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)

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.

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.

Adoptive transfer of costimulated T cells induces lymphocytosis in patients with relapsed/refractory non-Hodgkin lymphoma following CD34+-selected hematopoietic cell transplantation

Blood ◽  
2003 ◽  
Vol 102 (6) ◽  
pp. 2004-2013 ◽  
Author(s):  
Ginna G. Laport ◽  
Bruce L. Levine ◽  
Edward A. Stadtmauer ◽  
Stephen J. Schuster ◽  
Selina M. Luger ◽  
...  
Keyword(s):  
T Cells ◽  
Hodgkin Lymphoma ◽  
Cell Transplantation ◽  
Adoptive Transfer ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
High Dose ◽  
Non Hodgkin Lymphoma ◽  
Cytokine Activation

Abstract We explored the feasibility and toxicity of administering escalating doses of anti-CD3/CD28 ex vivo costimulated T cells as a therapeutic adjunct for patients with relapsed, refractory, or chemotherapy-resistant, aggressive non-Hodgkin lymphoma (NHL) following high-dose chemotherapy and CD34+-selected hematopoietic cell transplantation (HCT). Sixteen patients had infusions on day 14 after HCT of autologous T cells that had been stimulated using beads coated with anti-CD3 and anti-CD28 monoclonal antibodies. At baseline, the subjects had severe quantitative and functional T-cell impairments. The culture procedure partially reversed impaired cytokine responsiveness in T cells in vitro and in vivo. Transient dose-dependent infusion toxicities were observed. There was a rapid reconstitution of lymphocytes; however, there were persistent defects in CD4 T cells. Most interestingly, 5 patients had a delayed lymphocytosis between day 30 and day 120 after HCT. Maximal clinical responses included 5 patients with a complete response (CR), 7 patients with a partial response (PR), and 4 patients with stable disease. At a median follow-up of 33 months (range, 26-60 months), 5 patients are alive with stable or relapsed disease and 3 patients remain in CR. In conclusion, this phase 1 trial demonstrates that adoptive transfer of autologous costimulated T cells (1) is feasible in heavily pretreated patients with advanced NHL, (2) is associated with a rapid recovery of lymphocyte counts, (3) reverses cytokine activation deficits in vitro, and (4) is associated with delayed lymphocytosis in a subset of patients.

scholarly journals Origin of human mast cells: development from transplanted hematopoietic stem cells after allogeneic bone marrow transplantation

Blood ◽  
1994 ◽  
Vol 84 (9) ◽  
pp. 2954-2959 ◽  
Author(s):  
M Fodinger ◽  
G Fritsch ◽  
K Winkler ◽  
W Emminger ◽  
G Mitterbauer ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
Mast Cells ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
Donor Genotype

Although mast cells are hematopoietic cells, little is known about the origin of their precursors in vivo. In this study, the origin (donor v recipient genotype) of human mast cells (MCs) was analyzed in a patient who underwent allogeneic bone marrow transplantation (BMT). The patient presented with secondary acute myeloid leukemia (French-American- British classification, M2) arising from refractory anemia with excess of blast cells and bone marrow (BM) mastocytosis. Transplantation was performed in chemotherapy-induced complete remission. On days 88, 126, 198, and 494 after BMT, mast cells were enriched to homogeneity from bone marrow mononuclear cells (BM MNCs) by cell sorting for CD117+/CD34- cells. Purified mast cell populations were CD117(c-kit)+ (> 95%), CD34- (< 1%), CD3- (< 1%), CD14- (< 1%), and virtually free of contaminating cells as assessed by Giemsa staining. The genotype of MCs was analyzed after amplification by polymerase chain reaction (PCR) of a variable number tandem repeat (VNTR) region within intron 40 of the von Willebrand factor (vWF) gene. Unexpectedly, on days 88 and 126 after BMT, sorted MCs displayed recipient genotype as shown by vWF.VNTR-PCR. However, on days 198 and 494, PCR analysis showed a switch to donor genotype in isolated mast cells. Peripheral blood (PB) and BM MNC as well as highly enriched (sorted) CD3+ T cells (PB, BM), CD4+ helper T cells (PB), CD8+ T cells (PB), CD19+ B cells (PB), CD14+ monocytes (PB, BM), and CD34+ precursor cells (BM) showed donor genotype throughout the observation period. Together, these results provide evidence that human MCs developed in vivo from transplanted hematopoietic stem cells. Engraftment and in vivo differentiation of MCs from early hematopoietic progenitor cells may be a prolonged process.

scholarly journals Mesenchymal stromal cells in hematopoietic cell transplantation

