Prevention of murine sclerodermatous chronic graft-versus-host disease by Rapamycin Belle L, Binsfeld M, Caers J, Dubois S, Briquet A, Hannon M, Beguin.

Slides:



Advertisements
Similar presentations
Absence of Xeno-rejection and Xenoantibody Production in IL-7 KO Recipients After Xenoheart, but not after Xenoskin Transplantation. Shengqiao Li, Yuan.
Advertisements

A Crucial Role for Host APCs in the Induction of Donor CD4 + CD25 + Regulatory T Cell-Mediated Suppression of Experimental Graft-versus-Host Disease Isao.
Abstract Immune Reconstitution and Clinical Outcome After Donor Lymphocyte Infusion for Relapsed Disease After Reduced-Intensity Allogeneic Hematopoietic.
Patient Characteristic
Recombinant CD95-Fc (APG101) prevents graft-versus-host disease in mice without disabling antitumor cytotoxicity and T-cell functions by Natalie Hartmann,
Reduced Graft-versus-Host Disease in C3-Deficient Mice Is Associated with Decreased Donor Th1/Th17 Differentiation  Qing Ma, Dan Li, Roza Nurieva, Rebecca.
Host-Derived CD8+ Dendritic Cells Protect Against Acute Graft-versus-Host Disease after Experimental Allogeneic Bone Marrow Transplantation  Michael Weber,
Inhibition of the IRE-1α/XBP-1 pathway prevents chronic GVHD and preserves the GVL effect in mice by Steven D. Schutt, Yongxia Wu, Chih-Hang Anthony Tang,
Depletion of Naïve Lymphocytes with Fas Ligand Ex Vivo Prevents Graft-versus-Host Disease without Impairing T Cell Support of Engraftment or Graft-versus-Tumor.
Influence of Donor Microbiota on the Severity of Experimental Graft-versus-Host- Disease  Isao Tawara, Chen Liu, Hiroya Tamaki, Tomomi Toubai, Yaping Sun,
Stromal-Derived Factor-1α and Interleukin-7 Treatment Improves Homeostatic Proliferation of Naïve CD4+ T Cells after Allogeneic Stem Cell Transplantation 
Host-Derived Interleukin-18 Differentially Impacts Regulatory and Conventional T Cell Expansion During Acute Graft-Versus-Host Disease  Robert Zeiser,
IL-2–Targeted Therapy Ameliorates the Severity of Graft-versus-Host Disease: Ex Vivo Selective Depletion of Host-Reactive T Cells and In Vivo Therapy 
Juyang Kim, Wongyoung Kim, Hyun J. Kim, Sohye Park, Hyun-A
Th2 Cell Therapy of Established Acute Graft-Versus-Host Disease Requires IL-4 and IL- 10 and Is Abrogated by IL-2 or Host-Type Antigen-Presenting Cells 
Chronic graft-versus-host disease after granulocyte colony-stimulating factor-mobilized allogeneic stem cell transplantation: the role of donor T-cell.
Inhibition of EGFR Tyrosine Kinase by Erlotinib Prevents Sclerodermatous Graft-Versus- Host Disease in a Mouse Model  Florence Morin, Niloufar Kavian,
Induction of Immunity to Neuroblastoma Early after Syngeneic Hematopoietic Stem Cell Transplantation Using a Novel Mouse Tumor Vaccine  Weiqing Jing,
Marked in Vivo Donor Regulatory T Cell Expansion via Interleukin-2 and TL1A-Ig Stimulation Ameliorates Graft-versus-Host Disease but Preserves Graft-versus-
Ping Zhang, Jieying Wu, Divino Deoliveira, Nelson J. Chao, Benny J
Induction of heme oxygenase-1 before conditioning results in improved survival and reduced graft-versus-host disease after experimental allogeneic bone.
Preventive Azithromycin Treatment Reduces Noninfectious Lung Injury and Acute Graft- versus-Host Disease in a Murine Model of Allogeneic Hematopoietic.
Mesenchymal Stem Cells (MSCs) Attenuate Cutaneous Sclerodermatous Graft-Versus- Host Disease (Scl-GVHD) through Inhibition of Immune Cell Infiltration.
