Therapeutics for Graft-versus-Host Disease: From Conventional Therapies to Novel Virotherapeutic Strategies

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has a curative potential for many hematologic malignancies and blood diseases. However, the success of allo-HSCT is limited by graft-versus-host disease (GVHD), an immunological syndrome that involves inflammation and tissue damage mediated by donor lymphocytes. Despite immune suppression, GVHD is highly incident even after allo-HSCT using human leukocyte antigen (HLA)-matched donors. Therefore, alternative and more effective therapies are needed to prevent or control GVHD while preserving the beneficial graft-versus-cancer (GVC) effects against residual disease. Among novel therapeutics for GVHD, oncolytic viruses such as myxoma virus (MYXV) are receiving increased attention due to their dual role in controlling GVHD while preserving or augmenting GVC. This review focuses on the molecular basis of GVHD, as well as state-of-the-art advances in developing novel therapies to prevent or control GVHD while minimizing impact on GVC. Recent literature regarding conventional and the emerging therapies are summarized, with special emphasis on virotherapy to prevent GVHD. Recent advances using preclinical models with oncolytic viruses such as MYXV to ameliorate the deleterious consequences of GVHD, while maintaining or improving the anti-cancer benefits of GVC will be reviewed.

[1]  Nancy Y. Villa,et al.  Ex vivo virotherapy with myxoma virus does not impair hematopoietic stem and progenitor cells. , 2016, Cytotherapy.

[2]  J. Goldberg,et al.  CD34-Selected Hematopoietic Stem Cell Transplants Conditioned with Myeloablative Regimens and Antithymocyte Globulin for Advanced Myelodysplastic Syndrome: Limited Graft-versus-Host Disease without Increased Relapse. , 2015, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[3]  C. Lengerke,et al.  Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey , 2015, Leukemia.

[4]  G. McFadden,et al.  Prevention of EBV lymphoma development by oncolytic myxoma virus in a murine xenograft model of post-transplant lymphoproliferative disease. , 2015, Biochemical and biophysical research communications.

[5]  Nancy Y. Villa,et al.  Myxoma virus suppresses proliferation of activated T lymphocytes yet permits oncolytic virus transfer to cancer cells. , 2015, Blood.

[6]  C. Bordignon,et al.  Improving the safety of cell therapy with the TK-suicide gene , 2015, Front. Pharmacol..

[7]  M. Hallek,et al.  [Allogeneic haematopoietic stem cell transplantation - an overview]. , 2015, Klinische Monatsblatter fur Augenheilkunde.

[8]  S. Mineishi,et al.  State-of-the-art acute and chronic GVHD treatment , 2015, International Journal of Hematology.

[9]  J. Ritz,et al.  Aberrant B-cell homeostasis in chronic GVHD. , 2015, Blood.

[10]  G. Rosner,et al.  Single-agent GVHD prophylaxis with posttransplantation cyclophosphamide after myeloablative, HLA-matched BMT for AML, ALL, and MDS. , 2014, Blood.

[11]  J. Jagdeo,et al.  Treatment of chronic graft-versus-host disease with bortezomib. , 2014, Blood.

[12]  M. Tanimoto,et al.  Programmed Death-1 Pathway in Host Tissues Ameliorates Th17/Th1-Mediated Experimental Chronic Graft-versus-Host Disease , 2014, The Journal of Immunology.

[13]  S. Choi,et al.  Current and emerging strategies for the prevention of graft-versus-host disease , 2014, Nature Reviews Clinical Oncology.

[14]  L. Gonçalves,et al.  Randomized double-blind clinical trial comparing clobetasol and dexamethasone for the topical treatment of symptomatic oral chronic graft-versus-host disease. , 2014, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[15]  C. Cancrini,et al.  HLA-haploidentical stem cell transplantation after removal of αβ+ T and B cells in children with nonmalignant disorders. , 2014, Blood.

[16]  G. Hill,et al.  The biology of graft-versus-host disease: experimental systems instructing clinical practice. , 2014, Blood.

[17]  R. Skinner,et al.  Recent advances in the management of graft-versus-host disease , 2014, Archives of Disease in Childhood.

[18]  R. Krance,et al.  Long-term outcome after haploidentical stem cell transplant and infusion of T cells expressing the inducible caspase 9 safety transgene. , 2014, Blood.

[19]  C. Peschel,et al.  Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. , 2014, Blood.

[20]  A. Mócsai,et al.  Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage , 2014, Nature Medicine.

[21]  W. Wiktor-Jedrzejczak,et al.  Prophylaxis and treatment of GVHD: EBMT–ELN working group recommendations for a standardized practice , 2014, Bone Marrow Transplantation.

[22]  F. Baron,et al.  Thinking Out of the Box—New Approaches to Controlling GVHD , 2014, Current Hematologic Malignancy Reports.

