Only the CD62L+ subpopulation of CD4+CD25+ regulatory T cells protects from lethal acute GVHD

Blood ◽  
2005 ◽  
Vol 105 (5) ◽  
pp. 2220-2226 ◽  
Author(s):  
Joerg Ermann ◽  
Petra Hoffmann ◽  
Matthias Edinger ◽  
Suparna Dutt ◽  
Francis G. Blankenberg ◽  
...  
Keyword(s):  
T Cells ◽  
Allogeneic Bone Marrow Transplantation ◽  
Treg Cells ◽  
Allogeneic Bone ◽  
Protective Function ◽  
Graft Versus Host ◽  
Characteristic Features ◽  
Related Mortality

AbstractCD4+CD25+ regulatory T (Treg) cells are potent modulators of alloimmune responses. In murine models of allogeneic bone marrow transplantation, adoptive transfer of donor CD4+CD25+ Treg cells protects recipient mice from lethal acute graft-versus-host disease (aGVHD) induced by donor CD4+CD25- T cells. Here we examined the differential effect of CD62L+ and CD62L- subsets of CD4+CD25+ Treg cells on aGVHD-related mortality. Both subpopulations showed the characteristic features of CD4+CD25+ Treg cells in vitro and did not induce aGVHD in vivo. However, in cotransfer with donor CD4+CD25- T cells, only the CD62L+ subset of CD4+CD25+ Treg cells prevented severe tissue damage to the colon and protected recipients from lethal aGVHD. Early after transplantation, a higher number of donor-type Treg cells accumulated in host mesenteric lymph node (LN) and spleen when CD4+CD25+CD62L+ Treg cells were transferred compared with the CD62L- subset. Subsequently, CD4+CD25+CD62L+ Treg cells showed a significantly higher capacity than their CD62L- counterpart to inhibit the expansion of donor CD4+CD25- T cells. The ability of Treg cells to efficiently enter the priming sites of pathogenic allo-reactive T cells appears to be a prerequisite for their protective function in aGVHD.

Human Mesenchymal Stem Cells Attenuate Graft-Versus-Host Disease and Maintain Graft-Versus-Leukemia in Murine Allogeneic Bone Marrow Transplantation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1907-1907 ◽  
Author(s):  
Jeffery J Auletta ◽  
Saada Eid ◽  
Matthew Keller ◽  
Leland Metheny ◽  
Rocio Guardia-Wolff ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Graft Versus Host Disease ◽  
Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Graft Versus Host ◽  
Graft Versus Leukemia

Abstract Abstract 1907 Defining in vivo effects and biodistribution of human bone marrow-derived mesenchymal stem cell (hMSCs) following allogeneic bone marrow transplantation (alloBMT) could impact the clinical utility of MSC therapy for the prevention and treatment of graft-versus-host disease (GvHD). Using an established model of murine alloBMT, we defined hMSC effects on GvHD and graft-versus-leukemia (GvL) activity. We first studied whether hMSC could modulate in vitro murine T-cell (TC) alloreactivity in mixed leukocyte cultures (MLCs). Specifically, hMSCs added to MLCs significantly reduced TC proliferation in a concentration-dependent manner distinct from human fibroblasts. In contrast to MLC cultures alone, MLCs containing hMSCs had significant reduction in TNFα, IFNγ, and IL-10 levels and higher levels of PGE2 and TGFβ1. Modulation in the inflammatory milieu was associated with changes in TC phenotypes, including more naïve and less activated TC surface marker expression (CD62L+CD69−) and the induction of CD4+CD25+FoxP3+ T-regulatory cells. To determine whether hMSCs could modulate in vivo mTC alloreactivity, irradiated recipient B6D2F1 (H-2bxd) mice were transplanted with allogeneic C57BL/6 (H-2b) BM and purified splenic TCs (B6→B6D2F1) and then were tail-vein injected with hMSC infusions (1 million per injection) on days one and four post-transplant. Syngeneic transplant recipients (B6D2F1→B6D2F1) were used as controls. hMSC-treated alloBMT mice had significantly prolonged survival and improved clinical GvHD scores, reduced splenic TC expansion and TNFα and IFNγ-producing TCs, and lower circulating TNFα and IFNγ levels versus untreated alloBMT mice. Bioluminescence imaging showed redistribution of labeled hMSCs from the lungs to abdominal organs within 72 hours following infusion. Importantly, GvHD target tissues (small and large bowel and liver) harvested from hMSC-treated alloBMT mice had significantly lower GvHD pathology scores than untreated alloBMT mice. We next determined the effects of hMSCs on GvL activity using the murine mastocytoma cell line, P815 (H-2d). TCs co-cultured with hMSCs maintained potent in vitro cytotoxic T-lymphocyte (CTL) activity comparable to untreated control CTLs. After challenge with P815 tumor cells, hMSCs-treated alloBMT mice had less severe GvHD, eradication of tumor burden, and improved leukemia-free survival compared to alloBMT control mice. Lastly, indomethacin (IM) added to MLC-hMSC co-cultures significantly reversed attenuation in both murine TC alloreactivity and surface activation expression. In addition, IM administered to hMSC-treated alloBMT mice reversed hMSC-associated survival advantage, suggesting that PGE2 in part mediates hMSC immunomodulatory effects. Together, our results show that hMSC infusions effectively attenuate GvHD and maintain GvL potency in alloBMT mice and reveal potential biomarkers and mechanisms of action underlying hMSC effects. Disclosures: Solchaga: Bimemetic Therapeutics: Employment. Cooke:Amgen: Provides experimental drug and central pharmacy support for 2 trials for which I am Co-PI.