IL-21 blockade reduces graft-versus-host disease mortality by supporting inducible T regulatory cell generation by Christoph Bucher, Lisa Koch, Christine.
LBH589 Enhances T Cell Activation In Vivo and Accelerates Graft-versus-Host Disease in Mice  Dapeng Wang, Cristina Iclozan, Chen Liu, Changqing Xia, Claudio.
Cytosine-Phosphorothionate-Guanine Oligodeoxynucleotides Exacerbates Hemophagocytosis by Inducing Tumor Necrosis Factor–Alpha Production in Mice after.
The histone methyltransferase Ezh2 is a crucial epigenetic regulator of allogeneic T-cell responses mediating graft-versus-host disease by Shan He, Fang.
Redirection of Regulatory T Cells With Predetermined Specificity for the Treatment of Experimental Colitis in Mice  Eran Elinav, Tova Waks, Zelig Eshhar 
by Sheng F. Cai, Xuefang Cao, Anjum Hassan, Todd A
PreImplantation Factor Reduces Graft-versus-Host Disease by Regulating Immune Response and Lowering Oxidative Stress (Murine Model)  Yehudith Azar, Reut.
Blocking LFA-1 Activation with Lovastatin Prevents Graft-versus-Host Disease in Mouse Bone Marrow Transplantation  Yang Wang, Dan Li, Dan Jones, Roland.
IL-6 Blockade Attenuates the Development of Murine Sclerodermatous Chronic Graft- Versus-Host Disease  Doanh Le Huu, Takashi Matsushita, Guihua Jin, Yasuhito.
IL-17 Gene Ablation Does Not Impact Treg-Mediated Suppression of Graft-Versus-Host Disease after Bone Marrow Transplantation  Lucrezia Colonna, Mareike.
Induction of Graft-versus-Leukemia (GVL) Effect without Graft-versus-Host Disease (GVHD) by Pretransplant Donor Treatment with Immunomodulators  Shoshana.
The Synthetic Triterpenoid, CDDO, Suppresses Alloreactive T Cell Responses and Reduces Murine Early Acute Graft-versus-Host Disease Mortality  Kai Sun,
Therapeutic Effects of a NEDD8-Activating Enzyme Inhibitor, Pevonedistat, on Sclerodermatous Graft-versus-Host Disease in Mice  Chien-Chun Steven Pai,
Treatment with a Rho Kinase Inhibitor Improves Survival from Graft-Versus-Host Disease in Mice after MHC-Haploidentical Hematopoietic Cell Transplantation 
Pharmacologic Expansion of Donor-Derived, Naturally Occurring CD4+Foxp3+ Regulatory T Cells Reduces Acute Graft-versus-Host Disease Lethality Without.
Volume 22, Issue 12, Pages (December 2014)
The Triterpenoid CDDO-Me Delays Murine Acute Graft-versus-Host Disease with the Preservation of Graft-versus-Tumor Effects after Allogeneic Bone Marrow.
Minor Antigen Distribution Predicts Site-Specific Graft-versus-Tumor Activity of Adoptively Transferred, Minor Antigen-Specific CD8 T Cells  Jessica C.
Double Haploidentical Hematopoietic Stem Cell Transplantation Results in Successful Engraftment of Bone Marrow from Both Donors without Graft-versus-Host.
Sequential Expression of Adhesion and Costimulatory Molecules in Graft-versus-Host Disease Target Organs after Murine Bone Marrow Transplantation across.
An Essential Role for IFN-γ in Regulation of Alloreactive CD8 T Cells Following Allogeneic Hematopoietic Cell Transplantation  Wannee Asavaroengchai,
Therapeutic Benefit of Bortezomib on Acute Graft-versus-Host Disease Is Tissue Specific and Is Associated with Interleukin-6 Levels  Chien-Chun Steven.
Blocking Activator Protein 1 Activity in Donor Cells Reduces Severity of Acute Graft- Versus-Host Disease through Reciprocal Regulation of IL-17–Producing.
Essential Role of Interleukin-12/23p40 in the Development of Graft-versus-Host Disease in Mice  Yongxia Wu, David Bastian, Steven Schutt, Hung Nguyen,
Hydrodynamic Delivery of Human IL-15 cDNA Increases Murine Natural Killer Cell Recovery after Syngeneic Bone Marrow Transplantation  Isabel Barao, Maite.
