Pretreatment of murine donor grafts with L-leucyl-L-leucine methyl ester: Elimination of graft-versus-host disease without detrimental effects on engraftment

Bruce R. Blazar, Dwain L Thiele, Daniel A. Vallera

Research output: Contribution to journalArticle

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Abstract

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 < .001) higher percentages of donor cells (mean = 93% v 74%) and significantly (P < .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 4 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.

Original languageEnglish (US)
Pages (from-to)798-805
Number of pages8
JournalBlood
Volume75
Issue number3
StatePublished - Feb 1 1990

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leucylleucine
Graft vs Host Disease
Grafts
T-cells
Transplants
Bone Marrow
Lymphocyte Depletion
T-Lymphoid Precursor Cells
T-Lymphocytes
Bone
leucyl-leucine-methyl ester
leucine methyl ester
Dipeptides
Dilution
Natural Killer Cells
Assays
Esters
Monocytes
Spleen

ASJC Scopus subject areas

  • Hematology

Cite this

Pretreatment of murine donor grafts with L-leucyl-L-leucine methyl ester : Elimination of graft-versus-host disease without detrimental effects on engraftment. / Blazar, Bruce R.; Thiele, Dwain L; Vallera, Daniel A.

In: Blood, Vol. 75, No. 3, 01.02.1990, p. 798-805.

Research output: Contribution to journalArticle

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abstract = "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 < .001) higher percentages of donor cells (mean = 93{\%} v 74{\%}) and significantly (P < .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 4 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.",
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