Mucosal delivery of murine interleukin-2 (IL-2) and IL-6 by recombinant strains of Lactococcus lactis coexpressing antigen and cytokine.
Lactococcus lactis is a nonpathogenic and noncolonizing bacterium which is being developed as a vaccine delivery vehicle for immunization by mucosal routes. To determine whether lactococci can also deliver cytokines to the immune system, we have constructed novel constitutive expression strains of L. lactis which accumulate a test antigen, tetanus toxin fragment C (TTFC), within the cytoplasmic compartment and also secrete either murine interleukin-2 (IL-2) or IL-6. When mice were immunized intranasally with various different expression strains of L. lactis, the anti-TTFC antibody titers increased more rapidly and were substantially higher in mice immunized with the bacterial strains which secreted IL-2 or IL-6 in addition to their production of TTFC. This adjuvant effect was lost when the recombinant strains of L. lactis were killed by pretreatment with mitomycin C and could therefore be attributed to the secretion of IL-2 or IL-6 by the recombinant lactococci. These results provide the first example of the use of a cytokine-secreting, noninvasive experimental bacterial vaccine vector to enhance immune responses to a coexpressed heterologous antigen and point the way to experiments which will test the possible therapeutic efficacy of this mode of cytokine delivery.
Steidler
L
L
Department of Molecular Biology, Flanders Inter-University Institute for Biotechnology, and University of Ghent, B-9000 Ghent, Belgium.
Robinson
K
K
Chamberlain
L
L
Schofield
K M
KM
Remaut
E
E
Le Page
R W
RW
Wells
J M
JM
D000281:Administration, Intranasal; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D005260:Female; D007114:Immunization; D007070:Immunoglobulin A / Q000097:blood; D007376:Interleukin-2 / Q000235:genetics*; D015850:Interleukin-6 / Q000235:genetics*; D013294:Lactococcus lactis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology*; D011995:Recombination, Genetic; D013744:Tetanus Toxin / Q000235:genetics / Q000276:immunology*
D000907:Antibodies, Bacterial; D007070:Immunoglobulin A; D007376:Interleukin-2; D015850:Interleukin-6; D010446:Peptide Fragments; D013744:Tetanus Toxin; C040635:tetanus toxin fragment C