[23]  C. Ebens,et al.  Notch signaling in hematopoietic cell transplantation and T cell alloimmunity. , 2013, Blood reviews.

[24]  G. Freeman,et al.  Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-versus-host disease lethality. , 2013, Blood.

[25]  A. Beg,et al.  Pharmacologic inhibition of PKCα and PKCθ prevents GVHD while preserving GVL activity in mice. , 2013, Blood.

[26]  M. Idzko,et al.  The Nlrp3 inflammasome regulates acute graft-versus-host disease , 2013, The Journal of experimental medicine.

[27]  G. McFadden,et al.  Oncolytic myxoma virus: the path to clinic. , 2013, Vaccine.

[28]  G. McFadden,et al.  Myxoma Virus Protein M029 Is a Dual Function Immunomodulator that Inhibits PKR and Also Conscripts RHA/DHX9 to Promote Expanded Host Tropism and Viral Replication , 2013, PLoS pathogens.

[29]  D. Roelen,et al.  Proteasome Inhibition Profoundly Affects Activated Human B Cells , 2013, Transplantation.

[30]  J. Apperley,et al.  Treatment and management of graft-versus-host disease: improving response and survival , 2013, Therapeutic advances in hematology.

[31]  J. Licht,et al.  Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. , 2013, Immunity.

[32]  G. McFadden,et al.  Myxoma and Vaccinia Viruses Bind Differentially to Human Leukocytes , 2013, Journal of Virology.

[33]  K. MacDonald,et al.  Biology of graft-versus-host responses: recent insights. , 2013, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[34]  M. Pasquini,et al.  2013 report from the Center for International Blood and Marrow Transplant Research (CIBMTR): current uses and outcomes of hematopoietic cell transplants for blood and bone marrow disorders. , 2013, Clinical transplants.

[35]  M. Tanimoto,et al.  Chronic graft-versus-host disease: disease biology and novel therapeutic strategies. , 2013, Acta medica Okayama.

[36]  G. McFadden,et al.  Selective purging of human multiple myeloma cells from autologous stem cell transplantation grafts using oncolytic myxoma virus. , 2012, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[37]  G. Núñez,et al.  Orchestrating Inflammasomes , 2012, Science.

[38]  J. O’Shea,et al.  STAT3 transcription factor promotes instability of nTreg cells and limits generation of iTreg cells during acute murine graft-versus-host disease. , 2012, Immunity.

[39]  G. McFadden,et al.  Virotherapy Using Myxoma Virus Prevents Lethal Graft-versus-Host Disease following Xeno-Transplantation with Primary Human Hematopoietic Stem Cells , 2012, PloS one.

[40]  J. Wingard,et al.  First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American Society of Blood and Marrow Transplantation. , 2012, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[41]  Bruce R. Blazar,et al.  Advances in graft-versus-host disease biology and therapy , 2012, Nature Reviews Immunology.

[42]  E. Scott,et al.  Acute myeloid leukemia targeting by myxoma virus in vivo depends on cell binding but not permissiveness to infection in vitro. , 2012, Leukemia research.

[43]  P. Kerr Myxomatosis in Australia and Europe: a model for emerging infectious diseases. , 2012, Antiviral research.

[44]  M. Tanimoto,et al.  Synthetic retinoid Am80 ameliorates chronic graft-versus-host disease by down-regulating Th1 and Th17. , 2012, Blood.

[45]  S. Kim,et al.  B cell homeostasis and the development of chronic graft-versus-host disease: implications for B cell-depleting therapy , 2012, Leukemia & lymphoma.

[46]  G. McFadden,et al.  Oncolytic Virotherapy for Hematological Malignancies , 2011, Advances in virology.

[47]  M. Caligiuri,et al.  Regulation of acute graft-versus-host disease by microRNA-155. , 2010, Blood.

[48]  S. Varambally,et al.  Inhibition of histone methylation arrests ongoing graft-versus-host disease in mice by selectively inducing apoptosis of alloreactive effector T cells. , 2012, Blood.

[49]  P. Chumakov,et al.  Oncolytic poxviruses , 2012, Molecular Genetics, Microbiology and Virology.

[50]  A. Sepulveda,et al.  Absence of Stat1 in donor CD4⁺ T cells promotes the expansion of Tregs and reduces graft-versus-host disease in mice. , 2011, The Journal of clinical investigation.

[51]  M. Idzko,et al.  Danger signals activating innate immunity in graft-versus-host disease , 2011, Journal of Molecular Medicine.

[52]  C. Cutler,et al.  Rituximab for prevention and treatment of graft-versus-host disease , 2011, International journal of hematology.

