Blood, 1 May 2002, Vol. 99, No. 9, pp. 3081-3081
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.
Claudio Anasetti
Fred Hutchinson Cancer Research
Center