Critical and Opposing Effects of T Cell-Derived TNFα and Interferon-γ on IL-17 Induction Assessed in Vitro and in Vivo Following Allogeneic Bone Marrow Transplantation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3482-3482
Author(s):  
Minghui Li ◽  
Kai Sun ◽  
Mark Hubbard ◽  
Doug Redelman ◽  
Angela Panoskaltsis-Mortari ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Allogeneic Bmt

Abstract IL-17-producing CD4 T cells (Th17) are a recently identified T helper subset that plays a role in mediating host defense to extracellular bacteria infections and is involved in the pathogenesis of many autoimmune diseases. In vitro induction of IL-17 in murine CD4+ T cells has been shown to be dependent on the presence of the proinflammatory cytokines TGF-β and IL-6 whereas IFNγ can suppress the development of Th17 cells. In the current study, we examined the roles of TNFα and IFNγ on IL-17 production by purified T cells in vitro and in vivo after allogeneic bone marrow transplantation (BMT). We present findings that expression of TNFα by the T cell itself is necessary for optimal development of Th17 under in vitro polarizing conditions. A novel role for T cell-derived TNFα in Th17 induction was observed when in vitro polarization of Tnf−/−CD4+ T cells resulted in marked reductions in IL-17+CD4+ T cells compared to Tnf+/+CD4+ T cells. In marked contrast, T cell-derived IFNγ markedly inhibited Th17 development as more IL-17+CD4+ T cells were found in Ifnγ−/−CD4+ T cells than in Ifnγ+/+CD4+ T cells, and of particular interest was the dramatic increase in IL-17+CD8+ cells from Ifnγ−/− mice. To determine if T cell-derived TNFα or IFNγ can regulate Th17 development in vivo we examined the differentiation of alloreactive donor T cells following allogeneic BMT. We have found that donor-derived Th17 cells can be found in lymphoid tissues and GVHD-affected organs after allogeneic BMT. However, transfer of Tnf−/− CD4+ T cells after allogeneic BMT resulted in marked reductions in Th17 cells in the spleen (18×103 vs 7×103, P<0.05). In agreement with the in vitro data and in contrast to what was observed with transfer of Tnf−/− CD4+ T cells, transfer of donor Ifnγ−/− T cells resulted in marked increases in not only IL-17+CD4+ but also IL-17+CD8+ T cells infiltrating the liver (7×103 vs 14×103, P<0.05; 4×104 vs 12.5×104, P<0.05). These results suggest that the donor T cell-derived TNFα and IFNγ opposingly regulate IL-17 induction of both CD4+ and CD8+ T cells in vitro and after allogeneic BMT which correlates with GVHD pathology.

scholarly journals Host CD4+CD25+ T cells can expand and comprise a major component of the Treg compartment after experimental HCT