[53]  Kailin Xu,et al.  Control of mouse graft-versus-host disease following allogeneic bone marrow transplantation by blocking the CD28/B7 signaling pathway with lentiviral vector-mediated RNA interference. , 2011, Immunology letters.

[54]  R. Storb,et al.  Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria. , 2011, Blood.

[55]  J. Kanda,et al.  Alemtuzumab for the prevention and treatment of graft-versus-host disease , 2011, International journal of hematology.

[56]  C. Perreault,et al.  SMAD3 prevents graft-versus-host disease by restraining Th1 differentiation and granulocyte-mediated tissue damage. , 2011, Blood.

[57]  Thomas B. Sundberg,et al.  Manipulating the Bioenergetics of Alloreactive T Cells Causes Their Selective Apoptosis and Arrests Graft-Versus-Host Disease , 2011, Science Translational Medicine.

[58]  S. Choi,et al.  HDAC Inhibition and Graft Versus Host Disease , 2011, Molecular medicine.

[59]  W. Pear,et al.  Notch signaling is a critical regulator of allogeneic CD4+ T-cell responses mediating graft-versus-host disease. , 2009, Blood.

[60]  J. Grandis,et al.  Sequential activation of inflammatory signaling pathways during graft-versus-host disease (GVHD): early role for STAT1 and STAT3. , 2011, Cellular immunology.

[61]  M. Martinka,et al.  Cutaneous GVHD is associated with the expansion of tissue-localized Th1 and not Th17 cells. , 2010, Blood.

[62]  E. Holler,et al.  Consensus conference on clinical practice in chronic graft-versus-host disease (GVHD): first-line and topical treatment of chronic GVHD. , 2010, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[63]  M. Idzko,et al.  Graft-versus-host disease is enhanced by extracellular ATP activating P2X7R , 2010, Nature Medicine.

[64]  B. Kwon Intervention with costimulatory pathways as a therapeutic approach for graft-versus-host disease , 2010, Experimental & Molecular Medicine.

[65]  Kailin Xu,et al.  Engineered regulatory T cells prevent graft-versus-host disease while sparing the graft-versus-leukemia effect after bone marrow transplantation. , 2010, Leukemia research.

[66]  M. Robin,et al.  Th17/Treg ratio in human graft-versus-host disease. , 2010, Blood.

[67]  W. Shannon,et al.  In vivo administration of hypomethylating agents mitigate graft-versus-host disease without sacrificing graft-versus-leukemia. , 2010, Blood.

[68]  G. McFadden,et al.  The viral tropism of two distinct oncolytic viruses, reovirus and myxoma virus, is modulated by cellular tumor suppressor gene status , 2010, Oncogene.

[69]  Nancy Y. Villa,et al.  Myxoma and vaccinia viruses exploit different mechanisms to enter and infect human cancer cells. , 2010, Virology.

[70]  E. Robinet,et al.  Genetically engineered T-cells expressing a ganciclovir-sensitive HSV-tk suicide gene for the prevention of GvHD. , 2010, Current opinion in investigational drugs.

[71]  G. McFadden,et al.  Oncolytic viral purging of leukemic hematopoietic stem and progenitor cells with Myxoma virus. , 2010, Cytokine & growth factor reviews.

[72]  C. Bordignon,et al.  Clinical impact of suicide gene therapy in allogeneic hematopoietic stem cell transplantation. , 2010, Human gene therapy.

[73]  Ryan M. O’Connell,et al.  Physiological and pathological roles for microRNAs in the immune system , 2010, Nature Reviews Immunology.

[74]  G. McFadden,et al.  Pharmacological Manipulation of the Akt Signaling Pathway Regulates Myxoma Virus Replication and Tropism in Human Cancer Cells , 2010, Journal of Virology.

[75]  M. Pasquini,et al.  2010 report from the Center for International Blood and Marrow Transplant Research (CIBMTR): current uses and outcomes of hematopoietic cell transplants for blood and bone marrow disorders. , 2010, Clinical transplants.

[76]  D. Hanauer,et al.  New perspectives on the biology of acute GVHD , 2010, Bone Marrow Transplantation.

[77]  R. Storb,et al.  The role of B cells in the pathogenesis of graft-versus-host disease. , 2009, Blood.

[78]  M. Prlic,et al.  PKCθ Is Required For Alloreactivity And GVHD But Not For Immune Responses Toward Leukemia And Infection In Mice , 2010 .

[79]  E. Scott,et al.  Myxoma Virus Targets Primary Human Leukemic Stem and Progenitor Cells While Sparing Normal Hematopoietic Stem and Progenitor Cells , 2009, Leukemia.

[80]  G. McFadden,et al.  Human cancer cells have specifically lost the ability to induce the synergistic state caused by tumor necrosis factor plus interferon-beta. , 2009, Cytokine.