Marked in Vivo Donor Regulatory T Cell Expansion via Interleukin-2 and TL1A-Ig Stimulation Ameliorates Graft-versus-Host Disease but Preserves Graft-versus-
The Triterpenoid CDDO-Me Delays Murine Acute Graft-versus-Host Disease with the Preservation of Graft-versus-Tumor Effects after Allogeneic Bone Marrow.
Immunologic Resolution of Human Chronic Graft-versus-Host Disease
Host Basophils Are Dispensable for Induction of Donor T Helper 2 Cell Differentiation and Severity of Experimental Graft-versus-Host Disease  Isao Tawara,
Th2 Cell Therapy of Established Acute Graft-Versus-Host Disease Requires IL-4 and IL- 10 and Is Abrogated by IL-2 or Host-Type Antigen-Presenting Cells 
A Radio-Resistant Perforin-Expressing Lymphoid Population Controls Allogeneic T Cell Engraftment, Activation, and Onset of Graft-versus-Host Disease in.
Dynamic Change and Impact of Myeloid-Derived Suppressor Cells in Allogeneic Bone Marrow Transplantation in Mice  Dapeng Wang, Yu Yu, Kelley Haarberg,
Mammalian Target of Rapamycin Inhibitors Permit Regulatory T Cell Reconstitution and Inhibit Experimental Chronic Graft-versus-Host Disease  Haruko Sugiyama,
Tracking ex vivo-expanded CD4+CD25+ and CD8+CD25+ regulatory T cells after infusion to prevent donor lymphocyte infusion-induced lethal acute graft-versus-host.
In Situ Activation and Expansion of Host Tregs: A New Approach to Enhance Donor Chimerism and Stable Engraftment in Major Histocompatibility Complex-Matched.
Suppression of Murine Colitis and its Associated Cancer by Carcinoembryonic Antigen- Specific Regulatory T Cells  Dan Blat, Ehud Zigmond, Zoya Alteber,
Recipient B Cells Are Not Required for Graft-Versus-Host Disease Induction  Catherine Matte-Martone, Xiajian Wang, Britt Anderson, Dhanpat Jain, Anthony.
Donor antigen-presenting cells regulate T-cell expansion and antitumor activity after allogeneic bone marrow transplantation  Jian-Ming Li, Edmund K.
Brile Chung, Eric Dudl, Akira Toyama, Lora Barsky, Kenneth I. Weinberg 
CD25 Blockade Delays Regulatory T Cell Reconstitution and Does Not Prevent Graft- versus-Host Disease After Allogeneic Hematopoietic Cell Transplantation 
In Vivo Expansion of Regulatory T cells With IL-2/IL-2 mAb Complexes Prevents Anti- factor VIII Immune Responses in Hemophilia A Mice Treated With Factor.
Specific donor Vβ-associated CD4+ T-cell responses correlate with severe acute graft- versus-host disease directed to multiple minor histocompatibility.
Induction of Lethal Graft-versus-Host Disease by Anti-CD137 Monoclonal Antibody in Mice Prone to Chronic Graft-versus-Host Disease  Wonyoung Kim, Juyang.
Cutaneous Gene Expression by DNA Microarray in Murine Sclerodermatous Graft- Versus-Host Disease, a Model for Human Scleroderma  Lixin Zhou, David Askew,
Anti-PD-1H Antibody Prevents Graft Versus Host Disease
Figure 5. Hematopoietic cell specific Atg5 deficiency results in aberrant proliferation and mitochondrial dysfunction in hematopoietic cells. (A) Apoptosis.
