Transplantation of IL-2-transduced murine bone marrow is associated with dose-dependent toxicity

Objective. The purpose of this study was to investigate the effects of inte rleukin-2 (IL-2) gene-transduced hematopoietic progenitor cells or cytotoxi c function and systemic toxicity following syngeneic bone marrow transplant ation. Material and Methods. Marrow of 5-fluorouracil pretreated donor mice were t ransfected with a retroviral vector containing the murine IL-2 gene and tra nsplanted into lethally irradiated syngeneic hosts, Results. productive insertion of the IL-2 gene could he demonstrated at var ious intervals post-transplant without impairment of hematopoietic engraftm ent, Endogenously augmented IL-2 release resulted in a selective increase i n CD4(+), CD8(+), and NK1.1(+) population in spleen and bone marrow, as wel l as significant cytolytic activity against syngeneic leukemia cells in vit ro, Our results also illustrate the interdependence among the magnitude of systemic IL-2 levels, the number of IL-2-transduced cells in the transplant inoculum, and the appearance of systemic toxicity, Infusion of marrow tran sduced with high-titer, high-expressing IL-2 retrovirus resulted in signifi cant morbidity and mortality in the recipients. Our studies demonstrate tha t mortality was secondary to severe lymphocytic infiltration of liver and l ung, which was associated with increased expression of intercellular adhesi on molecule-1 and vascular adhesion molecule-1, Reducing the number of IL-2 -transduced cells in the bone marrow inoculum, however, resulted in signifi cantly improved survival with no adverse events being evident during the po st-transplant period. Conclusion. Delivery of IL-2 to the bone marrow can be achieved by transpla ntation of genetically modified hematopoietic cells, however, the overall f easibility is strongly influenced by the number of transduced cells in the bone marrow inocolum and/or the expression pattern of IL-2 in vivo, (C) 200 0 International Society for Experimental Hematology. Published by Elsevier Science.