|
|
 Previous Article | Table of Contents | Next Article 
Differential effects of ifosfamide on the capacity of cytotoxic T
lymphocytes and natural killer cells to lyse their target cells correlate
with intracellular glutathione levels
G Multhoff, T Meier, C Botzler, M Wiesnet, A Allenbacher, W Wilmanns and RD Issels
GSF-Forschungszentrum fur Umwelt und Gesundheit GmbH, Institut fur
Klinische Hamatologie, Munich, FRG.
We established an in vitro model to study the influence of ifosfamide
treatment on intracellular glutathione (GSH) levels in activated human
effector cells with specific phenotypes and immunologic functions. Besides
its role as the major intracellular reductant, GSH has been shown to affect
the initiation and progression of lymphocyte activation after stimulation
with lectins. An incubation of activated human peripheral blood lymphocytes
(PBL) with 4-hydroxyifosfamide, the activated form of ifosfamide (4-OH-IF),
resulted in a depletion of the intracellular GSH levels and a significant
inhibition of the proliferative capacity in a dose-dependent manner. The
cytotoxic activity of separated CD3- natural killer (NK) cells and CD3+
allospecific, cytotoxic T lymphocytes (CTL), either untreated or treated
with 4-OH-IF at different concentrations, was compared in a standard
51chromium release assay (CML). There were three major findings. (1) The
capacity of CD3+ major histocompatibility complex (MHC)-restricted CTL to
lyse their specific allogeneic target cells was substantially reduced by
preincubation of the effector cells with 4-OH- IF. This inhibition of the
lytic activity in CD3+ CTL correlated with a substantial depletion of the
intracellular GSH levels in this population. Rapid reconstitution of
depleted GSH levels and restoration of cytotoxic activity of CTL was
achieved by incubation of the effector cells with thiols, eg, glutathione
ester (GSH-ester) or 2- mercaptoethanesulfonate (mesna). (2) In contrast,
the lytic activity in CD3- NK cells was not substantially affected (up to
100 mumol/L 4-OH- IF). This result correlates with the capacity of NK cells
to maintain their intracellular GSH levels after an ifosfamide treatment.
(3) In comparison with CD3+ CTL, CD3- NK cells are more resistant to an
ifosfamide treatment because they have higher initial GSH levels and a more
than fourfold higher relative rate of GSH synthesis.
Volume 85,
Issue 8,
pp. 2124-2131,
04/15/1995
Copyright © 1995 by The American Society of Hematology
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
S. Stangl, A. Wortmann, U. Guertler, and G. Multhoff
Control of Metastasized Pancreatic Carcinomas in SCID/Beige Mice with Human IL-2/TKD-Activated NK Cells
J. Immunol.,
May 15, 2006;
176(10):
6270 - 6276.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. C. Kuppner, A. Scharner, V. Milani, C. von Hesler, K. E. Tschop, O. Heinz, and R. D. Issels
Ifosfamide impairs the allostimulatory capacity of human dendritic cells by intracellular glutathione depletion
Blood,
November 15, 2003;
102(10):
3668 - 3674.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. H Al-Humadi, J. K. Ma, D. M Lewis, J. Y. Ma, M. W Barger, and P. D Siegel
Dose-dependent thiol and immune responses to ovalbumin challenge in Brown Norway rats
Toxicology and Industrial Health,
August 1, 2002;
18(7):
343 - 352.
[Abstract]
[PDF]
|
|
|
|
|
