The Maturing Immune System: Implications for Development and Testing HIV-1 Vaccines for Children and Adolescents

Heather B. Jaspan; Stephen D. Lawn; Jeffrey T. Safrit; Linda-Gail Bekker

Disclosures

AIDS. 2006;20(4):483-494. 

In This Article

Adolescent Immunity

An increase in gonadotropic hormones that promote the secretion of androgens and oestrogens in both boys and girls characterize puberty. Both Leydig cells and ovaries produce testosterone and 17-β-oestradiol (17-β-E2). In normal children, testosterone levels begin to rise at a bone age of about 12 years in boys and at 10 years in girls. However, dihydroepiandrosterone (DHEA) levels begin to rise earlier, at about 7 years of age in boys and 8 years of age in girls. Both 17-β-oestradiol (17-β-E2) and testosterone levels increase substantially through the pubertal stages and are highest at pre-menopausal adulthood.[43]

Various lines of evidence suggest that immunological responses and sex steroid hormones are linked at physiological and cellular levels. The increased risk of autoimmunity among pubertal and post-pubertal females (and males to a lesser degree) strongly suggests that sex steroids affect immune function.[44] T cells and macrophages express intra- and extracellular receptors for oestrogens and androgens, implying a direct effect of these hormones on the immune system.[45] B cells, however, express only intracellular oestrogen and androgen receptors.[46] As a result, sex steroid hormones have many effects on the innate and adaptive immune system (reviewed in[47] and summarized in Table 1 ).

Oestrogens exert dose-dependant effects on the immune system; physiological levels of 17-β-E2 are immunostimulatory whereas higher levels have been shown to be immunosupressive.[48] Oestrogen stimulates IgG and IgM secretion by human peripheral blood mononuclear cells (PBMC) in vitro.[49] At the vaginal mucosal surface, an important site for prevention of acquisition of HIV infection, a greater drop in IgG, but not IgA, occurs during the follicular phase of the menstrual cycle in adolescent females compared to adults.[50] Monocytes, macrophages and antigen presentation also seem to be affected by oestrogen ( Table 1 ). Oestrogen (E2) has effects on T-cell immunity, causing fluctuations in CTL activity in the human endometrium during the menstrual cycle. CTL activity is high in the pre-ovulatory phase and absent in the post-ovulatory phase.[51]

Androgens secreted at higher levels during male and female puberty may influence immune responses. The most well known, testosterone, may suppress the stress response to infection; evidence supporting this comes from observations that adrenal and immune corticosterone responses to endotoxin in animals are inhibited by testosterone.[48] These stress responses are maximal prior to puberty in both male and female mice.[52] DHEA and its metabolite, androstenediol (AED), appear to have the opposite effect to testosterone; they protect mice from lethal bacterial infections and lipopolysaccharide (LPS) challenge.[53] Specific effects on the immune system are found in Table 1 .

The pleiotropic immunological effects of sex hormones and the recognized differences in immune function between adolescents and adults suggest that there may be gender-dependent differences in the immunogenicity and efficacy of vaccines. Some evidence supports this supposition. A vaccine against Plasmodium chabaudi malaria is more efficacious in male than female mice; this difference was partially abrogated by pretreatment of the female mice with testosterone.[54] In humans, responses to tetanus toxoid were lower among female adolescents receiving booster immunizations compared to males.[55] Perhaps of greatest relevance is the recent demonstration that glycoprotein-D-adjuvant vaccine for herpes simplex virus-2 (HSV-2) showed some efficacy in HSV-1 and HSV-2 non-immune females but no efficacy at all among males.[56]

The numbers of certain subsets of T cells differ in adolescents compared to adults and between the age-matched adolescent sexes.[30,57,58] Serum concentrations of immune activation markers among adolescents have been found to be significantly associated with race and age.[59] An important change that occurs in adolescence is the gradual involution of the thymus,[58] which is the source of naive CD45RA T cells. Thymic involution has traditionally been thought to occur prior to adolescence, but in more recent studies, thymic output has been demonstrated into adulthood.[60] Nevertheless, age-related changes in thymic function may affect immune responses to vaccinations at different ages.

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