Blood ◽  
2009 ◽  
Vol 113 (3) ◽  
pp. 733-743 ◽  
Author(s):  
Allison L. Bayer ◽  
Monica Jones ◽  
Jackeline Chirinos ◽  
Lesley de Armas ◽  
Taylor H. Schreiber ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hematopoietic Cell Transplantation ◽  
Extended Period ◽  
Treg Cells ◽  
Allogeneic Bone ◽  
Vaccine Responses ◽  
Antitumor Vaccine

Abstract Reconstitution of the recipient lymphoid compartment following hematopoietic cell transplantation (HCT) is typically delayed. The present studies investigated the residual host CD4+CD25+Foxp3+ (Treg) compartment after several conditioning regimens, including T cell–depleted and T cell–replete HCT and observed (1) a small number of recipient Treg cells survived aggressive conditioning; (2) the surviving, that is, residual Tregs underwent marked expansion; and (3) recipient CD4+FoxP3+ cells composed the majority of the Treg compartment for several months post-syngeneic HCT. Notably, residual Tregs also dominated the compartment post-HCT with T cell–depleted (TCD) major histocompatibility complex–matched allogeneic bone marrow but not following T cell–replete transplantations. The residual Treg cell compartment was functionally competent as assessed by in vitro lymphoid suppression and in vivo autoimmune disease transfer assay. These observations support the notion that functional host Tregs initially occupy a niche in lymphopenic transplantation recipients, undergo significant expansion, and contribute to the compartment for an extended period before donor-derived CD4+FoxP3+ T cells eventually compose the majority of the compartment. In total, the findings suggest that the presence of host Tregs may be important to consider regarding elicitation of immune (eg, antitumor, vaccine) responses in recipients during the early post-transplant period involving autologous and certain allogeneic HCT regimens.

In Vitro Cultured Allogeneic Cytotoxic T Cells Mediate Hematopoietic GVHD without Gut GVHD Despite Expression of Functional LPAM (α4β7 Integrin).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1306-1306
Author(s):  
Ram Kalpatthi ◽  
Kathleen Nicol ◽  
Lindsay Hendey ◽  
Michael W. Boyer
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Cytotoxic T Cells ◽  
Graft Versus Host Reaction ◽  
Control Group ◽  
Allogeneic Bone ◽  
Graft Versus Host ◽  
Radiation Control

Abstract Graft-versus-host disease (GVHD) remains a significant complication of allogeneic bone marrow transplantation. We and others have shown that in vitro cultured CD8 cytotoxic T cells (CTL) have attenuated GVHD compared to naïve cells, while retaining GVL activity. It has been shown that expression of α4β7 integrin on CD8 T cells is important for gut homing specificity in GVHD. Recently, retinoic acid (RA) has been shown to upregulate α4β7 expression on naïve T cells. Thus, we hypothesize that in vitro cultured CTL without RA lack the ability to cause GVHD in part due to deficient α4β7 expression. We used an established murine GVHD model in which spleen and lymph node cells from B6SJL mice were stimulated with splenocytes from DBA mice and were restimulated on day 7. Cultures were supplemented with IL-2 & IL-7 with and without addition of RA (100nm) on day 2. Day 14 comparison of CTL with and without RA revealed comparable CD4 (1.7% vs 0.7% respectively) and CD8 populations (96% vs 97% respectively). Phenotyping of CTL with and without RA showed CD8 α4β7 expression of 58% and 0.8% and CD8 CCR9 53% and 10% respectively. In vitro cytotoxicity was comparable between CTL with and without RA: 51% vs 41% at an effector target ratio of 10:1 (n=3, p=0.3). Both CTL groups had comparable in vitro migration towards to SDF, IP-10 & MIP-3α (p= ns). However RA treated CTL had increased migration towards TECK (chemokine expressed in small intestine); 17.3% vs 4.6% (n=4, p=0.01) and decreased migration towards TARC (chemokine expressed in skin); 2% vs 13% (n=4, p=0.03). For in vivo homing, 107 labeled cells from each CTL with (CFSE) and without RA (TRITC) were coinjected intravenously and mice were sacrificed 16 hours later for analysis. RA treated CTL had increased homing to peyer’s patch and MLN compared to CTL without RA. [Homing index (CTLRA/CTL) 2.3 and 2.5 respectively]. This finding is exaggerated in the radiated host [Homing index (CTLRA/CTL) 15 for PP and 11 for MLN]. CTL generated with or without RA (5x106 cells each) were injected intravenously in to irradiated (600 Rads) B6D2F1 recipients (3 groups; Radiation control, CTL with and without RA). Mice were followed for clinical GVHD scores and sacrificed when moribund. CBC and histopathologic GVHD scores (Liver, skin, lung, small and large intestines) were obtained. Both CTL groups developed lethal bone marrow (BM) aplasia around day 24 as compared to radiation control group; however, clinical and histopathologic GVHD scores were similar in all groups (Table 1). Our data demonstrate that both CTL with and without RA cause a lethal hematopoietic graft versus host reaction. Despite high α4β7 and CCR9 expression, significant in vitro migration to TECK and in vivo homing to gut associated lymphoid tissues, RA treated CTL did not cause significant GVHD in gut, liver or skin. This suggests that defective gut homing alone may not be sufficient to explain the attenuated GVHD from cultured CTL. Future studies are planned to confirm these findings in other GVHD models and to elucidate the mechanisms of attenuated GVHD from cultured CTL. Table 1 (Data from Day 24 sacrifice) Parameter (Mean) Radiation control CTL CTLRA p value* * CTL or CTLRA vs Radiation control group Hb (g/dL) 12.2 3.8 3.1 0.0001 WBC x106/L 1000 300 300 0.07 Platelets x103/L 667,200 50,200 29,500 0.003 BM cells from 2 femur (106) 15.3 0.9 1.1 0.0006 Combined GVHD histology score 4.9 4.4 4.2 0.3

