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Increasing evidence indicates that the capacity to induce protective Th1 immune responses is impaired in early childhood, an observation that can be partially attributed to deficiencies in antigen-presenting-cell function. Synthesis of interleukin 12 (IL-12), a key Th1-trophic cytokine, is markedly reduced in the neonatal period, though there is a paucity of knowledge concerning the ontogeny of IL-12-synthetic capacity throughout the childhood years. Hence, we examined the production of bioactive IL-12 p70 by circulating mononuclear cells in a population of healthy individuals. As expected, the capacity to synthesize IL-12 p70 in response to either lipopolysaccharide or heat-killed Staphylococcus aureus was markedly impaired at birth, even after priming of cells with gamma interferon. Surprisingly however, IL-12 p70 synthesis by peripheral blood mononuclear cells from both 5-and 12-year-old children was still substantially below that seen in adults, and this did not appear to be related to excessive production of IL-10. In contrast, dendritic cells from adults and neonates, derived from monocytes with granulocyte-macrophage colony-stimulating factor and IL-4, synthesized equivalent amounts of IL-12 p70 in response to microbial stimulation. This indicates that the impaired capacity for IL-12 synthesis in childhood is not an intrinsic property of circulating mononuclear cells but rather can be readily overcome in response to appropriate maturational stimuli. Because IL-12 arose predominantly from circulating HLA-DR ؉ cells that lacked B-cell-and monocyte-specific markers, we propose that the slow maturation of IL-12-synthetic capacity in the childhood years can be attributed to deficiencies in the number and/or function of dendritic cells.It is acknowledged that early childhood is characterized by an increased susceptibility to infectious diseases, and this has been attributed both to immaturity of the immune system at birth and to the sluggish development of immune competence in the postnatal and early childhood years. This vulnerability to infections appears to be particularly pronounced in relation to intracellular pathogens, reflecting functional immaturity of cell-mediated immunity. However, considerable gaps still exist in current understanding of the mechanisms underlying immune maturation in healthy children.While intrinsic properties of T cells undoubtedly contribute to the immunological immaturity observed in the neonatal period (1,3,16,17,25), it is also clear that many of the "deficiencies" observed in neonatal immune function are dependent on antigen-presenting cells (APCs) (28, 35). Neonatal T cells proliferate relatively poorly when stimulated with freshly isolated allogeneic neonatal dendritic cells (DC) but proliferate as strongly as adult T cells when stimulated with adult DC (18,24). Similarly, the reduced capacity of neonatal T cells to produce the key T helper type 1 (Th1) cytokine gamma interferon (IFN-␥) is markedly improved when these T cells are cultured with adult, rather than cord, APCs ...

Objective. The receptor-binding B subunit of Escherichia coli heat-labile enterotoxin (EtxB) is a highly stable, nontoxic protein that is capable of modulating immune responses. This study was conducted to determine whether mucosal administration of EtxB can block collagen-induced arthritis (CIA) and to investigate the mechanisms involved.Methods. Clinical arthritis in DBA/1 mice was monitored following mucosal administration of EtxB on 4 occasions. The dependence of disease prevention on receptor binding by EtxB and the associated alterations to the immune response to type II collagen (CII) were assessed. Adoptive transfer experiments and lymph node cell cocultures were used to investigate the underlying mechanisms.Results. Both intranasal and intragastric delivery of EtxB were effective in preventing CIA; a 1-g dose of EtxB was protective after intranasal administration. A non-receptor-binding mutant of EtxB failed to prevent disease. Intranasal EtxB lowered both the incidence and severity of arthritis when given either at the time of disease induction or 25 days later. EtxB markedly reduced levels of anti-CII IgG2a antibodies and interferon-␥ (IFN␥) production while not affecting levels of IgG1, interleukin-4 (IL-4), or IL-10. Disease protection could be transferred by CD4؉ T cells from treated mice, an effect that was abrogated upon depletion of the CD25؉ population. In addition, CD4؉CD25؉ T cells from treated mice were able to suppress anti-CII IFN␥ production by CII-primed lymph node cells.Conclusion. Mucosal administration of EtxB can be used to prevent or treat CIA. Modulation of the anti-CII immune response by EtxB is associated with a reduction in Th1 cell reactivity without a concomitant shift toward Th2. Instead, EtxB mediates its effects through enhancing the activity of a population of CD4؉ regulatory T cells.

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