Differential effects of cyclosporin A on the alloreactivity of fresh and ex vivo-expanded T lymphocytes.
GVHD remains a major source of morbidity and mortality after non-T cell-depleted BMT. The use of donor T lymphocytes expressing a suicide gene could lead to specific immunomodulation after BMT. We are currently evaluating such an approach in a phase I clinical study. A 12-day ex vivo expansion is required to generate gene-modified donor T lymphocytes. CsA is commonly used for GVHD prophylaxis. We analyzed, in a murine GVHD model, the effects of CsA administration on the alloreactivity of fresh or ex vivo-expanded T cells. Variable amounts of fresh or ex vivo-expanded T cells were administered in conjunction with a marrow graft to lethally irradiated allogeneic mice. As expected, a protective effect of CsA with a delayed GVHD-related mortality (P < 0.01 vs saline treatment) was observed in mice receiving fresh splenocytes. However, CsA treatment had no effect (P = NS) in mice experiencing lethal GVHD induced by ex vivo-expanded T cells whether or not the T cells had been 'rested' in low-dose IL-2 prior to in vivo administration. In agreement with the in vivo findings, CsA also inhibited the in vitro proliferation of alloreactive fresh T cells while having no significant inhibitory effect on the alloreactivity of ex vivo-expanded T lymphocytes. Overall, we demonstrate that the alloreactivity of ex vivo-expanded T lymphocytes is not sensitive to CsA and that this differential effect of CsA is not related to the alloreactive potential of the infused T cells. These findings could be highly relevant when considering allogeneic T cell therapy approaches.
Contassot
E
E
Laboratoire de Thérapeutique Immuno-moléculaire, Etablissement de Transfusion Sanguine de Franche-Comté, Besançon, France.
Robinet
E
E
Angonin
R
R
Laithier
V
V
Bittencourt
M
M
Pavy
J J
JJ
Cahn
J Y
JY
Hervé
P
P
Tiberghien
P
P
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000276:immunology; D002455:Cell Division / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D018014:Gene Transfer Techniques; D006086:Graft vs Host Disease / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D013937:Thymidine Kinase / Q000235:genetics; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D007371:Interferon-gamma; D016572:Cyclosporine; D013937:Thymidine Kinase