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Hematopoietic stem-cell transplantation between family members is the treatment of choice for many hematological malignancies, such as blood, bone marrow, and lymphatic cancers. Donor T cells present in the transplant are vital to restore the recipient’s immune system after the procedure. However, donor T cells that react to the recipient’s antigens can cause graft-versus-host disease (GVHD), a frequent life-threatening complication that occurs when the donor’s bone marrow attacks the recipient’s organs and tissues. French researchers recently found that taking advantage of differential T-cell replication kinetics could help ward off GVHD while partially sparing a pool of donor T cells that enable immune restoration.
Researchers from the Biologie et Thérapeutique des Pathologies Immunitaires in Paris transplanted mice with bone marrow containing mature T cells transgenically modified to express thymidine kinase (TK; Blood 2001, 98, 2071–2076). Recipient mice were then administered a drug called ganciclovir (GCV), which is toxic to TK-expressing cells when they divide. Because the reactive donor T cells are thought to divide much earlier than the nonreactive T cells, there could be a window for GCV administration that would mainly kill the host-reactive donor TK T cells.
This process, known as suicide gene therapy, was demonstrated previously, but in the current study the scientists wanted to find out how well the T cells reinstated the immune system once the GVHD was controlled. To test this, the researchers analyzed the origin of T-cell reconstitution after controlling the GVHD, and they found that a portion of the donor T cells was maintained after GCV treatment. The researchers had earlier demonstrated that these cells could eliminate the lymphocytic choriomeningitis virus in a study published in the December 10, 2000, issue of Human Gene Therapy.
Because these results show that suicide gene therapy can block GVHD in animals, this process might also be effective in humans.
“Lethal irradiation induces the destruction of the immune system of mice,” explains José L. Cohen, coauthor of the study. “In humans, chemoradiotherapy also induces the destruction of the immune system. This is the reason why it was important to determine if, after GCV treatment, nondividing donor T cells persisted, so that they could favor reconstitution of the immune system.”
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