TNF-alpha gene therapy with myeloid progenitor cells lacks the toxicities of systemic TNF-alpha therapy.
We examined the antileukemic activity and the toxicity of HPC transduced with human tumor necrosis factor (TNF) cDNA. Both clonal (32Dcl3) and BM-derived primary hematopoietic progenitors (BM-Prog) expressing hTNF-alpha gene (32DTNF-alpha and BMTNF-alpha cells, respectively) inhibited the development of leukemia in mice with a small dose of 32Dp210 cells, a myeloid leukemia cell line. Whether the trans-gene expressing 32DTNF-alpha cells produce toxicities commonly associated with systemic TNF-alpha therapy was determined by examining the effect of TNF-alpha-secreting progenitor cells on body weight, tissue histology, growth of HPC, and engraftment of BMT. Administration of a low or high dose of TNF-alpha-secreting 32DTNF-alpha cells to mice failed to produce loss in body weight, a measure of TNF-alpha-related cachexia. There was also no evidence of tissue necrosis or mononuclear cell (MNC) infiltration in lung, liver, kidney, or intestine of mice injected with transduced progenitor cells. Furthermore, 32DTNF-alpha cells showed no effect on the clonal growth of HPC in colony-forming assays or loss of cellularity in BM, spleen, or blood. Finally, TNF-alpha-secreting cells were found not to interfere with the engraftment of BM transplant and hematopoietic reconstitution thereafter. We conclude from these findings that unlike systemic administration of TNF-alpha, TNF-alpha gene therapy with transduced HPC is nontoxic and may have a role in eradicating residual leukemia after BMT.
Division of Hematology/Oncology, Henry Ford Health System, Detroit, MI 48202, USA.
S C
SC
Gautam
Y X
YX
Xu
K R
KR
Pindolia
R
R
Yegappan
N
N
Janakiraman
R A
RA
Chapman
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002100:Cachexia / Q000139:chemically induced; D002460:Cell Line; D015316:Genetic Therapy; D006085:Graft Survival / Q000187:drug effects; D006402:Hematologic Diseases / Q000139:chemically induced; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D016219:Immunotherapy, Adoptive; D007951:Leukemia, Myeloid / Q000628:therapy; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology* / Q000633:toxicity*
D014409:Tumor Necrosis Factor-alpha