Allogeneic bone marrow transplantation (BMT) as a treatment for leukemia is limited by posttransplant complications including leukemia relapse and graft-versus-host disease (GVHD). Post-transplant donor leukocyte infusion (DLI) for the treatment or prevention of leukemia relapse is a relatively new form of therapy that has provided potent antileukemic reactivity with less severe GVHD than seen with lymphocytes administered at the time of transplantation. Little is known about the antileukemic effector cells or why GVHD is less severe following delayed lymphocyte infusion. This project will use murine models of allogeneic marrow transplantation 1) to identify the antileukemic effector cells associated with delayed lymphocyte infusion, 2) to determine why GVHD is less severe following delayed lymphocyte infusion, 3) to investigate the underlying mechanisms involved in suppression of GVHD after delayed lymphocyte infusion and 4) to determine how the antileukemic reactivity of delayed lymphocyte infusion can be augmented without increasing GVHD. A murine marrow transplant model will be used to assess the impact of increased immunogenetic disparity on the antileukemic effect of delayed lymphocyte infusion.
Specific Aim 1 will identify the effector cells responsible for mediating the antileukemic reactivity and will determine why GVHD is less severe following delayed lymphocyte infusion. Ex vivo cell depletion will be combined with in vivo leukemia studies to address the hypothesis that CD8 positive T cells are critical to the antileukemic effect. In vitro studies will test the hypothesis that donor CD4 cells are selectively tolerized following delayed lymphocyte infusion, resulting in reduced GVH reactivity. The anergic CD4 cells will be isolated, functionally characterized, and studied further to determine whether anergy can be reversed.
Specific Aim 2 will investigate experimental means of targeting the antileukemic effectors for enhanced antitumor reactivity without increasing the severity of GVHD. These experiments have clinical relevance for more effective treatment of relapsed acute leukemia. Experiments in Specific Aim 3 will test the hypothesis that suppressor cells, identified in preliminary studies, are responsible for inducing anergy in donor CD4 cells. A novel flow cytometric assay (standard cell dilution assay) will be used to identify whether the suppressor cells are T cell or natural suppressor-like cells. Overall, this project attempts to address the important issues that need to be resolved for optimizing the clinical use of delayed lymphocyte infusion therapy.
| Johnson, B D; Becker, E E; LaBelle, J L et al. (1999) Role of immunoregulatory donor T cells in suppression of graft-versus-host disease following donor leukocyte infusion therapy. J Immunol 163:6479-87 |
| Johnson, B D; Becker, E E; Truitt, R L (1999) Graft-vs.-host and graft-vs.-leukemia reactions after delayed infusions of donor T-subsets. Biol Blood Marrow Transplant 5:123-32 |
