Studies of the use of L-leucyl-L-leucine methyl ester in canine allogeneic marrow transplantation.
L-leucyl-L-leucine methyl ester (Leu-Leu-OMe) is a lysosomotropic agent that selectively kills cytotoxic T cells and their precursors, natural killer cells, and monocytes but not helper T cells or other cells of hematopoietic origin. In this study, the effects of treatment of bone marrow and peripheral blood buffy coat with Leu-Leu-OMe on the outcome of allogeneic marrow transplantation were studied in several canine models. Whereas incubation of autologous marrow with Leu-Leu-OMe had no adverse effects on subsequent engraftment, incubation of marrow from dog leukocyte antigen (DLA)-identical littermates resulted in a high rate of graft failure. Previous studies have demonstrated that the addition of peripheral blood buffy coat allows engraftment of unrelated DLA-nonidentical marrow, and in this study we found that incubation of buffy coat with Leu-Leu-OMe did not alter this graft promoting effect. In a final experiment it was demonstrated that incubation of both marrow and peripheral blood buffy coat did not prevent the development of graft-versus-host disease in recipients of marrow from DLA-haploidentical littermates. In considering the eventual application of Leu-Leu-OMe in the clinic, these results are less encouraging than those previously reported using murine models.
Raff
R F
RF
Fred Hutchinson Cancer Research Center, Seattle, WA 98104.
Severns
E M
EM
Storb
R
R
Graham
T C
TC
Sale
G
G
Schuening
F G
FG
Appelbaum
F R
FR
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000379:methods*; D003602:Cytotoxicity, Immunologic; D004151:Dipeptides / Q000627:therapeutic use*; D004285:Dogs; D006085:Graft Survival / Q000187:drug effects; D006086:Graft vs Host Disease / Q000209:etiology; D006649:Histocompatibility Antigens / Q000032:analysis; D007113:Immunity, Innate / Q000187:drug effects; D007694:Killer Cells, Natural / Q000276:immunology; D008212:Lymphocyte Depletion
D004151:Dipeptides; D006649:Histocompatibility Antigens; C045139:leucyl-leucine-methyl ester