Augmentation of GVL Reactivity Without GVHD

Summary

Principal Investigator: William Drobyski
Affiliation: Medical College of Wisconsin
Country: USA
Abstract: The graft versus leukemia (GVL) effect is one of the most potent demonstrations of effective adoptive immunotherapy after allogeneic bone marrow transplantation (BMT). Unfortunately, GVL reactivity is often coexpressed with graft versus host disease (GVHD) which is the major complication of this therapy. For the past five years, we have examined a clinically feasible approach whereby thymidine kinase gene-modified alloreactive donor T cells are selectively eliminated early post-BMT to modulate donor T cell survival. Using this strategy in a murine BMT model, we have been able to show that there is a therapeutic window during which GVHD can be significantly reduced without loss of the GVL effect. We have also observed that GVHD results in a loss of self tolerance leading to the development of autoimmunity and that this is attributable to the absence of CD4+ CD25+ regulatory T cells (Tregs) post-BMT. These studies lead us to hypothesize that the interaction between alloreactive donor T cells and Tregs plays a dominant role in the biology of GVL and GVH responses and efforts to separate them in allogeneic marrow transplant recipients. To that end, the goal of this competing renewal is to examine how the temporal kinetics and tissue migration of alloreactive donor T cells and regulatory T cells during the evolution of GVL and GVH responses affect the ability to dissociate GVL/GVH reactivity. The specfic aims of the grant are: (1) to define the temporal kinetics of GVL and GVH reactivity, (2) to characterize the role of regulatory T cells in modulating the severity of GVHD, and (3) to determine how the interaction between Tregs and alloreactive donor T cells affects the ability to separate GVL and GVH reactivity. These studies will take advantage of novel, clinically relevant murine models to address these questions. The overall goal is that this proposal will provide important preclinical data that will further our understanding of how Tregs modulate GVL and GVH reactivity and will serve as a foundation for the application of this overall strategy into the clinic. The relevance of this project to public health derives from the fact that GVHD is the major complication of allogeneic stem cell transplantation. Better understanding of how to reduce this complication while at the same time preserving the beneficial effects that result from the transplant will lead to new therapies and better outcomes for patients.
Funding Period: 2000-05-01 - 2011-06-30
more information: NIH RePORT

Top Publications

  1. pmc A critical role for the retinoic acid signaling pathway in the pathophysiology of gastrointestinal graft-versus-host disease
    Xiao Chen
    Division of Hematology Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
    Blood 121:3970-80. 2013
  2. pmc CD8+ Foxp3+ regulatory T cells are induced during graft-versus-host disease and mitigate disease severity
    Amy J Beres
    Bone Marrow Transplant Program, Medical College of Wisconsin, Milwaukee, WI 53226, USA
    J Immunol 189:464-74. 2012
  3. pmc Tocilizumab for the treatment of steroid refractory graft-versus-host disease
    William R Drobyski
    Bone Marrow Transplant Program, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
    Biol Blood Marrow Transplant 17:1862-8. 2011
  4. pmc Emergence of T cells that recognize nonpolymorphic antigens during graft-versus- host disease
    Hemalatha Rangarajan
    Bone Marrow Transplant Program, Medical College of Wisconsin, Milwaukee, WI 53226, USA
    Blood 119:6354-64. 2012
  5. pmc Instability of Foxp3 expression limits the ability of induced regulatory T cells to mitigate graft versus host disease
    Amy Beres
    Bone Marrow Transplant Program and the Departments of Microbiology, Pathology, and Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
    Clin Cancer Res 17:3969-83. 2011
  6. doi Immunosuppressive effects of multiple myeloma are overcome by PD-L1 blockade
    William H D Hallett
    Department of Pediatrics, Division of Hematology Oncology, Milwaukee, Wisconsin, USA
    Biol Blood Marrow Transplant 17:1133-45. 2011
  7. pmc Blockade of interleukin-23 signaling results in targeted protection of the colon and allows for separation of graft-versus-host and graft-versus-leukemia responses
    Rupali Das
    Bone Marrow Transplant Program, Milwaukee, WI 53226, USA
    Blood 115:5249-58. 2010
  8. pmc Interleukin 17 is not required for autoimmune-mediated pathologic damage during chronic graft-versus-host disease
    Xiao Chen
    Bone Marrow Transplant Program, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA
    Biol Blood Marrow Transplant 16:123-8. 2010
  9. pmc Blockade of interleukin-6 signaling augments regulatory T-cell reconstitution and attenuates the severity of graft-versus-host disease
    Xiao Chen
    Bone Marrow Transplant Program, and Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
    Blood 114:891-900. 2009
  10. pmc Interleukin-23 secretion by donor antigen-presenting cells is critical for organ-specific pathology in graft-versus-host disease
    Rupali Das
    Bone Marrow Transplant Program, Medical College of Wisconsin, Milwaukee, WI 53226, USA
    Blood 113:2352-62. 2009

