Photodynamic purging of immunoreactive T cells: the magic bullet?

Chen and colleagues (page 3083) found that photodynamic purging of immunoreactive T lymphocytes in marrow grafts can prevent graft-versus-host disease (GVHD) while sparing graft-versus-lymphoma effects in rodents. The study employed 4,5-dibromorhodamine methyl ester (TH9402), a photosensitizer that is concentrated in the mitochondria, where it produces oxidation upon exposure to visible light and leads to cell death. Efflux of TH9402 from the cell membrane requires P-glycoprotein that is highly expressed in resting but not in activated T-cells. Donor T cells were activated by host alloantigens ex vivo and immunoreactive T cells were selectively depleted by exposure to TH9402 and light. When purged T cells and donor marrow were transplanted into the specific host, GVHD was prevented while activity against a host-type lymphoma was preserved and recipient mice were “cured.” In contrast, transplantation into third parties produced GVHD. Data from TH9402 titration experiments suggested that lymphoma was eliminated not by tumor-specific T cells but, rather, by residual host-reactive T cells that became cytotoxic because of the superior ability of lymphoma to present antigen.

These data in mice imply that photodynamic purging with TH9402 and light can selectively deplete host-reactive T cells, while T cells reactive against tumor or infectious agents can be spared. If the biology of these findings can be extended to human cells, this approach will deserve consideration for testing in clinical trials. The requirement for lengthy ex vivo T-cell activation before purging will create a logistical challenge for preserving the viability of hemopoietic progenitors until after purging is complete: T cells and hemopoietic progenitors may have to be harvested separately. Selective depletion by photodynamic purging may represent a step forward in the prevention of GVHD in humans, given the current use of broad T-cell depletion ex vivo or broad immunosuppression in vivo.