Autologous stem cell transplantation for autoimmunity induces immunologic self-tolerance by reprogramming autoreactive T cells and restoring the CD4+CD25+ immune regulatory network

Kleer, Ismé de; Vastert, Bas; Klein, Mark; Teklenburg, Gijs; Arkesteijn, Ger; Yung, Gisella Puga; Albani, S.; Kuis, Wietse; Wulffraat, Nico; Prakken, Berent J.

doi:10.1182/blood-2005-07-2800

Cited by 214 publications

(169 citation statements)

References 49 publications

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“…Improvement of regulatory function is already established as part of the beneficial effects of autologous transplantation. 4,5,40 Indeed, in our MS patients AHSCT increased Treg counts from the first year until the 2-year follow-up. Furthermore, CD4 + CD25 hi Tregs presented higher expression of immunoregulatory molecules after AHSCT, which may have contributed to restore selftolerance and to control autoimmunity.…”

Section: Discussionmentioning

confidence: 99%

“…Elimination of autoreactive cells, thymic reactivation and restoration of regulatory processes are described as the main therapeutic mechanisms of AHSCT for autoimmune disease, including MS. [4][5][6][7][8][9][10] Combined, they promote control of autoimmunity and clinical amelioration. 30,31 In MS, Muraro et al 7,8 showed installation of a new and diverse T-cell receptor (TCR) repertoire and thymic reactivation after AHSCT.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3] Clinical remission after AHSCT depends on qualitative immunological changes that promote immune tolerance. Restoration of the CD4 + CD25 + regulatory T-cell (Treg) immune compartment 4,5 and profound resetting of the adaptive immune system 6 have been described. Suppression of inflammatory activity in MS patients undergoing AHSCT does not depend on persisting lymphopenia and is associated with de novo regeneration of the T-cell repertoire.…”

Section: Introductionmentioning

confidence: 99%

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Autologous hematopoietic SCT normalizes miR-16, -155 and -142-3p expression in multiple sclerosis patients

Arruda

Lorenzi

Sousa

et al. 2014

Bone Marrow Transplant

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Autologous hematopoietic SCT (AHSCT) has been investigated in the past as a therapeutic alternative for multiple sclerosis (MS). Despite advances in clinical management, knowledge about mechanisms involved with clinical remission post transplantation is still limited. Abnormal microRNA and gene expression patterns were described in MS and have been suggested as disease biomarkers and potential therapeutic targets. Here we assessed T-and B-cell reconstitution, microRNAs and immunoregulatory gene expression after AHSCT. Early immune reconstitution was mainly driven by peripheral homeostatic proliferation. AHSCT increased CD4 + CD25 hi FoxP3 + regulatory T-cell counts and expression of CTLA-4 and GITR (glucocorticoid-induced TNFR) on CD4 + CD25 hi T cells. We found transient increase in exhausted PD-1 + T cells and of suppressive CD8 + CD28 − CD57 + T cells. At baseline, CD4 + and CD8 + T cells from MS patients presented upregulated miR-16, miR-155 and miR-142-3p and downregulated FOXP3, FOXO1, PDCD1 and IRF2BP2. After transplantation, the expression of FOXP3, FOXO1, PDCD1 and IRF2BP2 increased, reaching control levels at 2 years. Expression of miR-16, miR-155 and miR-142-3p decreased towards normal levels at 6 months post therapy, remaining downregulated until the end of follow-up. These data strongly suggest that AHSCT normalizes microRNA and gene expression, thereby improving the immunoregulatory network. These mechanisms may be important for disease control in the early periods after AHSCT.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Autologous hematopoietic SCT normalizes miR-16, -155 and -142-3p expression in multiple sclerosis patients

Arruda

Lorenzi

Sousa

et al. 2014

Bone Marrow Transplant

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“…The frequency of Treg increased up to normal levels upon successful treatment by autologous stem cell transplantation (Ref. 81). However, a more recent study has suggested that while a difference in Treg frequency is observed between active and quiescent sJIA patients, Treg numbers in quiescent sJIA disease were raised compared with healthy controls as well as compared with active sJIA.…”

Section: Biology Of Treg In Juvenile Arthritismentioning

confidence: 99%

T regulatory cells in childhood arthritis – novel insights

Pesenacker

Wedderburn

2013

Expert Rev. Mol. Med.

