in the literature, as negative results are seldom published, and there have been few comparative studies with other immunosuppressive regimens. Most animal models have failed to show any effect on GVHD. Several questions remain to be answered for optimization of stromal cell therapy. Which source is optimal-BM, fat, cord or decidua? Can stromal cells be replaced by exosomes, which culture conditions are most appropriate and at what passage and how frequently should cells be administered? More research is required to move stromal cell therapy forward to become an established treatment for acute and chronic GVHD.

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“…[18][19][20] The protective effect of donor CD4 1 CD25 1 Tregs in graft-versus-host disease has been previously demonstrated. 21,22 In addition to the inhibition of T effector cells (Teffs) by CD4 1 CD25 1 Tregs, whether allogeneic donor CD4 1 CD25 1 Tregs has regulatory effects on recipient macrophages or other antigen-presenting cells in vivo has not yet been determined. In this study, we investigated the effects of allogeneic donor mouse CD4 1 CD25 1 Tregs on recipient mouse F4/80 1 macrophages in vivo by the adoptive transfer of allogeneic CD4 1 CD25 1 Tregs directly into the peritoneal cavity of immunodeficient NOD-scid mice.…”

Section: Introductionmentioning

confidence: 99%

Induction of M2-like macrophages in recipient NOD-scid mice by allogeneic donor CD4+CD25+ regulatory T cells

Liu

Hou

et al. 2012

Cell Mol Immunol

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CD4 1 CD25 1 regulatory T cells (Tregs) play an important role in maintaining host immune tolerance via regulation of the phenotype and function of the innate and adaptive immune cells. Whether allogeneic CD4 1 CD25 1 Tregs can regulate recipient mouse macrophages is unknown. The effect of allogeneic donor CD4 1 CD25 1 Tregs on recipient mouse resident F4/80 1 macrophages was investigated using a mouse model in which allogeneic donor CD4 1 CD25 1 Tregs were adoptively transferred into the peritoneal cavity of host NOD-scid mice. The phenotype and function of the recipient macrophages were then assayed. The peritoneal F4/80 1 macrophages in the recipient mice that received the allogeneic CD4 1 CD25 1 Tregs expressed significantly higher levels of CD23 and programmed cell death-ligand 1(PD-L1) and lower levels of CD80, CD86, CD40 and MHC II molecules compared to the mice that received either allogeneic CD4 1 CD25 2 T cells (Teffs) or no cells. The resident F4/80 1 macrophages of the recipient mice injected with the allogeneic donor CD4 1 CD25 1 Tregs displayed significantly increased phagocytosis of chicken red blood cells (cRBCs) and arginase activity together with increased IL-10 production, whereas these macrophages also showed decreased immunogenicity and nitric oxide (NO) production. Blocking arginase partially but significantly reversed the effects of CD4 1 CD25 1 Tregs with regard to the induction of the M2 macrophages in vivo. Therefore, the allogeneic donor CD4 1 CD25 1 Tregs can induce the M2 macrophages in recipient mice at least in part via an arginase pathway. We have provided in vivo evidence to support the unknown pathways by which allogeneic donor CD4 1 CD25 1 Tregs regulate innate immunity in recipient mice by promoting the differentiation of M2 macrophages.

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Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation

Cited by 947 publications

References 24 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

Stromal cells–are they really useful for GVHD?

Induction of M2-like macrophages in recipient NOD-scid mice by allogeneic donor CD4+CD25+ regulatory T cells

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