title: The adjuvant LT-K63 can restore delayed maturation of follicular dendritic cells and poor persistence of both protein- and polysaccharide-specific antibody-secreting cells in neonatal mice.
abstract: Ab responses in early life are low and short-lived; therefore, induction of protective immunity requires repeated vaccinations. One of the major limitations in early-life immunity is delayed maturation of follicular dendritic cells (FDCs), which play a central role in mediating the germinal center (GC) reaction leading to production of Ab-secreting cells (AbSCs). We assessed whether a nontoxic mutant of Escherichia coli heat-labile enterotoxin (LT-K63) and CpG1826 as model adjuvants could accelerate FDC maturation and immune response in neonatal mice, using a pneumococcal polysaccharide of serotype 1 conjugated to tetanus toxoid (Pnc1-TT) as a model vaccine. In neonatal NMRI mice, a single dose of Pnc1-TT coadministered with LT-K63 enhanced Pnc1-TT-induced GC reaction. In contrast, CpG1826 had no effect. Accordingly, LT-K63, but not CpG1826, accelerated the maturation of FDC networks, detected by FDC-M2(+) staining, characteristic for adult-like FDCs. This coincided with migration of MOMA-1(+) macrophages into the GCs that can enhance GC reaction and B cell activation. The FDC-M2(+) FDC networks colocalized with enhanced expression of TNF-α, which is critical for the maintenance of mature FDCs and is poorly expressed in neonates. The accelerated maturation of FDC networks correlated with increased frequency and prolonged persistence of polysaccharide- and protein-specific IgG(+) AbSCs in spleen and bone marrow. Our data show for the first time, to our knowledge, that an adjuvant (LT-K63) can overcome delayed maturation of FDCs in neonates, enhance the GC reaction, and prolong the persistence of vaccine-specific AbSCs in the BM. These properties are attractive for parenteral vaccination in early life.
authors: Department of Immunology, Landspitali, The National University Hospital of Iceland, Hringbraut, 101 Reykjavik, Iceland.
authors: Stefania P
authors: SP
authors: Bjarnarson
authors: Brenda C
authors: BC
authors: Adarna
authors: Hreinn
authors: H
authors: Benonisson
authors: Giuseppe
authors: G
authors: Del Giudice
authors: Ingileif
authors: I
authors: Jonsdottir
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D000831:Animals, Newborn; D000907:Antibodies, Bacterial / Q000096:biosynthesis*; D000921:Antibody-Producing Cells / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000627:therapeutic use*; D002454:Cell Differentiation / Q000276:immunology*; D018899:CpG Islands / Q000276:immunology; D020566:Dendritic Cells, Follicular / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D004768:Enterotoxins / Q000008:administration & dosage / Q000627:therapeutic use*; D029968:Escherichia coli Proteins / Q000008:administration & dosage / Q000096:biosynthesis* / Q000627:therapeutic use; D051379:Mice; D008815:Mice, Inbred Strains; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000627:therapeutic use; D011135:Polysaccharides, Bacterial / Q000008:administration & dosage / Q000276:immunology* / Q000627:therapeutic use; D013745:Tetanus Toxoid / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D000276:Adjuvants, Immunologic; D000907:Antibodies, Bacterial; D001427:Bacterial Toxins; C423449:CpG ODN 1826; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D009838:Oligodeoxyribonucleotides; D011135:Polysaccharides, Bacterial; D013745:Tetanus Toxoid; C092872:streptococcal polysaccharide-tetanus toxoid conjugate vaccine; C027538:heat-labile enterotoxin, E coli