Low-dose intraperitoneal Freund's adjuvant: toxicity and immunogenicity in mice using an immunogen targeting amyloid-beta peptide.
Complete Freund's adjuvant (CFA) is effective for potentiating immune responses in mice when administered subcutaneously, and is often more potent when given intraperitoneally (i.p.). However, the the potential toxicity of i.p. administration in mice has led investigators and Institutional Animal Care and Use committees to increasingly view the use of CFA i.p. with reservation. We evaluated whether an 80% reduction in the dose of CFA administered i.p. to mice, compared to the i.p. doses used in a previous analysis, could abrogate the untoward effects associated with its use, while still maintaining adjuvanticity. Using a novel immunogen targeting the N-terminus of the 42-amino acid amyloid-beta peptide, we compared low dose CFA administered i.p., with three other commonly used adjuvants given i.p.: alum, incomplete Freunds adjuvant (IFA) and monophoshoryl lipid A + trehalose dicorynomycolate (MPL + TDM). The results of the study showed that, though the reduction in intraperitoneal dose of CFA mitigated transient weight loss and leukocytosis observed previously with higher doses of i.p. CFA, all mice administered CFA or IFA i.p. developed abdominal adhesions and granulomatous peritonitis. Mice from all adjuvant groups, however, appeared to tolerate the respective adjuvants well and excellent comparative immunogenicity was observed in mice immunized with the Freunds and MPL + TDM adjuvants. Consequently, we conclude that though a high-titered, humoral response may be generated using low dose CFA administered i.p., the accompanying toxicity remains significant, and thus alternative adjuvants and/or routes should be considered.
Oscherwitz
Jon
J
Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48105, USA. joscher@umich.edu
Hankenson
F C
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Yu
Fen
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Cease
Kemp B
KB
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000633:toxicity*; D000534:Alum Compounds / Q000008:administration & dosage / Q000494:pharmacology; D023582:Alzheimer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D016229:Amyloid beta-Peptides / Q000276:immunology*; D000818:Animals; D000906:Antibodies / Q000097:blood; D001835:Body Weight; D003311:Cord Factors / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D005620:Freund's Adjuvant / Q000008:administration & dosage / Q000276:immunology* / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D007958:Leukocyte Count; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D013154:Spleen / Q000473:pathology
D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D000906:Antibodies; D003311:Cord Factors; D008050:Lipid A; C041524:aluminum sulfate; D005620:Freund's Adjuvant; C043399:6,6'-dicorynomycolyl trehalose; C048436:monophosphoryl lipid A