Impact of mTOR Inhibition on FoxP3+ Regulatory T Cells as Compared to Conventional T Cells after Allogeneic Bone Marrow Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 448-448 ◽  
Author(s):  
Robert Zeiser ◽  
Dennis B. Leveson-Gower ◽  
Elizabeth A. Zambricki ◽  
Jing-Zhou Hou ◽  
Robert Negrin
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
Regulatory T Cells ◽  
Allogeneic Bone Marrow Transplantation ◽  
Inhibitory Effect ◽  
Allogeneic Bone ◽  
Mtor Inhibition ◽  
The Impact

Abstract FoxP3+CD4+CD25+ regulatory T-cells (Treg) have been shown to effectively reduce the severity of experimental acute graft-versus-host disease (aGvHD) while sparing graft-versus-leukemia activity. These findings, in concert with the observation that human and murine Treg share functional characteristics, have fueled interest in clinical trials to control aGvHD. Recent data indicates that the immunosuppressant rapamycin (RAPA) in contrast to cyclosporine A does not interfere with in vivo function of Treg and could enhance Treg expansion in vitro by a yet unknown mechanism. To investigate the impact of mTOR inhibition on proliferating Treg and Tconv, both cell types were exposed to CD3/CD28 Mabs in the presence of different RAPA concentrations in vitro. Phosphorylation of mTOR downstream products p70S6K1 and 4E-BP1 were assessed by western blot and flow cytometry. Inhibition of the phosphorylation of p70S6K1 and 4E-BP1 was observed in both populations in the presence of RAPA. Interestingly, Treg were more resistant to mTOR inhibition as compared to Tconv and displayed significantly higher phosphorylated products in the presence of RAPA at 10 nM (MFI Treg vs Tconv, p&lt;0.001) and at 100nM (MFI Treg vs Tconv, p&lt;0.001). To investigate whether Treg and RAPA protect from aGvHD in a synergistic manner, BALB/c recipients were transplanted with H-2 disparate BM and 1.6x10e6 T-cells (FVB/N) after lethal irradiation (8 Gy). aGvHD lethality was only slightly reduced when suboptimal Tconv:Treg ratios were employed (4:1, 8:1), or when recipients were treated with a non-protective RAPA dose (0.5 mg/kg bodyweight). Combining a suboptimal Tconv:Treg ratio with a non-protective RAPA dose reduced expansion of luciferase expressing (luc+) Tconv and pro-inflamatory cytokines and improved survival indicative for an additive in vivo effect of RAPA and Treg. To evaluate the impact of RAPA on in vivo T cell expansion, either luc+ Tconv or luc+ Treg were adoptively transferred. In vivo bioluminescence imaging demonstrated that RAPA had a more potent inhibitory effect on proliferation of Tconv as compared to Treg (p&lt;0.05 vs. NS). We did not observe RAPA to increase FoxP3+ Treg numbers in vivo, or to enhance GITR or CTLA-4 expression. Thus, increased Treg numbers observed in RAPA containing expansion cultures are likely due to a lower susceptibility of this cell population to mTOR inhibition. This could explain the observed synergistic effect of RAPA and Treg in aGvHD protection which has relevance for clinical trials utilizing Treg to prevent aGvHD.

