CiteULike: AlfonsoVicenteSuarez's flagellin-tumor

Blocking of the TLR5 Activation Domain Hampers Protective Potential of Flagellin DNA Vaccine

Sukumar Saha — 2007-08-02T18:42:58-00:00

J Immunol, Vol. 179, No. 2. (15 July 2007), pp. 1147-1154.

Flagellin is a key component of the flagella of many pathogens, including Pseudomonas aeruginosa. Flagellin is an attractive vaccine candidate because it is readily produced and manipulated as a recombinant protein and has intrinsic adjuvant activity mediated through TLR5. Although DNA vaccines encoding native Pseudomonas B-type (FliC) or A-type (FlaA) flagellin are strongly immunogenic, the resultant Ab response interferes with the interaction of homologous flagellin with TLR5. This reduces the ability of the host to clear homologous, but not heterologous, flagellin-expressing P. aeruginosa. To circumvent this problem, a DNA vaccine encoding a mutant FliC R90A flagellin was developed. The mutant Ag encoded by this vaccine was highly immunogenic, but its ability to interact with TLR5 was reduced by >100-fold. Vaccination with this flagellin mutant DNA vaccine induced cross-reactive Abs against both FliC and FlaA, but few Abs capable of interfering with TLR5 activation. The flagellin mutant DNA vaccine provided excellent protection against both FliC- and FlaA-expressing P. aeruginosa. These findings suggest that vaccines against flagellated pathogens should avoid inducing Abs against TLR5 and raise the possibility that flagellated bacteria evade host elimination by facilitating the production of Abs that reduce the host's ability to mount an innate immune response.

Antitumor Activity of the TLR-5 Ligand Flagellin in Mouse Models of Cancer

Lucia Sfondrini — 2007-08-02T16:40:40-00:00

J Immunol, Vol. 176, No. 11. (1 June 2006), pp. 6624-6630.

Flagellin, the structural protein subunit of the bacterial flagellum, is specifically recognized by TLR-5 and has potent immunomodulatory effects. The antitumor effects of purified Salmonella typhimurium flagellin were evaluated in mice transplanted s.c. with a weakly immunogenic murine tumor or with its variant stably transfected to express the highly antigenic human HER-2 oncoprotein. Peritumoral administration of flagellin 8-10 days after tumor implantation did not affect the growth rate of the weakly immunogenic tumor but significantly inhibited growth of the antigenic variant tumor. In contrast, flagellin administered at the time of implantation of the antigenic tumor led to accelerated tumor growth. These contrasting effects of flagellin on tumor growth correlated with the type of immune response induced; i.e., late flagellin administration was associated with an increased IFN-gamma:IL-4 ratio and the decreased frequency of CD4+CD25+ T regulatory cells, whereas flagellin treatment at the time of tumor implantation decreased the IFN-gamma:IL-4 ratio and increased CD4+CD25+ T cell frequency. When the early flagellin treatment was combined with administration of CpG-containing oligodeoxynucleotides, tumor growth was completely suppressed, indicating synergy between flagellin and CpG-containing oligodeoxynucleotides. Together, these data provide evidence that flagellin can have contrasting effects on tumor growth.