Increase in proliferation rate and normalization of TNF-alpha secretion by blockage of gene transfer-induced apoptosis in lymphocytes using low-dose cyclosporine A.
Efficient gene transfer of lymphocytes is extremely difficult. We have shown previously that induction of apoptosis may play a role in the gene transfer resistance of lymphocytes. Anti-CD3 antibody can be used as a surrogate for receptor-mediated gene transfer in T lymphocytes. However, anti-CD3 antibody has been shown to be the causative agent of apoptosis in receptor-mediated gene transfer. In this study, we show that blockage of apoptosis by addition of low-dose cyclosporine A can lead to normalization of elevated TNF-alpha secretion and to a significant increase in the proliferation rate of transfected lymphocytes. In contrast, this had no negative effect on cytotoxic activity of immunologic effector cells called cytokine-induced killer cells. Therefore, blockage of apoptosis should have an impact on the use of lymphocytes transfected with cytokine genes as immunologic effector cells in cancer gene therapy protocols.
Röpke
G
G
Ebert
O
O
Märten
A
A
Lefterova
P
P
Micka
B
B
Buttgereit
P
P
Niemitz
S
S
Trojaneck
B
B
Schmidt-Wolf
G
G
Rücker
A V
AV
Huhn
D
D
Wittig
B
B
Schmidt-Wolf
I G
IG
D017209:Apoptosis / Q000187:drug effects*; D017252:CD3 Complex / Q000276:immunology; D002455:Cell Division; D002478:Cells, Cultured; D002860:Chromium Radioisotopes / Q000378:metabolism; D016572:Cyclosporine / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism*
D017252:CD3 Complex; D002860:Chromium Radioisotopes; D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D016572:Cyclosporine