Only MHC-Identical Donor CD4+CD25+ Regulatory T Cells Convey Full Protection from Lethal Graft-Versus-Host Disease

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3516-3516 ◽  
Author(s):  
Julia Albrecht ◽  
Kristina Doser ◽  
Reinhard Andreesen ◽  
Joerg Ermann ◽  
Matthias Edinger ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Graft Versus Host Disease ◽  
Cd8 T Cells ◽  
Allogeneic Bone Marrow Transplantation ◽  
Treg Cells ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host ◽  
Host Type

Abstract Natural CD4+CD25+ regulatory T cells (Treg) contribute to tolerance induction after transplantation. We previously showed that the adoptive transfer of donor-derived Treg cells prevents lethal graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT) in murine disease models. In contrast, host-type Treg cells failed to protect when co-transplanted under identical conditions. We now examined whether MHC compatibility between Treg cells and conventional CD25−CD4+ and CD8+ T cells (Tconv) is required for the suppression of alloresponses, or whether elimination of host-type Treg by allo-aggressive donor Tconv cells occurred. To address this issue, mixed lymphocyte reactions were performed in which CFSE-labelled responder T cells (Tresp), Treg cells and antigen presenting cells (APC) were systematically varied with regard to their MHC haplotype. When BALB/c (H-2d) Tresp cells were stimulated with mixed BALB/c and C57BL/6 (H-2b) APC, cultures contained 26.0 ± 3.1% and 86.2 ± 2.2% proliferating CD4+ and CD8+ T cells, respectively, on 6 d. In the presence of syngeneic BALB/c Treg cells, proliferation was decreased to 9.1 ± 4.7% and 25.1 ± 4.9% for CD4+ and CD8+ Tresp cells, respectively. In contrast, in cultures with allogeneic C57BL/6 Treg cells, proliferation remained at 22.1 ± 1.8% for CD4+ and 89.6 ± 0.4% for CD8+ Tresp cells. Comparable results were obtained with C57BL/6 Tresp cells after stimulation with F1 (C57BL/6 × BALB/c; H-2b/d) or 3rd party (DBA/1; H-2q) APC. Lack of suppression in co-cultures of MHC-mismatched Tresp and Treg cells was not caused by an early elimination of allogeneic Treg cells, as those were still detectable after 6 d of allostimulation. In corresponding in vivo studies, CB6F1 or DBA/1 recipients were protected from lethal GVHD only when Tconv and Treg cells were derived from MHC-identical donors, but not when they were from two MHC-disparate strains. Transplantation of 1 × 106 C57BL/6 Tconv cells resulted in 100% lethality of CB6F1 recipients by d56. When co-transplanted with 1 × 106 C57BL/6 Treg cells, all recipients survived for 100d, whereas only 40% survived after co-transfer of the same number of BALB/c Treg (n = 15; p = 0.004). Similarly, when 1 × 106 BALB/c Tconv cells were transplanted into CB6F1 recipients, all animals died from GVHD by d46. In contrast, all recipients of BALB/c Tconv and Treg cells (ratio1:1) survived for 100d, but only 10% of recipient mice survived after co-transfer of C57BL/6 Treg (n = 10; p < 0.001). Similar results were obtained after BALB/c and C57BL/6 T cell transfer into DBA/1 (3rd party) recipients. In conclusion, these data indicate that MHC-identity between Tconv and Treg cells is required for maximum suppression of an alloresponse and that Treg cells isolated from a 3rd party donor might not be suited for the prevention of GVHD after allogeneic BMT.