[81]  M. Hessner,et al.  Blockade of interleukin-6 signaling augments regulatory T-cell reconstitution and attenuates the severity of graft-versus-host disease. , 2009, Blood.

[82]  G. Baier,et al.  PKC theta cooperates with PKC alpha in alloimmune responses of T cells in vivo. , 2009, Molecular immunology.

[83]  X. Li,et al.  Costimulatory pathways in transplantation: challenges and new developments , 2009, Immunological reviews.

[84]  W. Swaim,et al.  Increased T-bet+ cytotoxic effectors and type I interferon-mediated processes in chronic graft-versus-host disease of the oral mucosa. , 2009, Blood.

[85]  Christopher G. King,et al.  IL-17 contributes to CD4-mediated graft-versus-host disease. , 2009, Blood.

[86]  B. Blazar,et al.  Acute graft-versus-host disease: from the bench to the bedside. , 2005, Blood.

[87]  Arnon Nagler,et al.  A survey of fully haploidentical hematopoietic stem cell transplantation in adults with high-risk acute leukemia: a risk factor analysis of outcomes for patients in remission at transplantation. , 2008, Blood.

[88]  H. Baker,et al.  The Addition of Tumor Necrosis Factor plus Beta Interferon Induces a Novel Synergistic Antiviral State against Poxviruses in Primary Human Fibroblasts , 2008, Journal of Virology.

[89]  J. Antin,et al.  Current and future approaches for control of graft-versus-host disease , 2008, Expert review of hematology.

[90]  T. Yi,et al.  Absence of donor Th17 leads to augmented Th1 differentiation and exacerbated acute graft-versus-host disease. , 2008, Blood.

[91]  S. Amadori,et al.  Analysis of regulatory T-cell changes in patients with idiopathic thrombocytopenic purpura receiving B cell-depleting therapy with rituximab. , 2008, Blood.

[92]  G. Schwarzer,et al.  Corticosteroids for preventing graft-versus-host disease after allogeneic myeloablative stem cell transplantation. , 2008, The Cochrane database of systematic reviews.

[93]  Kerstin Amann,et al.  The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis , 2008, Nature Medicine.

[94]  C. Dinarello,et al.  Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase-dependent DC functions and regulates experimental graft-versus-host disease in mice. , 2008, The Journal of clinical investigation.

[95]  P. Mclaughlin,et al.  Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab. , 2008, Blood.

[96]  G. Schwarzer,et al.  Corticosteroids in the prevention of graft-vs-host disease after allogeneic myeloablative stem cell transplantation: a systematic review and meta-analysis , 2008, Leukemia.

[97]  D. Jain,et al.  Effector memory CD4+ T cells mediate graft-versus-leukemia without inducing graft-versus-host disease. , 2008, Blood.

[98]  J. Serody,et al.  The biology and therapeutic potential of natural regulatory T-cells in the bone marrow transplant setting , 2008, Leukemia & lymphoma.

[99]  L. Naldini,et al.  Generation of potent and stable human CD4+ T regulatory cells by activation-independent expression of FOXP3. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[100]  R. Ortíz-López,et al.  Oncolytic virotherapy. , 2008, Annals of hepatology.

[101]  L. Kanz,et al.  Haploidentical allogeneic hematopoietic cell transplantation in adults using CD3/CD19 depletion and reduced intensity conditioning: an update. , 2008, Blood cells, molecules & diseases.

[102]  G. McFadden,et al.  The role of cell signaling in poxvirus tropism: the case of the M-T5 host range protein of myxoma virus. , 2008, Biochimica et biophysica acta.

[103]  F. Locatelli,et al.  Searching for alternative hematopoietic stem cell donors for pediatric patients , 2008, Bone Marrow Transplantation.

[104]  Stephanie J. Lee,et al.  Recognizing and managing chronic graft-versus-host disease. , 2008, Hematology. American Society of Hematology. Education Program.

[105]  R. Medzhitov Recognition of microorganisms and activation of the immune response , 2007, Nature.

[106]  D. Jacobsohn,et al.  Acute graft-versus-host disease. , 1990, Cancer treatment and research.

[107]  G. McFadden,et al.  Myxoma virus and oncolytic virotherapy: a new biologic weapon in the war against cancer , 2007, Expert opinion on biological therapy.

[108]  D. Hockenbery,et al.  A randomized, placebo-controlled trial of oral beclomethasone dipropionate as a prednisone-sparing therapy for gastrointestinal graft-versus-host disease. , 2007, Blood.

[109]  W. Shlomchik,et al.  Graft-versus-host disease , 2007, Nature Reviews Immunology.

[110]  M. Kubo,et al.  Involvement of the Programmed Death-1/Programmed Death-1 Ligand Pathway in CD4+CD25+ Regulatory T-Cell Activity to Suppress Alloimmune Responses , 2007, Transplantation.

