Costimulatory molecules in the developing human gastrointestinal tract: A pathway for fetal allergen priming

Background: Antigen-specific responses can be detected in umbilical cord bl ood mononuclear cells. The fetal immune system must therefore attain a leve l of maturity compatible with the initiation of such responses as well as b e exposed to antigen. Objective: We sought to assess the expression of costimulatory molecules in fetal gut and the presence of cytokines in amniotic fluid at this time as a preliminary analysis of the suitability of the fetal gut as a site of ant igen priming during intrauterine life. Methods: Human fetal gut was analyzed for cells expressing costimulatory mo lecules through use of immunohistochemistry. Amniotic fluid was studied by ELISA, for cytokines regulating the nature of the response, and as a source of the common dietary antigen ovalbumin. Results: MHC class II-positive cells were abundant over the period examined (11-24 weeks of gestation), other sin-face antigens showing spatial and te mporal variation in expression. From 11 to 14 weeks of gestation, CD68-posi tive and CD40-positive cells, like MHC class II-positive cells, were presen t throughout the lamina propria; few CD3-positive cells (T cells) were obse rved. With the emergence of lymphoid aggregates (14-16 weeks), CD83-positiv e cells (dendritic cells) and CD20-positive cells (B cells) could be detect ed in fetal gut; however, expression was restricted to the lymphoid aggrega tes. In contrast, MHC class II, CD40, and CD68 continued to be expressed in the lamina propria. CD28-positive cells were also evident from 14 weeks of gestation, occurring throughout the lamina propria and lymphoid aggregates ; this corresponded to the increasing numbers of CD3-positive cells. The oc casional CD86-positive, CD40L-positive, or CTLA4-positive cell could be see n in or around lymphoid aggregates after 14 weeks of gestation. Lymphoid fo llicles forming after 16 weeks of gestation contained MHC class II-positive , CD83-positive, CD20-positive, CD40-positive, CD86-positive, CD3-positive, CD28-positive, CD40L-positive, and CTLA4-positive cells. MHC class II-posi tive, CD40-positive, CD68-positive, CD3-positive, and CD28-positive cells c ontinued to be present in the lamina propria at this time. At all times stu died, CD14 was not expressed in the lamina propria or lymphoid follicles. P rostaglandin E-2, TGF beta (1), and IL-10 dominated the amniotic fluid cyto kine milieu, and ovalbumin was also detectable in amniotic fluid from 3 of 26 women who had detectable circulating levels. Conclusion: Of the costimulatory molecules studied, CD40 was the most abund ant. However, both of the ligand families studied (CD40-CD40L and CD86-CD28 /CD152) could provide the costimulatory signals required for the initiation of antigen-specific reactivity in the gastrointestinal tract of the human fetus as early as 16 weeks of gestation. The cytokine milieu would favor th e development of T(H)2-type reactivity to antigens, such as ovalbumin, that are present at this time.