Graft-vs-host disease (GVHD) is a potentially lethal complication of allogenic bone marrow transplantation (BMT). A reliable strategy to successfully treat GVHD once initiated has not yet been developed. The applicant has shown that F(ab')2 fragments of CD3 epsilon specific MoAb administered to mice after allogeneic BMT reverses the clinical effects of GVHD and leads to tolerance induction. In leukemia-bearing hosts, however, excessive or ill-timed administration of anti-CD3 F(ab')2 leads to leukemia relapse. The primary goal of this research is to identify mechanisms responsible for the successful treatment of GVHD with anti-CD3 F(ab')2 MoAb in vivo. Extensive preliminary data implicated cytokines in the pathology and regulation of GVHD. The two-part hypothesis to be tested states that (i) depletion of T-cells through activation-induced cell death (AICD or apoptosis) by anti-CD3 (Fab')2 MoAb is an essential prerequisite for treatment of established GVHD and (ii) anti CD3 F(ab')2 activates NK-1.1+ T-cells to secrete cytokines which lead to tolerance induction. Murine models have been developed to test this hypothesis.
Four specific aims are proposed: (a) To assess the importance of AICD in the successful treatment of established GVHD with anti-CD3 F(ab')2 MoAb in vivo and correlate T-cell death with activation state of the T-cells in vitro and in vivo; (b) To determine whether NK-1.1+ T-cells or CD3+ double-negative T-cells contribute to suppression of GVHD after signaling through CD3 epsilon using phenotypic and functional assays in vitro; (c) To ascertain whether IL-4 or other cytokines are essential to the mechanism involved in therapy of GVHD with anti-CD3 F(ab')2 using homozygous deletion mutant mice (""""""""knockout mice""""""""); and (d) To examine immunological factors that contribute to post-BMT leukemia relapse after treatment with anti CD3 F(ab')2 MoAb and the ability of donor leukocyte infusions to prevent relapse. A unique aspect of the proposed studies is the parallel evaluation of the effects of MoAb therapy in vivo on graft-vs-leukemia (GVL) reactivity using acute T-cell lymphoblastic leukemia in AKR mice as a model. Mechanistic insights gained from the studies, together with the biological principles identified, will facilitate the translational application of MoAb to clinical BMT.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA039854-11A2
Application #
2007505
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1984-09-01
Project End
2002-01-31
Budget Start
1997-04-18
Budget End
1998-01-31
Support Year
11
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Pediatrics
Type
Schools of Medicine
DUNS #
073134603
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
LaBelle, James L; Truitt, Robert L (2002) Characterization of a murine NKT cell tumor previously described as an acute myelogenous leukemia. Leuk Lymphoma 43:1637-44
Johnson, Bryon D; Konkol, Marja C; Truitt, Robert L (2002) CD25+ immunoregulatory T-cells of donor origin suppress alloreactivity after BMT. Biol Blood Marrow Transplant 8:525-35
LaBelle, James L; Hanke, Carrie A; Blazar, Bruce R et al. (2002) Negative effect of CTLA-4 on induction of T-cell immunity in vivo to B7-1+, but not B7-2+, murine myelogenous leukemia. Blood 99:2146-53
Johnson, B D; Dagher, N; Stankowski, W C et al. (2001) Donor natural killer (NK1.1+) cells do not play a role in the suppression of GVHD or in the mediation of GVL reactions after DLI. Biol Blood Marrow Transplant 7:589-95
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
Truitt, R L; Johnson, B D; Hanke, C et al. (1999) Photochemical treatment with S-59 psoralen and ultraviolet A light to control the fate of naive or primed T lymphocytes in vivo after allogeneic bone marrow transplantation. J Immunol 163:5145-56
Johnson, B D; Hanke, C A; Becker, E E et al. (1998) Sca1(+)/Mac1(+) nitric oxide-producing cells in the spleens of recipients early following bone marrow transplant suppress T cell responses in vitro. Cell Immunol 189:149-59
Johnson, B D; McCabe, C; Hanke, C A et al. (1995) Use of anti-CD3 epsilon F(ab')2 fragments in vivo to modulate graft-versus-host disease without loss of graft-versus-leukemia reactivity after MHC-matched bone marrow transplantation. J Immunol 154:5542-54
Johnson, B D; Truitt, R L (1995) Delayed infusion of immunocompetent donor cells after bone marrow transplantation breaks graft-host tolerance allows for persistent antileukemic reactivity without severe graft-versus-host disease. Blood 85:3302-12

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