Donor CD4+CD25+ T cells promote engraftment and tolerance following MHC-mismatched hematopoietic cell transplantation

Blood ◽  
2005 ◽  
Vol 105 (4) ◽  
pp. 1828-1836 ◽  
Author(s):  
Alan M. Hanash ◽  
Robert B. Levy
Keyword(s):  
T Cells ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Disease Recurrence ◽  
Hematopoietic Cell ◽  
Allogeneic Bone ◽  
Hematopoietic Stem

AbstractAllogeneic bone marrow transplantation (BMT) is a potentially curative treatment for both inherited and acquired diseases of the hematopoietic compartment; however, its wider use is limited by the frequent and severe outcome of graft-versus-host disease (GVHD). Unfortunately, efforts to reduce GVHD by removing donor T cells have resulted in poor engraftment and elevated disease recurrence. Alternative cell populations capable of supporting allogeneic hematopoietic stem/progenitor cell engraftment without inducing GVHD could increase numbers of potential recipients while broadening the pool of acceptable donors. Although unfractionated CD4+ T cells have not been shown to be an efficient facilitating population, CD4+CD25+ regulatory cells (T-reg's) were examined for their capacity to support allogeneic hematopoietic engraftment. In a murine fully major histocompatibility complex (MHC)-mismatched BMT model, cotransplantation of donor B6 T-reg's into sublethally conditioned BALB/c recipients supported significantly greater lineage-committed and multipotential donor progenitors in recipient spleens 1 week after transplantation and significantly increased long-term multilineage donor chimerism. Donor engraftment occurred without GVHD-related weight loss or lethality and was associated with tolerance to donor and host antigens by in vitro and in vivo analyses. Donor CD4+CD25+ T cells may therefore represent a potential alternative to unfractionated T cells for promotion of allogeneic engraftment in clinical hematopoietic cell transplantation. (Blood. 2005;105:1828-1836)

HDAC11 Inhibits T-Cell Response to Alloantigens and Reduces Gvhd In Mice.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1466-1466
Author(s):  
Dapeng Wang ◽  
Fengdong Cheng ◽  
Yu Yu ◽  
Kenrick Semple ◽  
Lirong Peng ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Allogeneic Bone Marrow Transplantation ◽  
T Cell Response ◽  
Allogeneic Bone ◽  
Allogeneic Bmt ◽  
Significant Difference

Abstract Abstract 1466 Background: Histone acetyltransferases and histone deacetylases (HDAC) regulate gene expression through acetylation-deacetylation of histones. HDACs are the target of a family of compounds known as HDAC inhibitors, which have been shown to suppress pro-inflammatory cytokines and reduce acute graft-versus-host disease (GVHD) while preserving the graft-versus-leukemia (GVL) effect after allogeneic bone marrow transplantation (BMT) in mice. However, the role of individual HDAC members in the development of GVHD is not clear. Recently, HDAC11, the newest member of the HDAC family has emerged as an important transcriptional regulator of inflammatory responses in antigen-presenting cells (APCs)1. Here, we evaluated the role of HDAC11 on APCs and T cells in the allogeneic BMT setting in mice with genetic disruption of HDAC11. Method: Proliferation of wild-type (WT) and HDAC11 knock-out (KO) T cells in response to allogeneic antigens was compared by [H3] thymidine incorporation assay. Using the same method, we also tested the antigen presentation ability of WT and HDAC11 KO APCs. For in vivo studies, we used a clinical relevant mouse model of BMT: C57BL/6 (B6) ® BALB/c. To evaluate the role of HDAC11 in the function of T cells and APCs, WT and KO mice on B6 background were used as donors and recipients, respectively. Recipient survival was monitored daily and GVHD symptom was evaluated at least twice a week. HDAC11 KO mice were supplied by Merck and Co., Inc. Results: In vitro, HDAC11 KO T cells proliferated stronger than WT T cells under the stimulation of allogeneic APCs. Recipients of HDAC11 KO T cells lost significantly more body weight (p < 0.05), and died significantly sooner than those of WT T cells (p < 0.01). The pathologic score of KO recipients was higher than that of WT recipients in each of GVHD target organs including lung, liver, small intestine and colon. Mechanistically, we found that there were significantly more total and IFNγ-producing donor T cells in the recipients of KO cells than those of WT cells (p < 0.05). Collectively, HDAC11 KO T cells have higher activity in response to alloantigens in vitro and induced more severe GVHD in vivo compared to WT T cells. In contrast, KO and WT APCs had a similar ability to stimulate allogeneic T cells in vitro, and no significant difference in GVHD development was observed in WT or KO recipients after allogeneic BMT. Conclusion: HDAC11 negatively regulates T-cell function, but has no significant effect on APC function. This finding provides a rationale to promote T-cell immunity or tolerance by inhibiting or enhancing HDAC11, respectively. 1 Villagra et al. Nature Immunology, 10:92-100, 2009. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Donor-type CD4+CD25+ Regulatory T Cells Suppress Lethal Acute Graft-Versus-Host Disease after Allogeneic Bone Marrow Transplantation

