ABSTRACT
Infectious diarrheal diseases are the second leading cause of death in children under 5 years, making vaccines against these diseases a high priority. It is known that certain vaccine adjuvants, chiefly bacterial ADP-ribosylating enterotoxins, can induce mucosal antibodies when delivered parenterally. Based on this, we reasoned vaccine-specific mucosal cellular immunity could be induced via parenteral immunization with these adjuvants. Here, we show that, in contrast to the Toll-like receptor-9 agonist CpG, intradermal immunization with non-toxic double-mutant heat-labile toxin (dmLT) from enterotoxigenic Escherichia coli drove endogenous, antigen-specific CD4+ T cells to expand and upregulate the gut-homing integrin α4ß7. This was followed by T-cell migration into gut-draining lymph nodes and both small and large intestines. We also found that dmLT produces a balanced T-helper 1 and 17 (Th1 and Th17) response, whereas T cells from CpG immunized mice were predominantly Th1. Immunization with dmLT preferentially engaged CD103+ dendritic cells (DCs) compared with CpG, and mice deficient in CD103+ DCs were unable to fully license antigen-specific T-cell migration to the intestinal mucosae following parenteral immunization. This work has the potential to redirect the design of existing and next generation vaccines to elicit pathogen-specific immunity in the intestinal tract with non-mucosal immunization.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , Dendritic Cells/immunology , Diarrhea/immunology , Enterotoxigenic Escherichia coli/immunology , Enterotoxins/immunology , Escherichia coli Infections/immunology , Escherichia coli Proteins/immunology , Escherichia coli Vaccines/immunology , Intestines/immunology , Adjuvants, Immunologic , Animals , CD4-Positive T-Lymphocytes/microbiology , Cell Movement , Cells, Cultured , Diarrhea/microbiology , Enterotoxigenic Escherichia coli/genetics , Enterotoxins/genetics , Escherichia coli Proteins/genetics , Escherichia coli Vaccines/genetics , Humans , Immunity, Mucosal , Immunization , Infusions, Parenteral , Integrin alpha4/metabolism , Integrin beta Chains/metabolism , Intestines/microbiology , Mice , Mutation/genetics , Phenotype , Receptors, Lymphocyte Homing/metabolismABSTRACT
We reviewed the records of 10 children with optic neuritis in whom recovery of vision was poor or incomplete. Our cases were otherwise similar to those described in previous studies in that they were always bilateral, often accompanied by a viral prodrome (seven of 10), and usually associated with disc oedema (seven of 10). Seven of twenty eyes had a final visual acuity of 6/60 or worse and only one patient regained 6/6 vision in either eye. In three patients the best vision in either eye was 6/60 or worse. Recovery of vision was often slow, taking up to six years. Five of 10 patients have developed multiple sclerosis (MS), and one child had acute disseminated encephalomyelitis (ADEM) with optic neuritis. Optic neuritis in children does not always carry a good prognosis for recovery of vision; however, the failure of vision recovery in a short period of time does not necessarily indicate a poor outcome. Some children with optic neuritis develop MS, which can develop even when optic neuritis follows a viral illness.
