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.