[111]  X. Puente,et al.  LPS Responsiveness and Neutrophil Chemotaxis In Vivo Require PMN MMP-8 Activity , 2007, PloS one.

[112]  W. Murphy,et al.  Immunobiology of allogeneic hematopoietic stem cell transplantation. , 2007, Annual review of immunology.

[113]  J. Ferrara Novel strategies for the treatment and diagnosis of graft-versus-host-disease. , 2007, Best practice & research. Clinical haematology.

[114]  G. McFadden,et al.  Myxoma virus in the European rabbit: interactions between the virus and its susceptible host. , 2007, Veterinary research.

[115]  D. Harlan,et al.  T cell–directed therapies: lessons learned and future prospects , 2007, Nature Immunology.

[116]  J. Ritz,et al.  Impact of conditioning regimen intensity on outcome of allogeneic hematopoietic cell transplantation for advanced acute myelogenous leukemia and myelodysplastic syndrome. , 2006, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[117]  Richard A Flavell,et al.  Transforming growth factor-beta regulation of immune responses. , 2006, Annual review of immunology.

[118]  J. Cheng,et al.  Infection of human cancer cells with myxoma virus requires Akt activation via interaction with a viral ankyrin-repeat host range factor. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[119]  C. Bordignon,et al.  Suicide gene therapy of graft-versus-host disease induced by central memory human T lymphocytes. , 2005, Blood.

[120]  N. Chao,et al.  Prophylaxis and treatment of acute graft-versus-host disease. , 2006, Seminars in hematology.

[121]  Catherine J. Wu,et al.  Induction of tumor immunity following allogeneic stem cell transplantation. , 2006, Advances in immunology.

[122]  H. Deeg,et al.  The clinical spectrum of acute graft-versus-host disease. , 2006, Seminars in hematology.

[123]  J. Ferrara,et al.  Pathophysiology of graft-versus-host disease. , 2006, Seminars in hematology.

[124]  H. Deeg,et al.  Myeloablative vs nonmyeloablative allogeneic transplantation for patients with myelodysplastic syndrome or acute myelogenous leukemia with multilineage dysplasia: a retrospective analysis , 2006, Leukemia.

[125]  J. Sierra,et al.  Donor age and degree of HLA matching have a major impact on the outcome of unrelated donor haematopoietic cell transplantation for chronic myeloid leukaemia , 2006, Bone Marrow Transplantation.

[126]  Jiang Zhu,et al.  Host-reactive CD8+ memory stem cells in graft-versus-host disease , 2005, Nature Medicine.

[127]  T. Sayers,et al.  Differential effects of proteasome inhibition by bortezomib on murine acute graft-versus-host disease (GVHD): delayed administration of bortezomib results in increased GVHD-dependent gastrointestinal toxicity. , 2005, Blood.

[128]  R. Korngold,et al.  A crucial role for antigen-presenting cells and alloantigen expression in graft-versus-leukemia responses , 2005, Nature Medicine.

[129]  M. V. D. van den Brink,et al.  Absence of inducible costimulator on alloreactive T cells reduces graft versus host disease and induces Th2 deviation. , 2005, Blood.

[130]  J. Wagner,et al.  Effect of graft-versus-host disease prophylaxis on 3-year disease-free survival in recipients of unrelated donor bone marrow (T-cell Depletion Trial): a multi-centre, randomised phase II–III trial , 2005, The Lancet.

[131]  H. Deeg,et al.  A phase I/II study of mycophenolate mofetil in combination with cyclosporine for prophylaxis of acute graft-versus-host disease after myeloablative conditioning and allogeneic hematopoietic cell transplantation. , 2005, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[132]  A. Hinke,et al.  Cyclosporine A and Mycophenolate Mofetil vs Cyclosporine A and Methotrexate for graft-versus-host disease prophylaxis after stem cell transplantation from HLA-identical siblings , 2005, Bone Marrow Transplantation.

[133]  J. Serody,et al.  Leukocyte migration and graft-versus-host disease. , 2005, Blood.

[134]  G. Yanik,et al.  Acute graft versus host disease: pathophysiology, risk factors, and prevention strategies. , 2005, Clinical advances in hematology & oncology : H&O.

[135]  A. García‐Díez,et al.  Life-threatening graft-vs-host disease. , 2005, Clinics in dermatology.

[136]  A. Rudensky,et al.  Targeting of inducible costimulator (ICOS) expressed on alloreactive T cells down-regulates graft-versus-host disease (GVHD) and facilitates engraftment of allogeneic bone marrow (BM). , 2005, Blood.