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In recent years, there have been many new developments in the field of regulatory T cells (Treg), challenging the consensus on their behaviour, classification and role(s) in disease. The role Treg might play in autoimmune disease appears to be more complex than previously thought. Here, we discuss the current knowledge of regulatory T cells through animal and human research and illustrate the recent developments in childhood autoimmune arthritis (juvenile idiopathic arthritis (JIA)). Furthermore, this review summarises our understanding of the fields and assesses current and future implications for Treg in the treatment of JIA.

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“…Few studies with different methods, each of them in a small number of patients, have analyzed the immune reconstitution process after aHSCT for various types of autoimmune disease, including multiple sclerosis, 35 SSc, 29,30 juvenile arthritis 36 and SLE. 37 All studies reported that long-term remission in patients who received aHSCT was associated with a de novo regeneration of the T-cell compartment that can be delayed for years after T-cell depleting conditioning for aHSCT.…”

Section: Controlmentioning

confidence: 99%

Peripheral blood regulatory T cells in patients with diffuse systemic sclerosis (SSc) before and after autologous hematopoietic SCT: a pilot study

Baraut

Grigore

Jean-Louis

et al. 2013

Bone Marrow Transplant

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The present pilot study aims to evaluate the frequency and the function of regulatory T (Treg) cells in patients with diffuse cutaneous SSc (dcSSc) before and after autologous hematopoietic SCT (aHSCT). Peripheral blood lymphocytes from seven dcSSc patients were analyzed before and 24 months after aHSCT and were compared with those from seven healthy donors (controls).Treg (aTreg) cell subsets was performed using four-color flow cytometry. Treg-suppressive capability was measured after coculture with autologous T effector cells by evaluation of T-cell proliferation using 3 H-thymidine incorporation. Peripheral CD4 þ CD25 high FoxP3 þ (2 ± 0.5 vs 4.2 ± 1.1, Po0.01), CD4 þ CD25 þ TGF-b þ (6.9 ± 1.8 vs 14.6 ± 5.0, Po0.05) and CD4 þ CD25 þ IL-10 þ (10.7 ± 0.5 vs 16.1±3.2, Po0.01) Tregs as well as CD4 þ CD25 high CD127 low Tregs suppressive capacity (Po0.05) were decreased in dcSSc patients vs controls. After aHSCT (n ¼ 7), the percentages of CD4 þ CD25 high FoxP3 þ (4.1 ± 1.8) and CD4 þ CD25 þ IL-10 þ (15.7 ± 2.2) Treg cells and the suppressive activity of CD4 þ CD25 high CD127 low were restored to the levels in controls. The decreased frequency and the functional defect of peripheral Treg cells from patients with dcSSc are reversed following aHSCT to reach those observed in controls. This pilot study brings evidence of an effective restoration of nTreg and aTreg subsets, and recovery of nTreg suppressive function following aHSCT.

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Autologous stem cell transplantation for autoimmunity induces immunologic self-tolerance by reprogramming autoreactive T cells and restoring the CD4+CD25+ immune regulatory network

Cited by 214 publications

References 49 publications

Autologous hematopoietic SCT normalizes miR-16, -155 and -142-3p expression in multiple sclerosis patients

Autologous hematopoietic SCT normalizes miR-16, -155 and -142-3p expression in multiple sclerosis patients

T regulatory cells in childhood arthritis – novel insights

Peripheral blood regulatory T cells in patients with diffuse systemic sclerosis (SSc) before and after autologous hematopoietic SCT: a pilot study

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