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Combination Of Regulatory T Cells and Rapamycin As Treatment For Experimental Chronic Graft-Versus-Host Disease
Belle, Ludovic; Ehx, Grégory; SOMJA, Joan et al.
2013In Blood, 122 (21), p. 4474
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Keywords :
Regulatory T cells; GVHD; Rapamycin
Abstract :
[en] Background Chronic graft-versus-host disease (cGvHD) is one of the main complications of allogeneic hematopoietic cell transplantation (allo-HCT). Donor CD4+ conventional T cells (Tconv) as well as regulatory T cells (Treg) are the key-players in its pathogenesis. Rapamycin (sirolimus, rapa) is a mTor inhibitor that can suppress activation and proliferation of Tconv without inhibiting Treg. Aims To assess the impact of a combined treatment with Tregand rapa on experimental cGvHD. Methods Lethally irradiated BALB/c mice were injected with 10x106 bone marrow cells and 70x106 splenocytes from B10.D2 donor mice. Mice were divided in four groups on day -1 and treatments were started on day 20 with either PBS, rapa 1 mg/kg/Day, Treg 1.106 cells (D+20), or rapa 1 mg/kg/Day + Treg 1.106 cells (D+20). Treg (CD4+ CD25+ cells) were purified from spleen cells from donor B10.D2 mice using the CD4+ CD25+ regulatory T cell isolation kit (Miltenyi Biotec, GmbH, Germany). Treg purity (defined as CD4+ FoxP3+ cells) was ≥ 70% of total cells and > 92% of CD4+T cells. The severity of sclerodermatous cGvHD was assessed with the following clinical scoring system. Briefly, animals were individually scored every 3 days for five parameters: weight loss (1, 10-20%; 2, > 20%), posture (1, kyphosis only at rest; 2, severe kyphosis when the animal moved), activity (1, moderate activity impairment; 2, no move unless stimulated), skin (1, erythema or scaling tail; 2, open lesion on the body surface) and hair loss (1, > 1 cm2; 2, > 2 cm2). Mice which reached a score of 8 were estimated to have terminal GvHD and were sacrificed. Terminal GvHD-free survivals between the 4 groups were compared using the Log-rank test. Results The effects of the treatments were evaluated 7 days after starting the treatments (D+27 post-transplantation). Numbers of total and central memory and effector memory CD4+ T cells/µL were significantly (p<0.05) decreased in rapa-, Treg-, and Treg + rapa- treated mice compared to PBS mice, while numbers of naïve CD4+ T cells/µL were significantly (p<0.05) decreased in Treg-, and Treg + rapa- treated mice. Further, proliferation of CD4+ T cells (assessed by Ki67 expression) was significantly decreased in rapa- (p<0.05) and Treg + rapa- treated mice (p<0.05). In addition, counts and proliferation of CD8+ T cells/µL were significantly (p<0.05) lower in rapa- and Treg+ rapa- treated mice compared to PBS mice. Importantly, terminal-GvHD-free survival was significantly shorter in PBS mice than in Treg (P=0.03), rapa (P=0.04), and Treg+ rapa mice (P=0.02). Conclusion Our results showed that Treg and rapa administration improved cGvHD in this model of cGvHD.
Disciplines :
Hematology
Author, co-author :
Belle, Ludovic ;  Université de Liège > GIGA-R : Hématologie
Ehx, Grégory  ;  Université de Liège > GIGA-R : Hématologie
SOMJA, Joan ;  Centre Hospitalier Universitaire de Liège - CHU > Service dermatopathologie
BINSFELD, Marilène ;  Centre Hospitalier Universitaire de Liège - CHU > Service d'hématologie biologique et immuno-hématologie
Hannon, Muriel ;  Université de Liège > GIGA-R : Hématologie
Caers, Jo  ;  Université de Liège > Département des sciences cliniques > Département des sciences cliniques
Fransolet, Gilles ;  Université de Liège > GIGA-R : Hématologie
Beguin, Yves  ;  Université de Liège > GIGA-R : Hématologie
Humblet-Baron, S
Baron, Frédéric  ;  Université de Liège > GIGA-R : Hématologie
Language :
English
Title :
Combination Of Regulatory T Cells and Rapamycin As Treatment For Experimental Chronic Graft-Versus-Host Disease
Publication date :
December 2013
Event name :
55th ASH Annual Meeting
Event date :
Du 5 au 8 décembre 2013
Audience :
International
Journal title :
Blood
ISSN :
0006-4971
eISSN :
1528-0020
Publisher :
American Society of Hematology, Washington, United States - District of Columbia
Volume :
122
Issue :
21
Pages :
4474
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 17 May 2017

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