[137]  Jiang Zhu,et al.  Alloreactive Memory T Cells Are Responsible for the Persistence of Graft-versus-Host Disease1 , 2005, The Journal of Immunology.

[138]  A. Hanash,et al.  Donor CD4+CD25+ T cells promote engraftment and tolerance following MHC-mismatched hematopoietic cell transplantation. , 2005, Blood.

[139]  Todd E DeFor,et al.  Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. , 2005, Blood.

[140]  P. Rao,et al.  Differentiation and Expansion of T Cells with Regulatory Function from Human Peripheral Lymphocytes by Stimulation in the Presence of TGF-β , 2005, The Journal of Immunology.

[141]  J. Serody,et al.  L-Selectin(hi) but not the L-selectin(lo) CD4+25+ T-regulatory cells are potent inhibitors of GVHD and BM graft rejection. , 2004, Blood.

[142]  D. Fisher,et al.  Partial CD8+ T-cell depletion of allogeneic peripheral blood stem cell transplantation is insufficient to prevent graft-versus-host disease , 2004, Bone Marrow Transplantation.

[143]  J. Wagner,et al.  Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. , 2004, The New England journal of medicine.

[144]  M. Labopin,et al.  Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia. , 2004, The New England journal of medicine.

[145]  Harriet Noreen,et al.  Impact of HLA class I and class II high-resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is associated with a strong adverse effect on transplantation outcome. , 2004, Blood.

[146]  T. Mak,et al.  CD30/CD30 Ligand (CD153) Interaction Regulates CD4+ T Cell-Mediated Graft-versus-Host Disease1 , 2004, The Journal of Immunology.

[147]  D. Jain,et al.  Donor APCs are required for maximal GVHD but not for GVL , 2004, Nature Medicine.

[148]  R. Storb,et al.  Allogeneic hematopoietic cell transplantation as treatment for hematological malignancies: a review , 2004, Springer Seminars in Immunopathology.

[149]  G. Hale,et al.  Alemtuzumab (Campath-1H) in allogeneic stem cell transplantation: where do we go from here? , 2004, Transplantation proceedings.

[150]  O. Joffre,et al.  Induction of antigen-specific tolerance to bone marrow allografts with CD4+CD25+ T lymphocytes. , 2004, Blood.

[151]  J. Serody,et al.  Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by the proteasome inhibitor bortezomib. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[152]  Russell G. Jones,et al.  PKCθ Signals Activation versus Tolerance In Vivo , 2004, The Journal of experimental medicine.

[153]  N. Chao,et al.  Transfer of allogeneic CD62L- memory T cells without graft-versus-host disease. , 2004, Blood.

[154]  J. Bolaños-Meade,et al.  Acute graft-versus-host disease. , 2004, Clinical advances in hematology & oncology : H&O.

[155]  J. Mary,et al.  Prognostic value of apoptotic cells and infiltrating neutrophils in graft-versus-host disease of the gastrointestinal tract in humans: TNF and Fas expression. , 2004, Blood.

[156]  C. Fathman,et al.  CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation , 2003, Nature Medicine.

[157]  A. Panoskaltsis-Mortari,et al.  Blockade of Programmed Death-1 Engagement Accelerates Graft-Versus-Host Disease Lethality by an IFN-γ-Dependent Mechanism1 , 2003, The Journal of Immunology.

[158]  M. Shlomchik,et al.  Memory CD4+ T cells do not induce graft-versus-host disease. , 2003, The Journal of clinical investigation.

[159]  A. Sharpe,et al.  Ligation of OX40 (CD134) regulates graft-versus-host disease (GVHD) and graft rejection in allogeneic bone marrow transplant recipients. , 2003, Blood.

[160]  J. Ferrara,et al.  Pretreatment of donors with interleukin-18 attenuates acute graft-versus-host disease via STAT6 and preserves graft-versus-leukemia effects. , 2003, Blood.

[161]  D. Bishop,et al.  Contrasting Alloreactive CD4+ and CD8+ T Cells: There's More to It Than MHC Restriction , 2003, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[162]  T. Nomura,et al.  Control of Regulatory T Cell Development by the Transcription Factor Foxp3 , 2002 .

[163]  Eun Young Choi,et al.  Immunodominance of H60 is caused by an abnormally high precursor T cell pool directed against its unique minor histocompatibility antigen peptide. , 2002, Immunity.

[164]  C. Fathman,et al.  Donor-type CD4+CD25+ Regulatory T Cells Suppress Lethal Acute Graft-Versus-Host Disease after Allogeneic Bone Marrow Transplantation , 2002, The Journal of experimental medicine.

[165]  John P Klein,et al.  Severity of chronic graft-versus-host disease: association with treatment-related mortality and relapse. , 2002, Blood.

