Analysis of a cholera toxin B subunit (CTB) and human mucin 1 (MUC1) conjugate protein in a MUC1-tolerant mouse model.
Since epithelial mucin 1 (MUC1) is associated with several adenocarcinomas at the mucosal sites, it is pertinent to test the efficacy of a mucosally targeted vaccine formulation. The B subunit of the Vibrio cholerae cholera toxin (CTB) has great potential to act as a mucosal carrier for subunit vaccines. In the present study we evaluated whether a MUC1 tandem repeat (TR) peptide chemically linked to CTB would break self-antigen tolerance in the transgenic MUC1-tolerant mouse model (MUC1.Tg) through oral or parenteral immunizations. We report that oral immunization with the CTB-MUC1 conjugate along with mucosal adjuvant, unmethylated CpG oligodeoxynucleotide (ODN) and interleukin-12 (IL-12) did not break self-antigen tolerance in MUC1.Tg mice, but induced a strong humoral response in wild-type C57BL/6 mice. However, self-antigen tolerance in the MUC1.Tg mouse model was broken after parenteral immunizations with different doses of the CTB-MUC1 conjugate protein and with the adjuvant CpG ODN co-delivered with CTB-MUC1. Importantly, mice immunized systemically with CpG ODN alone and with CTB-MUC1 exhibited decreased tumor burden when challenged with a mammary gland tumor cell line that expresses human MUC1.
Pinkhasov
Julia
J
Center for Infectious Diseases and Vaccinology (CIDV), The Biodesign Institute at Arizona State University, 1001 South McAllister Avenue, Tempe, AZ 85287-4501, USA.
Alvarez
M Lucrecia
ML
Pathangey
Latha B
LB
Tinder
Teresa L
TL
Mason
Hugh S
HS
Walmsley
Amanda M
AM
Gendler
Sandra J
SJ
Mukherjee
Pinku
P
D000818:Animals; D001324:Autoantigens / Q000276:immunology; D045744:Cell Line, Tumor; D002772:Cholera Toxin / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D007114:Immunization; D007274:Injections, Intraperitoneal; D018664:Interleukin-12 / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018396:Mucin-1 / Q000276:immunology*; D009374:Neoplasms, Experimental / Q000628:therapy*; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology
D001324:Autoantigens; C408982:CPG-oligonucleotide; D018396:Mucin-1; D009838:Oligodeoxyribonucleotides; D018664:Interleukin-12; D002772:Cholera Toxin
Clin Cancer Res. 2000 May;6(5):1693-701
10815887
Clin Cancer Res. 2001 Mar;7(3 Suppl):848s-855s
11300482
J Clin Oncol. 2000 Feb;18(3):574-83
10653872
Cancer Res. 1993 Mar 15;53(6):1437-43
8443822
Vaccine. 2006 Jun 5;24(23):5047-55
16621185
Cancer Immunol Immunother. 2000 Jan;48(10):588-94
10630311
Immunol Today. 1999 Nov;20(11):493-500
10529776
Immunol Rev. 2004 Jun;199:201-16
15233736
Eur J Immunol. 2003 Nov;33(11):3205-12
14579289
Gastroenterology. 1994 Feb;106(2):353-61
7905449
Mol Microbiol. 1994 Aug;13(4):745-53
7997185
Clin Cancer Res. 2003 Jul;9(7):2693-700
12855649
Cancer Res. 1994 Oct 1;54(19):5186-93
7923138
Nature. 1991 May 30;351(6325):371-7
2034287
Int J Cancer. 2001 Jul 1;93(1):97-106
11391628
J Surg Res. 1996 Jun;63(1):298-304
8667619
J Clin Invest. 1997 Dec 1;100(11):2783-92
9389743
J Immunother. 2003 Jan-Feb;26(1):47-62
12514429
J Immunother Emphasis Tumor Immunol. 1993 Aug;14(2):136-43
8280702
Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10795-9
7526379
Clin Cancer Res. 2006 Feb 1;12(3 Pt 1):869-77
16467101
Infect Immun. 2001 Sep;69(9):5716-25
11500448
Immunol Today. 1999 Feb;20(2):95-101
10098329
Immunol Lett. 2005 Mar 15;97(2):181-8
15752556
Acta Crystallogr D Biol Crystallogr. 2001 Feb;57(Pt 2):201-12
11173465
Breast Dis. 2004;20:53-63
15687707
J Mammary Gland Biol Neoplasia. 2002 Apr;7(2):209-21
12463741
Gene Ther. 2001 Jan;8(1):75-9
11402305
Cancer Res. 1996 Jul 15;56(14):3315-9
8764127
Am J Clin Pathol. 2002 Jul;118(1):47-51
12109855
Vaccine. 1999 Jun 4;17(20-21):2740-52
10418926
Tumour Biol. 1998;19 Suppl 1:1-20
9422084
J Pathol. 1997 Nov;183(3):311-7
9422987
Cancer Res. 1998 Jan 15;58(2):315-21
9443411
J Immunol. 2003 Feb 15;170(4):1980-6
12574367
J Exp Med. 1997 Feb 3;185(3):415-27
9053442
Immunol Cell Biol. 1989 Jun;67 ( Pt 3):183-95
2477330