2020 ◽  
Vol 4 (22) ◽  
pp. 5877-5887
Author(s):  
Andre J. Burnham ◽  
Lisa P. Daley-Bauer ◽  
Edwin M. Horwitz
Keyword(s):  
Cell Transplantation ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Hematopoietic Cell Transplantation ◽  
The United States ◽  
Hematopoietic Cell ◽  
Immunomodulatory Activity ◽  
Critical Determinant ◽  
Hematopoietic Stem

Abstract Mesenchymal stromal cells (MSCs) are widely recognized to possess potent immunomodulatory activity, as well as to stimulate repair and regeneration of diseased or damaged tissue. These fundamental properties suggest important applications in hematopoietic cell transplantation. Although the mechanisms of therapeutic activity in vivo are yet to be fully elucidated, MSCs seem to suppress lymphocytes by paracrine mechanisms, including secreted mediators and metabolic modulators. Most recently, host macrophage engulfment of apoptotic MSCs has emerged as an important contributor to the immune suppressive microenvironment. Although bone marrow–derived MSCs are the most commonly studied, the tissue source of MSCs may be a critical determinant of immunomodulatory function. The key application of MSC therapy in hematopoietic cell transplantation is to prevent or treat graft-versus-host disease (GVHD). The pathogenesis of GVHD reveals multiple potential targets. Moreover, the recently proposed concept of tissue tolerance suggests a new possible mechanism of MSC therapy for GVHD. Beyond GVHD, MSCs may facilitate hematopoietic stem cell engraftment, which could gain greater importance with increasing use of haploidentical transplantation. Despite many challenges and much doubt, commercial MSC products for pediatric steroid-refractory GVHD have been licensed in Japan, conditionally licensed in Canada and New Zealand, and have been recommended for approval by an FDA Advisory Committee in the United States. Here, we review key historical data in the context of the most salient recent findings to present the current state of MSCs as adjunct cell therapy in hematopoietic cell transplantation.

Alloantigeneic Reactions after Human Hematopoietic Cell Transplantation Induce Genomic Alterations in Epithelium: A Confirmation in Vivo and in Vitro Study and Implications to Secondary Neoplasia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 452-452
Author(s):  
Maria Themeli ◽  
Loizos Petrikkos ◽  
Miguel Waterhouse ◽  
Hartmut Bertz ◽  
Eleni Lagadinou ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Secondary Malignancy ◽  
Hacat Cells ◽  
Genomic Alterations ◽  
Allogeneic Hct ◽  
Dna Strand

Abstract We previously demonstrated frequent genomic alterations measured by microsatellite instability (MSI) in non-neoplastic epithelial tissues of pts who underwent allogeneic Hematopoietic Cell Transplantation (HCT) but not after autologous transplantation (Blood2006;107:3389–3396). Confirmation in a larger and independent patient cohort and demonstration in an in vitro system was needed. In total 176 buccal samples obtained from 71 unselected patients who underwent allogeneic HCT were analyzed for MSI with standard PCR for microsatellite markers (THO-1, SEE33, D14S120 and D1S80) and analysis by capillary electrophoresis. MSI was observed in 37 (52%) allo-transplanted pts but never in the 31 controls (16 healthy and 15 pts after auto-HCT, 47 samples). MSI+ pts were significantly older than MSI-pts (median age 60y vs 48y, p&lt;0.05). Other clinical features were not significantly different between MSI+ and MSI− pts: gender, myeloid vs lymphoid disease, sibling vs unrelated HCT, myeloablative vs reduced intensity conditioning, sex mismatched transplantation, bone marrow vs mobilized peripheral blood graft, T-cell depletion of the graft, use of methotrexate for GvHD prophylaxis, number of CD3+ cells/kg b.w. infused, occurrence and grade of mucositis during neutropenia, CMV reactivation, median ferritin levels post-transplant and occurrence of GvHD vs no GvHD. When GVHD was analyzed according to its severity we found that there was a trend for increasing risk of MSI for pts who experienced severe GvHD (RR=1.8) as compared to pts with no GvHD (RR=1). Secondary malignancy (5 skin-, 1 adeno-Ca) was diagnosed in 5 (14%) of the MSI+ pts and only in 1 (3%) MSI− pts. In an in vitro model of mutation analysis we tested the hypothesis that an alloantigenic stimulus is substantially involved in the mutation process. Briefly, keratinocyte DNA-repair proficient HaCaT cells were transfected with a reporter plasmid and genomic instability (GI) was detected and measured as hygromycin resistant clones. Treatment of HaCaT cells with H2O2 resulted in a time and dose dependent GI induction (1.9–5.7 fold). Cytokines abundant in alloreactions such as IFN-γ, TNF-α, TGF-β didn’t result in any GI in various concentrations and incubation times. Also, treatment with supernatants from different MHC non-matched Mixed Lymphocyte Cultures (MLC-SN) or with MLC separated from HaCaT cells with a semipermeable membrane didn’t induce any significant GI. In contrast, exposure of HaCaT cells to the whole MLC which includes activated cellular components (measured as BrdU+) resulted in significant induction of GI in 6 out of 8 different cases (mean 2.4-fold). GI was also evaluated in terms of DNA strand break formation by using the neutral comet assay. Treatment of HaCaT cells with whole MLC resulted in significant increase of DNA strand breaks as compared to HaCaT cells exposed to MLC-SN (p=0.039) or untreated controls (p=0.048). Western blot analysis revealed no significant alterations in the levels of MMR proteins upon treatment with MLC or MLC-SN. Exposure of HaCaT cells to MLC or MLC-SN resulted in increase of intracellular ROS levels as compared to untreated cells. The MLC treatment caused significantly higher increase of ROS levels than MLC-SN. The results of the present study confirm that GI of epithelial cells is a frequent phenomenon in patients after allogeneic HCT and give in vivo and in vitro support that alloantigeneic processes can be the cause of such a phenomenon. Progress in understanding DNA damage and repair after allogeneic HCT can potentially provide molecular biomarkers and therapeutic targets.

