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Prepublished online as a Blood First Edition Paper on April 17, 2002; DOI 10.1182/blood-2001-12-0353.
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Blood, 15 July 2002, Vol. 100, No. 2, pp. 375-382
PLENARY PAPER
P-glycoprotein targeting: a unique strategy to selectively
eliminate immunoreactive T cells
Martin Guimond,
Antonia Balassy,
Mélanie Barrette,
Sylvie Brochu,
Claude Perreault, and
Denis
Claude Roy
From the Division of Hematology-Immunology,
Maisonneuve-Rosemont Hospital Research Center, Department of Medicine,
Université de Montréal, and Theratechnologies Inc,
Montreal, QC, Canada.
T lymphocytes have been found to harbor P-glycoprotein (Pgp) and to
demonstrate modulation of its ion channel transporter function
according to the state of activation of T lymphocytes. We hypothesized
that cytotoxic chemicals that are extruded by Pgp could be used to
specifically eliminate immunoreactive T-cell populations. In this
study, we evaluated the capacity of 4,5-dibromorhodamine methyl ester
(TH9402), a photosensitizer structurally similar to rhodamine, a dye
transported by Pgp, and which becomes highly cytotoxic on activation
with visible light to selectively deplete alloreactive T lymphocytes.
Stimulation of T cells with mitogens or allogeneic major
histocompatibility complex-mismatched cells resulted in the
preferential retention of the TH9402 rhodamine-derivative in activated
T cells, both CD4+ and CD8+. Photodynamic cell
therapy of TH9402-exposed T cells led to the selective elimination of
immunoreactive T-cell populations. In addition, this treatment
preserved resting T cells and their capacity to respond to third-party
cells. Inhibition of Pgp enhanced cellular trapping of the dye in
nonactivated T cells and resulted in their depletion after exposure to
light. Targeting of Pgp-deficient cells may therefore represent an
appealing strategy for the prevention and treatment of
graft-versus-host disease and other alloimmune or autoimmune disorders.
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