2002 ◽  
Vol 196 (3) ◽  
pp. 389-399 ◽  
Author(s):  
Petra Hoffmann ◽  
Joerg Ermann ◽  
Matthias Edinger ◽  
C. Garrison Fathman ◽  
Samuel Strober
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Graft Versus Host Disease ◽  
Treg Cells ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor Type ◽  
Acute Graft

Acute graft-versus-host disease (aGVHD) is still a major obstacle in clinical allogeneic bone marrow (BM) transplantation. CD4+CD25+ regulatory T (Treg) cells have recently been shown to suppress proliferative responses of CD4+CD25− T cells to alloantigenic stimulation in vitro and are required for ex vivo tolerization of donor T cells, which results in their reduced potential to induce aGVHD. Here we show that CD4+CD25+ T cells isolated from the spleen or BM of donor C57BL/6 (H-2b) mice that have not been tolerized are still potent inhibitors of the alloresponse in vitro and of lethal aGVHD induced by C57BL/6 CD4+CD25− T cells in irradiated BALB/c (H-2d) hosts in vivo. The addition of the CD4+CD25+ Treg cells at a 1:1 ratio with responder/inducer CD4+CD25− T cells resulted in a &gt;90% inhibition of the mixed leukocyte reaction and marked protection from lethal GVHD. This protective effect depended in part on the ability of the transferred CD4+CD25+ T cells to secrete interleukin 10 and occurred if the Treg cells were of donor, but not host, origin. Our results demonstrate that the balance of donor-type CD4+CD25+ Treg and conventional CD4+CD25− T cells can determine the outcome of aGVHD.

scholarly journals In vivo administration of hypomethylating agents mitigate graft-versus-host disease without sacrificing graft-versus-leukemia

Blood ◽  
2010 ◽  
Vol 116 (1) ◽  
pp. 129-139 ◽  
Author(s):  
Jaebok Choi ◽  
Julie Ritchey ◽  
Julie L. Prior ◽  
Matthew Holt ◽  
William D. Shannon ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Allogeneic Bone ◽  
Hypomethylating Agents ◽  
Host Disease ◽  
Graft Versus Host ◽  
Suppressor Function ◽  
Graft Versus Leukemia

Abstract Regulatory T cells (Tregs) suppress graft-versus-host disease (GVHD) while preserving a beneficial graft-versus-leukemia (GVL) effect. Thus, their use in allogeneic stem cell transplantation (SCT) provides a promising strategy to treat GVHD. However, 3 obstacles prevent their routine use in human clinical trials: (1) low circulating number of Tregs in peripheral blood, (2) loss of suppressor function after in vitro expansion, and (3) lack of Treg-specific surface markers necessary for efficient purification. FOXP3 is exclusively expressed in Tregs and forced expression in CD4+CD25− T cells can convert these non-Tregs into Tregs with functional suppressor function. Here, we show that the FDA-approved hypomethylating agents, decitabine (Dec) and azacitidine (AzaC), induce FOXP3 expression in CD4+CD25− T cells both in vitro and in vivo. Their suppressor function is dependent on direct contact, partially dependent on perforin 1 (Prf1), but independent of granzyme B (GzmB), and surprisingly, Foxp3. Independence of Foxp3 suggests that genes responsible for the suppressor function are also regulated by DNA methylation. We have identified 48 candidate genes for future studies. Finally, AzaC treatment of mice that received a transplant of major histocompatibility complex mismatched allogeneic bone marrow and T cells mitigates GVHD while preserving GVL by peripheral conversion of alloreactive effector T cells into FOXP3+ Tregs and epigenetic modulation of genes downstream of Foxp3 required for the suppressor function of Tregs.

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