Anti-leukemia activity of a bacterial toxin with natural specificity for LFA-1 on white blood cells.
The oral bacterium, Aggregatibacter actinomycetemcomitans, produces a leukotoxin (LtxA) that is specific for white blood cells (WBCs) from humans and Old World primates by interacting with lymphocyte function antigen-1 (LFA-1) on susceptible cells. To determine if LtxA could be used as a therapeutic agent for the treatment of WBC diseases, we tested the in vitro and in vivo anti-leukemia activity of the toxin. LtxA kills human malignant WBC lines and primary leukemia cells from acute myeloid leukemia patients, but healthy peripheral blood mononuclear cells (PBMCs) are relatively resistant to LtxA-mediated cytotoxicity. Levels of LFA-1 on cell lines correlated with killing by LtxA and the toxin preferentially killed cells expressing the activated form of LFA-1. In a SCID mouse model for human leukemia, LtxA had potent therapeutic value resulting in long-term survival in LtxA-treated mice. Intravenous infusion of LtxA into a rhesus macaque resulted in a drop in WBC counts at early times post-infusion; however, red blood cells, platelets, hemoglobin and blood chemistry values remained unaffected. Thus, LtxA may be an effective and safe novel therapeutic agent for the treatment of hematologic malignancies.
Kachlany
Scott C
SC
Department of Oral Biology, New Jersey Dental School, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA. kachlasc@umdnj.edu
Schwartz
Amy B
AB
Balashova
Nataliya V
NV
Hioe
Catarina E
CE
Tuen
Michael
M
Le
Amy
A
Kaur
Manpreet
M
Mei
Yongyi
Y
Rao
Jia
J
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000378:metabolism / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D018922:HL-60 Cells; D006460:Hemolysin Proteins / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D008253:Macaca mulatta; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D011485:Protein Binding; D013379:Substrate Specificity
D000970:Antineoplastic Agents; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D006460:Hemolysin Proteins; D016169:Lymphocyte Function-Associated Antigen-1; C102677:lktA protein, bacteria