[166]  F. Uckun,et al.  Janus kinase 3 inhibitor WHI-P131/JANEX-1 prevents graft-versus-host disease but spares the graft-versus-leukemia function of the bone marrow allografts in a murine bone marrow transplantation model. , 2002, Blood.

[167]  M. Sykes,et al.  Donor-derived interferon gamma separates graft-versus-leukemia effects and graft-versus-host disease induced by donor CD8 T cells. , 2002, Blood.

[168]  B. Blazar,et al.  The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality. , 2002, Blood.

[169]  S. Burakoff,et al.  Cytolytic pathways in haematopoietic stem-cell transplantation , 2002, Nature Reviews Immunology.

[170]  Lieping Chen,et al.  Blockade of LIGHT/LTβ and CD40 signaling induces allospecific T cell anergy, preventing graft-versus-host disease , 2002 .

[171]  F. Uckun,et al.  Treatment of Post-Bone Marrow Transplant Acute Graft-Versus-Host Disease with a Rationally Designed JAK3 Inhibitor , 2002, Leukemia & lymphoma.

[172]  Lieping Chen,et al.  Blockade of LIGHT/LTbeta and CD40 signaling induces allospecific T cell anergy, preventing graft-versus-host disease. , 2002, The Journal of clinical investigation.

[173]  P. Mclaughlin,et al.  Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality. , 2001, Blood.

[174]  G. Freeman,et al.  CD4+CD25high Regulatory Cells in Human Peripheral Blood1 , 2001, The Journal of Immunology.

[175]  W. Harmsen,et al.  Prophylaxis of graft-versus-host disease with cyclosporine–prednisone is associated with increased risk of chronic graft-versus-host disease , 2001, Bone Marrow Transplantation.

[176]  J. Peschon,et al.  Ligation of 4-1BB (CDw137) Regulates Graft-Versus-Host Disease, Graft-Versus-Leukemia, and Graft Rejection in Allogeneic Bone Marrow Transplant Recipients1 , 2001, The Journal of Immunology.

[177]  R. Bronson,et al.  Th1 and Th2 mediate acute graft-versus-host disease, each with distinct end-organ targets. , 2000, The Journal of clinical investigation.

[178]  C. Springer,et al.  Prodrug-activating systems in suicide gene therapy. , 2000, The Journal of clinical investigation.

[179]  G. Hill,et al.  The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation. , 2000, Blood.

[180]  F. Fenner,et al.  Adventures with poxviruses of vertebrates. , 2000, FEMS microbiology reviews.

[181]  N. Chao,et al.  Pathophysiologic mechanisms of acute graft-vs.-host disease. , 1999, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[182]  R. Storb,et al.  A phase I-II clinical trial to evaluate removal of CD4 cells and partial depletion of CD8 cells from donor marrow for HLA-mismatched unrelated recipients. , 1999, Blood.

[183]  M. Shlomchik,et al.  Prevention of graft versus host disease by inactivation of host antigen-presenting cells. , 1999, Science.

[184]  L. Dinkelborg,et al.  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY A High-Affinity Human Antibody That Targets Tumoral Blood Vessels , 1999 .

[185]  R. Flavell,et al.  Cutting edge: sustained expansion of CD8+ T cells requires CD154 expression by Th cells in acute graft versus host disease. , 1999, Journal of immunology.

[186]  D. Taub,et al.  Differential effects of the absence of interferon-gamma and IL-4 in acute graft-versus-host disease after allogeneic bone marrow transplantation in mice. , 1998, The Journal of clinical investigation.

[187]  M. Martelli,et al.  Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. , 1998, The New England journal of medicine.

[188]  C. Anasetti,et al.  Role of CD28 in acute graft-versus-host disease. , 1998, Blood.

[189]  Y. Hsu,et al.  TWEAK, a New Secreted Ligand in the Tumor Necrosis Factor Family That Weakly Induces Apoptosis* , 1997, The Journal of Biological Chemistry.

[190]  J. Crawford,et al.  Total body irradiation and acute graft-versus-host disease: the role of gastrointestinal damage and inflammatory cytokines. , 1997, Blood.

[191]  Arul M. Chinnaiyan,et al.  The Receptor for the Cytotoxic Ligand TRAIL , 1997, Science.

[192]  R. Flavell,et al.  Blockade of CD40 ligand-CD40 interaction impairs CD4+ T cell-mediated alloreactivity by inhibiting mature donor T cell expansion and function after bone marrow transplantation. , 1997, Journal of immunology.

[193]  R. Collins,et al.  FK506 (Tacrolimus) monotherapy for prevention of graft-versus-host disease after histocompatible sibling allogenic bone marrow transplantation. , 1996, Blood.

[194]  J. Tschopp,et al.  Cytotoxic T cells deficient in both functional fas ligand and perforin show residual cytolytic activity yet lose their capacity to induce lethal acute graft-versus-host disease , 1996, The Journal of experimental medicine.

