Epithelial application of Pseudomonas aeruginosa exotoxin A results in a selective targeting to cells in the liver, spleen and lymph node.
Pseudomonas aeruginosa exotoxin A (PE) is a 67-kDa protein expressed under the selective pressure of a low iron environment. Previous studies using non-toxic PE chimeras containing a viral surface antigen, the V3 loop of MN gp120 from human immunodeficiency virus type 1 (HIV-1), resulted in not only an effective mucosal immunization but also a striking systemic immune response following epithelial application. Presently, we have examined the possibility that such a strong dual immune response was generated by the efficient targeting of critical cells of the immune system. Mice were dosed with 10 microg of toxic PE or a non-toxic mutant of PE (ntPE) by intratracheal instillation. Examination of lung, liver and spleen tissues isolated 4, 8 and 12 h following intratracheal instillation with PE demonstrated specific cell damage in these tissues which was not observed in mice dosed with ntPE. Based upon the location and characteristics of observed responses, the cells targeted by PE appear to be involved in the antigen presentation arm of the immune response. Since ntPE chimeras with inserted peptide antigen epitopes from a wide variety of pathogens are easy to prepare and administer, these results support this approach for mucosal immunization.
Daugherty
A L
AL
Drug Delivery/Biology Group, Department of Pharmaceutical Research and Development, Genentech Inc., MS #6, 1 DNA Way, South San Francisco, CA 94080-4990, USA.
McKee
M L
ML
FitzGerald
D J
DJ
Mrsny
R J
RJ
D036002:ADP Ribose Transferases; D000287:Administration, Topical; D000818:Animals; D001427:Bacterial Toxins / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D016503:Drug Delivery Systems; D004847:Epithelial Cells / Q000378:metabolism; D005098:Exotoxins / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D007107:Immune System / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008198:Lymph Nodes / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D011550:Pseudomonas aeruginosa / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000378:metabolism*; D014132:Trachea / Q000166:cytology / Q000378:metabolism; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D005098:Exotoxins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A