Prevention of lethal murine graft versus host disease by treatment of donor cells with L-leucyl-L-leucine methyl ester.

Charley, Michael R.; Thiele, Dwain L.; Bennett, Michael V. L.; Lipsky, Peter E.

doi:10.1172/jci112730

Cited by 27 publications

(18 citation statements)

References 21 publications

(10 reference statements)

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“…LeuLeuOMe was initially shown to be extremely effective in killing various immune and myeloid tumor cells of bone-marrow origin and to efficiently protect against graft-versus-host disease in a mouse model of bone marrow transplantation (29,48). Later studies suggested that other cell types are susceptible to the compound but with lower sensitivity (32,49).…”

Section: Leuleuome Triggers Cathepsin-dependent Apoptosis In Eight DImentioning

confidence: 99%

“…It has been * This work was supported by Ministry of Higher Education, Science, and shown that lysosomes are particularly sensitive toward oxidative stress (21)(22)(23)(24). In addition, LMP can be induced by anticancer agents, such as siramesine, a novel sigma-2 receptor ligand (25), cardenolide (UNBS1450) (26), biphosphinic palladacycle complex (27) and novel compounds that target p53-independent apoptosis (28), by detergents including LeuLeuOMe, which was shown to have a protective effect in a model of graft versus host disease (29) and is currently in phase II clinical trials, and by a number of other stimuli (17, 30 -33).…”

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confidence: 99%

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Cysteine Cathepsins Trigger Caspase-dependent Cell Death through Cleavage of Bid and Antiapoptotic Bcl-2 Homologues

Droga-Mazovec

Bojić

Petelin

et al. 2008

Journal of Biological Chemistry

338

262

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As a model for defining the role of lysosomal cathepsins in apoptosis, we characterized the action of the lysosomotropic agent LeuLeuOMe using distinct cellular models. LeuLeuOMe induces lysosomal membrane permeabilization, resulting in release of lysosomal cathepsins that cleave the proapoptotic Bcl-2 family member Bid and degrade the antiapoptotic member Bcl-2, Bcl-xL, or Mcl-1. The papain-like cysteine protease inhibitor E-64d largely prevented apoptosis, Bid cleavage, and Bcl-2/Bcl-xL/Mcl-1 degradation. The pancaspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp(OMe)fluoromethyl ketone failed to prevent Bid cleavage and degradation of anti-apoptotic Bcl-2 homologues but substantially decreased cell death, suggesting that cathepsin-mediated apoptosis in these cellular models mostly follows a caspase-dependent pathway. Moreover, in vitro experiments showed that one or more of the cysteine cathepsins B, L, S, K, and H could cleave Bcl-2, Bcl-xL, Mcl-1, Bak, and BimEL, whereas no Bax cleavage was observed. On the basis of inhibitor studies, we demonstrate that lysosomal disruption triggered by LeuLeuOMe occurs before mitochondrial damage. We propose that degradation of anti-apoptotic Bcl-2 family members by lysosomal cathepsins synergizes with cathepsin-mediated activation of Bid to trigger a mitochondrial pathway to apoptosis. Moreover, XIAP (X-chromosome-linked inhibitor of apoptosis) was also found to be a target of cysteine cathepsins, suggesting that cathepsins can mediate caspase-dependent apoptosis also downstream of mitochondria.

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Section: Leuleuome Triggers Cathepsin-dependent Apoptosis In Eight DImentioning

confidence: 99%

mentioning

confidence: 99%

Cysteine Cathepsins Trigger Caspase-dependent Cell Death through Cleavage of Bid and Antiapoptotic Bcl-2 Homologues

Droga-Mazovec

Bojić

Petelin

et al. 2008

Journal of Biological Chemistry

338

262

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“…The fact that long-term survival was uniformly observed in these mice despite development of severe transmural intestinal GVHD suggests that other aspects ofGVHD such as the profound immunosuppression reported to be present in B6 -* B6D2F1 GVHD mice but not in DBA/2 --B6D2Fl mice (20-22) or B6D2Fl recipients of Leu-Leu-OMe treated B6 donor cells (31) might be a far more important determinant of overall mortality rates. Indeed, even in the B6 --B6D2Fl strain combination in which recipients of Leu-Leu-OMe-treated donor cells consistently fail to exhibit clinically apparent wasting or diarrhea (17,18,31), histologic evaluation 4 wk after transplantation has also demonstrated extensive colonic inflammatory changes (data not shown). Since the early mortality observed in many strain combinations prevents detailed chronologic evaluation of enteropathic GVHD, the uniformly prolonged survival of B6D2Fl recipients of DBA/2 donor T cells afforded an opportunity to examine in detail the features of intestinal GVHD generated by various donor T cell populations.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the salutary effect of LeuLeu-OMe treatment of donor cells on the course of GVHD in B6 -> B6D2Fl mice suggests that cytotoxic lymphocytes play an essential role in the evolution of GVHD in this class I + II MHC antigen and multiple non-MHC antigen disparate strain combination. Furthermore, inasmuch as depletion of CD4(+) T cells, CD8(+) T cells, or NK cells alone does not prevent lethal GVHD in this strain combination (17,18), these findings demonstrated that Leu-Leu-OMe treatment ofdonor cells offers a unique approach to prevention of this complication of bone marrow transplantation.…”