Volume 10, Issue 5, Pages (February 2015)
Presentation transcript:

Prevention of murine sclerodermatous chronic graft-versus-host disease by Rapamycin Belle L, Binsfeld M, Caers J, Dubois S, Briquet A, Hannon M, Beguin Y, Humblet S and Baron F Hematolgy Research Unit, GIGA-I3, University of Liege, Liege, Belgium Background Results Conclusion Chronic GvHD occurs up to 50 % in long-term survivors and is the main cause of late mortality and morbidity after allo-HSCT. Despite its high frequency, current treatment of sclerodermatous cGvHD remains unsatisfactory and based on a long treatment with relatively high-dose corticosteroids. The most widely used mice model of chronic graft-versus-host disease (cGvHD) is an MHC-matched bone marrow transplantation model of sclerodermatous cGvHD. However, the mortality is low, making challenging to study the impact of potentially therapeutic compounds. The aim was to develop a more severe model of cGVHD and to assess the impact of Rapamycin administration. All mice from the severe model died a median of 32 days while 3 of 11 mice in the classical model survived beyond day 52. Mean survival was decreased in the severe model compared to the classical model (Fig. 1A). Recipient mice in the severe group experienced higher weight loss, hair loss and skin fibrosis (Fig. 1B-C). Numbers of CD8 + T lymphocytes and CD4 + T cells per microliter of blood at day 21 were lower in the severe group than in the classical model. Moreover, number and frequency of regulatory T cells (Tregs) was decreased in the severe model (Fig. 2). We then investigated whether rapamycin administration could prevent GVHD in the severe model. All mice treated with PBS died a median of 32 days after transplantation, while 7 of 13 mice given 1mg/kg/day i.p. rapamycin survived beyond day 52 (Fig. 3). Number of Tregs/µl was higher at day 21 in rapamycin-treated mice than in mice given PBS (Fig. 4A). Moreover, number of naïve CD4 + T, effector memory CD4 + T cells (EMT) and central memory CD4 + T cells (CMT) were higher in rapamycin mice. Finally, proliferation of EMT (assessed by flow cytometry using Ki-67) and CMT was higher in PBS than in rapamycin mice (Fig. 4B). We have developed a mice model of severe cGVHD. Interestingly, rapamycin prevented death from cGVHD in that model, perhaps through in vivo expansion of Treg. Figure 3. Rapamycin prevented deaths due to cGvHD. Seven days after receiving allo-HSCT, Balb/cJ mice were divided in two groups. One group receives daily injection of Rapamycin 1 mg/kg/day after day 7, one group with daily injection of PBS (placebo). (A) : Survival for the severe model. (B) : Survival for the classical model. (C) Representative pictures. Methods BA A Figure 4. CD4 T cell subpopulations and Tregs in blood. Blood was collected from cGvHD mice and a flow cytometry staining for CD4 T cells was performed. Cells were labelled with antibodies conjugated with fluorochromes. Data acquisition was realized on a FACSCantoII. (A). Focus on the Tregs cells (B). Central memory CD4 + T cells in each group. The well-described MHC-matched bone marrow transplantation model of sclerodermatous cGvHD use Balb/C and B10.D2 mice. Lethally irradiated Balb/C mice were injected with 10x10 6 bone marrow cells and 70x10 6 splenocytes from B10.D2 donor mice. Twenty-one days later, all mice developed cGvHD. For the severe model, donor B10.D2 mice were injected with 0.5x10 6 splenocytes from Balb/C twenty-one days before transplantation. “Sensitized” B10.D2 donor mice were then sacrificied. B10.D2 splenocytes and bone marrow cells were then injected into Balb/C recipient mice. For the experiments where preventive effects of rapamycin were investigated, allo-transplanted recipient Balb/C were treated from D+7 post-transplantation with rapamycin 1 mg/Kg/Day ip. ABC AD Figure 1. Mortality and cGvHD clinical score were higher and occurred earlier in the severe model. (A). Survival curves., all mice with a score of x ≥ 8 were sacrificied. (B). Clinical scores were calcultated by evaluating 5 criteria: Weight loss, Posture, Skin Lesions,, Hair loss and activity (0-1-2 points for each criteria). (C) Representative pictures CB Figure 2. Impact of severe cGvHD on absolute numbers per microliter of Regulatory T Cells (FoxP3 + CD4 + T cells) and CD4 T and CD8 T cell subpopulation at day+21 after allo-HSCT. (A). Focus on the CD4 + T cells (B). Comparison of CD8 + T cell numbers in each group (C). Absolute number of Regulatory T cells (D). T regs /CD4 of Central Memory T cells. Median.. Mann Whitney T test.. PBS Rapamycin AC B AB