Blood, 15 July 2002, Vol. 100, No. 2, pp. 373-373
New light on GVHD prevention
The holy grail of allogeneic stem cell transplantation
is to establish a donor immune system in the recipient without causing graft-versus-host disease (GVHD). Differences in the antigens presented
to T cells by GVHD target tissues and by recipient malignant cells or
viruses form the basis for approaches to separate GVHD from useful
donor immunity. Guimond et al (page 375) describe an elegant method of
selectively removing alloactivated T cells from the T-cell repertoire
that could find clinical application in the removal of T cells causing
GVHD from the stem cell transplantation. Noting that upon activation T
cells down-regulate their P-glycoprotein (Pgp) ion channel transporter,
they hypothesized that activated T cells would be more susceptible to
cell death from agents normally extruded by a functioning Pgp. The
agent chosen, the rhodamine-based dye TH9402, becomes cytotoxic upon
activation in visible light. Their experiments confirm that
TH9402-treated lymphocytes activated in an MLR are rapidly destroyed by
exposure to light. In contrast, the resting nonresponding T cells that
extruded the dye survived and retained cytotoxicity to third-party
cells. Not surprisingly, light exposure eliminated most of the T cells
expressing the high-affinity IL-2 receptor activation marker. But
some T cells expressing low IL-2r levels persisted, possibly
representing nonactivated CD4+CD25+ regulatory
T cells. Techniques targeting T-cell activation antigens such as CD25,
CD69, and most recently CD95 (Hartwig et al, Blood. 2002;99:3041-3049)
have already been shown to selectively deplete activated T
cells. These techniques prevent GVHD in animal models, and
clinical trials testing selective depletion in matched and mismatched
donor-recipient combinations are underway.
Concerns about toxicity from TH9402 aside, the photosensitizer approach
has the advantage of simplicity, low cost, and selectivity. Particularly attractive is the potential sparing of regulatory T cells,
which may suppress GVHD. But a limitation for all selective depletion
strategies is our incomplete knowledge of the antigens eliciting GVHD.
This limits our ability to correctly stimulate and subsequently remove
the culprits.
John Barrett
National Heart, Lung, and Blood
Institute