An Engineered Cell Surface Polypeptide for Selection, Tracking and Ablation of Genetically Modified Hematopoietically Derived Cells Based on Human EGFR.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1469-1469
Author(s):  
Xiuli Wang ◽  
Wen-Chung Chang ◽  
ChingLam W Wong ◽  
David Colcher ◽  
Mark Sherman ◽  
...  
Keyword(s):  
T Cells ◽  
Genetic Engineering ◽  
Cell Surface ◽  
Ex Vivo ◽  
Hematopoietic Cell ◽  
Selection Marker ◽  
Type I ◽  
Hematopoietic Stem

Abstract Abstract 1469 Hematopoietic cell-based therapies, including genetically manipulated cell products derived from either hematopoietic stem cells or T cells, is an emerging area in applied biotechnology. In both of these venues, a variety of genetic engineering approaches are being studied to endow cells with novel attributes, to increase their therapeutic potency and/or safety. Common to the field of ex vivo cellular genetic engineering is the need to purify cells that express desired quantities of therapeutic transgene(s) and cull out non-expressing cells that either lack transgene endowed therapeutic activity or safety features. However, current drug selection strategies are associated with prolonged ex vivo culture that drives terminal differentiation of the T cells, which has in turn been found to be associated with impaired antitumor efficacy of adoptively transferred CD8+ T cells in vivo. Thus, we were interested in developing a single transgene encoded polypeptide that can serve both as an ex vivo selection epitope and in vivo tracking marker/target for mAb-mediated cell ablation, while fulfilling the criteria of being functionally inert, non immunogenic, and amenable to commercially available cGMP-grade selection systems appropriate for clinical use. Here we describe a truncated human EGFR polypeptide (huEGFRt) devoid of extracellular N-terminal ligand binding domains and intracellular receptor tyrosine kinase domains. Retained features of huEGFRt include type I transmembrane cell surface localization and a conformationally intact binding epitope for pharmaceutical-grade anti-EGFR mAb, cetuximab/Erbitux™. Applying this system to cellular immunotherapy, we designed lentiviral vector prototypes housing multifunctional constructs combining huEGFRt with CD19-specific chimeric antigen receptors (CARs), and demonstrate that biotinylated-cetuximab immunomagnetic selection of transduced human T cells results in coordinate enrichment of CAR+ cells from 2% to over 90%. The huEGFRt-mediated selection did not affect the phenotype (i.e., TCR, CD3, CD4, CD8, CD28, and granzyme A expression), the in vitro expansion potential, nor the in vivo engraftment fitness (upon transfer into immunodeficient mice) of the T cells. Direct examination of EGF-binding and phospho-tyrosine analysis confirmed that this selection marker is functionally inert and has no negative effect on the T cell product. In addition, cytotoxicity against B cell malignancies and IFN-g/TNF-a production through the CD19-specific CAR was dramatically enhanced in the huEGFRt-selected population. The utility of huEGFRt in tracking the gene modified, transferred cells in vivo within easily obtained human tissues such as blood, bone marrow and tissue biopsies was then also proven via detection of huEGFRt using multiparameter flow cytometric analysis or FDA approved immunohistochemical techniques/reagents. In addition, we were able to demonstrate that Erbitux™ could mediate ADCC of huEGFRt+ T cells in vitro and inhibit the growth of huEGFRt+ CTLL2 cells in NOD/Scid mice, supporting the use of huEGFRt as a suicide gene via cetuximab-mediated ADCC after adoptive transfer. Together these data suggest that huEGFRt is a superior selection marker for any transduction system that can be applied to the generation of cell products for hematopoietic cell-based medical therapies. Disclosures: No relevant conflicts of interest to declare.

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.

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