Section: Introductionmentioning

confidence: 89%

“…Previous studies in our laboratory have noted that lethal GVHD induced in irradiated B6D2F1 (H-2bd) mice by transfer of B6 (H-2b) parental bone marrow cells (BMC) and spleen cells (SpC) is prevented by a brief preincubation of donor cells with L-leucyl-L-leucine methyl ester (Leu-LeuOMe) (17,18). Exposure of human or murine lymphocytes to Leu-Leu-OMe results in depletion of all natural killer (NK) cells and a fraction of T cells ( 18,19).…”

Section: Introductionmentioning

confidence: 99%

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Intestinal graft-versus-host disease is initiated by donor T cells distinct from classic cytotoxic T lymphocytes.

et al. 1989

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In these studies, the role of T helper and T cytotoxic cells in generating intestinal graft-vs.-host disease (GVHD) was examined. Treatment of C57BL/6J (B6) splenocytes with L-leucyl-L-leucine methyl ester (Leu-Leu-OMe) selectively removes natural killer cells, cytotoxic T lymphocyte (CIL) precursors, and the capacity to cause lethal GVHD in irradiated B6xDBA/2 Fl (B6D2Fl) mice while preserving T helper cell function. Neither control nor Leu-Leu-OMe-treated DBA/2 donor spleen and bone marrow cells were found to induce lethal GVHD in B6D2F1 recipients. However, extensive colonic GVHD developed in B6D2F1 recipients of DBA/2 bone marrow and spleen cells. Enteropathic GVHD in DBA/2 -* B6D2F1 mice was reduced in severity after anti-L3T4 + C treatment of donor cells, and was eliminated by anti-Thyl.2 + C or the combination of anti-L3T4 and anti-Lyt2 + C treatment of the donor cell inoculum. However, neither antiLyt2 + C, Leu-Leu-OMe, nor anti-Lyt2 + C and Leu-LeuOMe treatment of donor cells significantly decreased severity of gut GVHD. Leu-Leu-OMe treatment of DBA/2 or B6 SpC was comparably effective in preventing in vitro or in vivo generation of B6D2Fl-specific CiL. These findings, therefore, demonstrate that histologically severe enteropathic GVHD does not require participation of CIL and is not always associated with high mortality rates.

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Removal of peripheral blood monocytes by phenylalanine methyl ester has no effect on the colony growth of hematopoietic progenitor cells

Law

Schwartz

Alsop

et al. 1989

The International Journal of Cell Cloning

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Purification of hematopoietic cells often includes an adherence step for the removal of monocytes. Recent studies have shown that some hematopoietic cells are adherent and that plastic adhesion might activate monocyte/macrophage for cytokine production. We investigated the possibility of using L-phenylalanine methyl ester (PME) as an alternative approach to monocyte removal, particularly for large-scale cell separations. Cell yield, extent of monocyte removal and cloning efficiency of colony-forming progenitor cells were compared to that produced by plastic adhesion. Starting with mononuclear cells (MNC) from adult peripheral blood, cell recovery after PME treatment was higher than that achieved with adherence and fewer monocytes were present. Cloning efficiency of the granulocyte-monocyte colony-forming progenitor cells (CFU-gm) was not affected by the PME treatment. PME treatment and plastic adhesion of low-density cord blood cells produced comparable cell recovery, monocyte depletion and cloning efficiencies for CFU-gm and burst forming units for erythroid progenitor cells (BFU-e). The PME procedure was optimized for the purification of hematopoietic cells from large quantities (less than 1 x 10(9)) of low density. T cell-depleted peripheral blood MNC containing 60% to 85% monocytes. Compared to two cycles of plastic adhesion, PME treatment permitted higher cell recovery (5.9% vs. 1.3%), lower monocyte contamination (4.5% vs. 10.7%) and substantial cost, time and labor savings without compromising CFU-gm growth.

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Prevention of lethal murine graft versus host disease by treatment of donor cells with L-leucyl-L-leucine methyl ester.

Cited by 27 publications

References 21 publications

Cysteine Cathepsins Trigger Caspase-dependent Cell Death through Cleavage of Bid and Antiapoptotic Bcl-2 Homologues

Cysteine Cathepsins Trigger Caspase-dependent Cell Death through Cleavage of Bid and Antiapoptotic Bcl-2 Homologues

Intestinal graft-versus-host disease is initiated by donor T cells distinct from classic cytotoxic T lymphocytes.

Removal of peripheral blood monocytes by phenylalanine methyl ester has no effect on the colony growth of hematopoietic progenitor cells

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