Pretreatment of murine donor grafts with L-leucyl-L-leucine methyl ester: elimination of graft-versus-host disease without detrimental effects on engraftment.
Incubation of murine bone marrow and splenocytes with the dipeptide methyl ester, L-leucyl-L-leucine methyl ester (Leu-Leu-OMe), which results in the selective depletion of cytotoxic T cells and their precursors, natural killer cells, and monocytes, completely protected 30 recipients of fully allogeneic donor grafts from lethal graft-versus-host disease (GVHD). These results were comparable with those obtained in 30 recipients of anti-Thy 1.2 plus complement (C')-treated donor marrow. However, in contrast to antibody- and C'-dependent T-cell depletion, which reduces the level of donor cell engraftment in our model system, we did not observe such effects using Leu-Leu-OMe marrow pretreatment. As compared with the 24 H-2 typed recipients of anti-Thy 1.2 + C'-treated donor grafts, the 29 H-2 typed recipients of Leu-Leu-OMe-treated donor grafts had significantly (P less than .001) higher percentages of donor cells (mean = 93% v 74%) and significantly (P less than .001) lower percentages of host cells (mean = 6% v 15%) posttransplantation. In vitro limiting dilution assay (LDA) was performed to assess the comparative efficacy of cytolytic T-lymphocyte (CTL) precursor depletion by Leu-Leu-OMe or anti-Thy 1.2 + C' pretreatment. We observed greater levels of CTL precursor depletion in Leu-Leu-OMe treated as compared with anti-Thy 1.2 + C'-treated bone marrow plus spleen cells (BMS) obtained from nontransplanted mice. This suggests that the in vivo results cannot simply be attributed to a less efficacious functional inactivation of cytolytic T-cell precursors by Leu-Leu-OMe treatment as compared with anti-Thy 1.2 + C' treatment. Immunoreconstitution was similar in recipients of Leu-Leu-OMe-treated grafts and anti-Thy 1.2 + C'-treated grafts 100 days posttransplant. In our opinion, Leu-Leu-OMe marrow pretreatment deserves further investigation as a methodology to achieve GVHD prevention without significantly reducing the propensity toward host cell repopulation.
Blazar
B R
BR
Department of Pediatrics, University of Minnesota Hospitals and Clinics, Minneapolis, MN.
Thiele
D L
DL
Vallera
D A
DA
D000818:Animals; D000954:Antigens, Surface / Q000276:immunology; D001853:Bone Marrow / Q000187:drug effects*; D016026:Bone Marrow Transplantation / Q000276:immunology*; D004151:Dipeptides / Q000627:therapeutic use*; D006086:Graft vs Host Disease / Q000517:prevention & control; D006183:H-2 Antigens / Q000276:immunology; D006410:Hematopoiesis; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000187:drug effects; D051379:Mice; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects; D018800:Thy-1 Antigens
D000954:Antigens, Surface; D004151:Dipeptides; D006183:H-2 Antigens; D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; D018800:Thy-1 Antigens; C045139:leucyl-leucine-methyl ester