[195]  J. Ferrara,et al.  Pretreatment of donor mice with granulocyte colony-stimulating factor polarizes donor T lymphocytes toward type-2 cytokine production and reduces severity of experimental graft-versus-host disease. , 1995, Blood.

[196]  M. Martelli,et al.  Bone marrow transplantation across HLA barriers by increasing the number of transplanted cells. , 1995, Immunology today.

[197]  C. June,et al.  Acute graft-versus-host reaction can be aborted by blockade of costimulatory molecules. , 1995, Journal of immunology.

[198]  M. Toda,et al.  Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. , 1995, Journal of immunology.

[199]  N. Schmitz,et al.  Primary transplantation of allogeneic peripheral blood progenitor cells mobilized by filgrastim (granulocyte colony-stimulating factor) , 1995, Blood.

[200]  M. Eckhaus,et al.  Donor CD4-enriched cells of Th2 cytokine phenotype regulate graft-versus-host disease without impairing allogeneic engraftment in sublethally irradiated mice. , 1994, Blood.

[201]  A. Aruffo,et al.  Antibody to the ligand of CD40, gp39, blocks the occurrence of the acute and chronic forms of graft-vs-host disease. , 1994, The Journal of clinical investigation.

[202]  H Hengartner,et al.  Fas and perforin pathways as major mechanisms of T cell-mediated cytotoxicity. , 1994, Science.

[203]  P. Linsley,et al.  In vivo blockade of CD28/CTLA4: B7/BB1 interaction with CTLA4-Ig reduces lethal murine graft-versus-host disease across the major histocompatibility complex barrier in mice. , 1994, Blood.

[204]  C. Bordignon,et al.  Graft failures after T cell depleted marrow transplants for leukemia: clinical and in vitro characteristics. , 1987, Transplantation proceedings.

[205]  H. Deeg,et al.  Marrow transplantation for severe aplastic anemia: methotrexate alone compared with a combination of methotrexate and cyclosporine for prevention of acute graft-versus-host disease. , 1986, Blood.

[206]  B. Dupont,et al.  Transplantation for severe combined immunodeficiency with HLA-A,B,D,DR incompatible parental marrow cells fractionated by soybean agglutinin and sheep red blood cells. , 1983, Blood.

[207]  R. Good,et al.  TRANSPLANTATION FOR ACUTE LEUKAEMIA WITH HLA-A AND B NONIDENTICAL PARENTAL MARROW CELLS FRACTIONATED WITH SOYBEAN AGGLUTININ AND SHEEP RED BLOOD CELLS , 1981, The Lancet.

[208]  R. Good,et al.  ALLOGENEIC BONE MARROW TRANSPLANTATION USING STEM CELLS FRACTIONATED BY LECTINS: VI, IN VITRO ANALYSIS OF HUMAN AND MONKEY BONE MARROW CELLS FRACTIONATED BY SHEEP RED BLOOD CELLS AND SOYBEAN AGGLUTININ , 1980, The Lancet.

[209]  J. Sloane,et al.  CYCLOSPORIN A TO PREVENT GRAFT-VERSUS-HOST DISEASE IN MAN AFTER ALLOGENEIC BONE-MARROW TRANSPLANTATION , 1980, The Lancet.

[210]  R. Storb,et al.  Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. , 1979, The New England journal of medicine.

[211]  J. Sprent,et al.  Lethal graft-versus-host disease after bone marrow transplantation across minor histocompatibility barriers in mice. Prevention by removing mature T cells from marrow , 1978, The Journal of experimental medicine.

[212]  A. Meshorer,et al.  Hemopoietic stem cell transplantation using mouse bone marrow and spleen cells fractionated by lectins. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[213]  P. Neiman,et al.  Allogeneic marrow grafting for treatment of aplastic anemia. , 1974, Blood.

[214]  R. Gatti,et al.  Immunological reconstitution of sex-linked lymphopenic immunological deficiency. , 1968, Lancet.

[215]  Billingham Re The biology of graft-versus-host reactions. , 1966 .

[216]  R. Billingham The biology of graft-versus-host reactions. , 1966, Harvey lectures.

[217]  J. Loutit,et al.  “SECONDARY DISEASE” OF RADIATION CHIMERAS: A SYNDROME DUE TO LYMPHOID APLASIA , 1962, Annals of the New York Academy of Sciences.

[218]  E. Shelton,et al.  Modification of irradiation injury in mice and guinea pigs by bone marrow injections. , 1951, Journal of the National Cancer Institute.

[219]  L. Jacobson,et al.  The role of the spleen in radiation injury and recovery. , 1950, The Journal of laboratory and clinical medicine.