Abstract
BackgroundThe development of mucosal vaccines is crucial to efficiently control infectious agents for which mucosae are the primary site of entry. Major drawbacks of these protective strategies are the lack of effective mucosal adjuvant. Synthetic oligodeoxynucleotides that contain several unmethylated cytosine-guanine dinucleotide (CpG-ODN) motifs are now recognized as promising adjuvants displaying mucosal adjuvant activity through direct activation of TLR9-expressing cells. However, little is known about the efficacy of these molecules in stimulating the intestinal immune system in neonates.Methodology/Principal FindingsFirst, newborn mice received CpG-ODN orally, and the intestinal cytokine and chemokine response was measured. We observed that oral administration of CpG-ODN induces CXC and CC chemokine responses and a cellular infiltration in the intestine of neonates as detected by immunohistochemistry. We next compared the efficiency of the oral route to intraperitoneal administration in stimulating the intestinal immune responses of both adults and neonates. Neonates were more responsive to TLR9-stimulation than adults whatever the CpG-ODN administration route. Their intestinal epithelial cells (IECs) indirectly responded to TLR9 stimulation and contributed to the CXC chemokine response, whereas other TLR9-bearing cells of the lamina-propria produced CC chemokines and Th1-type cytokines. Moreover, we showed that the intestine of adult exhibited a significantly higher level of IL10 at homeostasis than neonates, which might be responsible for the unresponsiveness to TLR9-stimulation, as confirmed by our findings in IL10-deficient mice.Conclusions/SignificanceThis is the first report that deciphers the role played by CpG-ODN in the intestine of neonates. This work clearly demonstrates that an intraperitoneal administration of CpG-ODN is more efficient in neonates than in adults to stimulate an intestinal chemokine response due to their lower IL-10 intestinal level. In addition we report the efficiency of the oral route at inducing intestinal chemokine responses in neonate that might be taken into consideration for further vaccine development against neonatal diseases.
Highlights
Neonates and infants have an increased susceptibility to infection due to inherent limitations of their immune system
To investigate whether orally given CpG-ODN triggered cell trafficking into the draining lymph nodes, mesenteric lymph nodes (MLN) were removed from neonates 24 h after treatment with CpG-ODN and the cell composition phenotype was determined by flow cytometry
In the absence of IL10, CpG-ODN administration by IP route in adult mice induced an overexpression of CXCL1 (400-fold greater), CXL10 (356-fold greater), CCL2 (357-fold greater) and CCL7 (205-fold greater) (Fig. 6B). These chemokine over-expressions were about 10- to 20fold higher and even about 300-fold for CCL2 than those observed in adult IL10-sufficient mice (Fig. 6B). These results clearly demonstrate than IL10 can negatively control CpG-ODN-induced chemokine responses
Summary
Neonates and infants have an increased susceptibility to infection due to inherent limitations of their immune system. Under appropriate conditions, neonates can develop immune responses to vaccination that are qualitatively and quantitatively similar to adults [2,3,4,5]. One of the major drawbacks in the development of mucosal vaccines has been the lack of effective mucosal adjuvants [6]. The development of mucosal vaccines is crucial to efficiently control infectious agents for which mucosae are the primary site of entry. Major drawbacks of these protective strategies are the lack of effective mucosal adjuvant. Synthetic oligodeoxynucleotides that contain several unmethylated cytosine-guanine dinucleotide (CpG-ODN) motifs are recognized as promising adjuvants displaying mucosal adjuvant activity through direct activation of TLR9-expressing cells. Little is known about the efficacy of these molecules in stimulating the intestinal immune system in neonates
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