Detail Information

Publications14

  1. pmc A critical role for the retinoic acid signaling pathway in the pathophysiology of gastrointestinal graft-versus-host disease
    Xiao Chen
    Division of Hematology Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
    Blood 121:3970-80. 2013
    ..These findings identify an organ-specific role for RA in GVHD and provide evidence that blockade of the RA signaling pathway may represent a novel strategy for mitigating the severity of colonic GVHD...
  2. pmc CD8+ Foxp3+ regulatory T cells are induced during graft-versus-host disease and mitigate disease severity
    Amy J Beres
    Bone Marrow Transplant Program, Medical College of Wisconsin, Milwaukee, WI 53226, USA
    J Immunol 189:464-74. 2012
    ..These studies define a novel population of CD8(+) Tregs that play a role in mitigating the severity of GVHD after allogeneic stem cell transplantation...
  3. pmc Tocilizumab for the treatment of steroid refractory graft-versus-host disease
    William R Drobyski
    Bone Marrow Transplant Program, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
    Biol Blood Marrow Transplant 17:1862-8. 2011
    ..These results indicate that tocilizumab has activity in the treatment of steroid refractory GVHD and warrants further investigation as a therapeutic option for this disorder...
  4. pmc Emergence of T cells that recognize nonpolymorphic antigens during graft-versus- host disease
    Hemalatha Rangarajan
    Bone Marrow Transplant Program, Medical College of Wisconsin, Milwaukee, WI 53226, USA
    Blood 119:6354-64. 2012
    ..These data provide a mechanistic framework for how autoimmunity develops within the context of preexisting GVHD and provide additional insight into the pathophysiology of chronic GVHD...
  5. pmc Instability of Foxp3 expression limits the ability of induced regulatory T cells to mitigate graft versus host disease
    Amy Beres
    Bone Marrow Transplant Program and the Departments of Microbiology, Pathology, and Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
    Clin Cancer Res 17:3969-83. 2011
    ..The purpose of this study was to examine the ability of in vitro and in vivo iTregs to abrogate GVHD...
  6. doi Immunosuppressive effects of multiple myeloma are overcome by PD-L1 blockade
    William H D Hallett
    Department of Pediatrics, Division of Hematology Oncology, Milwaukee, Wisconsin, USA
    Biol Blood Marrow Transplant 17:1133-45. 2011
    ..These data demonstrate a role for PD-L1 in suppressing immune responses to myeloma and suggest that blockade of this pathway may enhance immunotherapy for this disease...
  7. pmc Blockade of interleukin-23 signaling results in targeted protection of the colon and allows for separation of graft-versus-host and graft-versus-leukemia responses
    Rupali Das
    Bone Marrow Transplant Program, Milwaukee, WI 53226, USA
    Blood 115:5249-58. 2010
    ..These studies demonstrate that blockade of IL-23 signaling is an effective strategy for separating GVH and GVL responses and identify IL-23 as a therapeutic target for the regulation of alloresponses in humans...
  8. pmc Interleukin 17 is not required for autoimmune-mediated pathologic damage during chronic graft-versus-host disease
    Xiao Chen
    Bone Marrow Transplant Program, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA
    Biol Blood Marrow Transplant 16:123-8. 2010
    ..Thus, the selective targeting of IL-17 may not be a viable clinical strategy for preventing the autoimmune manifestations that develop during cGVHD...
  9. pmc Blockade of interleukin-6 signaling augments regulatory T-cell reconstitution and attenuates the severity of graft-versus-host disease
    Xiao Chen
    Bone Marrow Transplant Program, and Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
    Blood 114:891-900. 2009
    ..These studies demonstrate that antibody blockade of the IL-6R serves to recalibrate the effector and regulatory arms of the immune system and represents a novel, potentially clinically translatable, strategy for the attenuation of GVHD...
  10. pmc Interleukin-23 secretion by donor antigen-presenting cells is critical for organ-specific pathology in graft-versus-host disease
    Rupali Das
    Bone Marrow Transplant Program, Medical College of Wisconsin, Milwaukee, WI 53226, USA
    Blood 113:2352-62. 2009
    ..Furthermore, these studies also identify IL-23 as a potential therapeutic target for the prevention of this life-threatening disorder...
  11. pmc Absence of regulatory T-cell control of TH1 and TH17 cells is responsible for the autoimmune-mediated pathology in chronic graft-versus-host disease
    Xiao Chen
    Bone Marrow Transplant Program, Medical College of Wisconsin, Milwaukee, WI 53226, USA
    Blood 110:3804-13. 2007
    ....
  12. pmc Homeostatic expansion and repertoire regeneration of donor T cells during graft versus host disease is constrained by the host environment
    Jack Gorski
    Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI, USA
    Blood 109:5502-10. 2007
    ..We thereby conclude that the host environment and not an intrinsic T-cell defect is primarily responsible for the lack of effective T-cell expansion and diversification of complex T-cell repertoires that occurs during GVHD...
  13. pmc Emergent autoimmunity in graft-versus-host disease
    Elizabeth Tivol
    Bone Marrow Transplant Program, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
    Blood 105:4885-91. 2005
    ....
  14. ncbi Alpha phenyl-tert-butyl nitrone (PBN) protects syngeneic marrow transplant recipients from the lethal cytokine syndrome occurring after agonistic CD40 antibody administration
    Maria Gendelman
    Bone Marrow Transplant Program, Medical College of Wisconsin, Milwaukee, WI 53226, USA
    Blood 105:428-31. 2005
    ....