Ex vivo soluble fas ligand treatment of donor cells to selectively reduce murine acute graft versus host disease.
BACKGROUND
Allogeneic bone marrow transplantation (BMT) and donor lymphocyte infusion (DLI) provide valuable treatments for a range of diseases. However, the therapeutic utility of BMT and DLI is reduced by the high incidence of graft-versus-host disease (GvHD) mediated by activated donor T lymphocytes directed against recipient alloantigens.


METHODS
Using mouse models, we developed and evaluated a strategy to selectively enhance activation-induced cell death (AICD) of anti-recipient T cells within transplant donor cell populations, with the goal of reducing GvHD. Responder T lymphocytes were incubated ex vivo with irradiated allogenic stimulator cells in a mixed lymphocyte reaction (MLR) in the presence of soluble Fas ligand (sFasL) to induce AICD in alloreactive cells.


RESULTS
This ex vivo sFasL treatment reduced proliferation to the allogeneic stimulator cells in vitro and abrogated acute GvHD capacity in vivo. In contrast, the secondary immune responsiveness of the ex vivo sFasL-treated responder T cells to an unrelated model antigen was preserved. Furthermore, upon adoptive transfer in a DLI model, ex vivo sFasL-treated T cells were able to reject a model tumor. Finally, ex vivo sFasL treatment of bone marrow cells did not reduce their hematopoietic engraftment capacity.


CONCLUSIONS
Thus, ex vivo treatment with sFasL appears to have potential for translation to clinical cell processing of BMT allografts and DLI infusions.
Georgantas
Robert W
RW
Division of Immunology and Hematopoiesis, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Bohana-Kashtan
Osnat
O
Civin
Curt I
CI
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016026:Bone Marrow Transplantation / Q000276:immunology*; D053222:Fas Ligand Protein; D005260:Female; D006086:Graft vs Host Disease / Q000517:prevention & control*; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects; D014019:Tissue Donors; D048069:Tumor Necrosis Factors / Q000494:pharmacology*
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D048069:Tumor Necrosis Factors