Differences in immune responses induced by oral and rectal immunizations with Salmonella typhi Ty21a: evidence for compartmentalization within the common mucosal immune system in humans

Abstract

Based on the concept of the common mucosal immune system, immunization at various inductive sites can induce an immune response at other, remote mucosal surfaces. The immune responses elicited through rectal and oral routes of antigen delivery were compared with respect to (i) measurement of antibody responses in serum and various external secretions of the vaccinees and (ii) characterization of the nature and homing potentials of circulating antibody-secreting cells (ASC). Specific ASC appeared in the circulation in 4 of 5 volunteers after oral and 9 of 11 volunteers after rectal immunization with Salmonella typhi Ty21a. The kinetics, magnitude, and immunoglobulin isotype distribution of the ASC responses were similar in the two groups. In both groups, almost all ASC (99 or 95% after oral or rectal immunization, respectively) expressed alpha4 beta7, the gut homing receptor (HR), whereas L-selectin, the peripheral lymph node HR, was expressed only on 22 or 38% of ASC, respectively. Oral immunization elicited a more pronounced immune response in saliva and vaginal secretion, while rectal immunization was more potent in inducing a response in nasal secretion, rectum, and tears. No major differences were found in the abilities of the two immunization routes to induce a response in serum or intestinal secretion. Thus, the rectal antigen delivery should be considered as an alternative to the oral immunization route. The different immune response profiles found in various secretions after oral versus rectal antigen administration provide evidence for a compartmentalization within the common mucosal immune system in humans.

FIG. 1

Kinetics of the circulating specific ASC response after oral (a; n = 4) or rectal (b; n = 6) immunization of humans with live S. typhi Ty21a vaccine. Each volunteer received one dose (at least 10⁹ live bacteria/dose) of vaccine on each of days 0, 2, 4, and 6. Each value represents the sum of IgA-, IgG-, and IgM ASC of one individual on a given day. PBMC, peripheral blood mononuclear cells.

FIG. 2

Expression of the gut HR α4β7 on circulating specific ASC and total ISC in volunteers 7 days after oral (a; n = 4) or rectal (b; n = 9) vaccination with S. typhi Ty21a. The bars indicate arithmetic means (±SD) of percentages of cells expressing α4β7 among IgA (black bars), IgG (white bars), and IgM (hatched bars) ASC and ISC.

FIG. 3

Expression of the peripheral lymph node HR l-selectin on circulating specific ASC and total ISC in volunteers 7 days after oral (a; n = 4) or rectal (b; n = 9) vaccination with S. typhi Ty21a. The bars indicate arithmetic means (±SD) of percentages of cells expressing l-selectin among IgA (black bars), IgG (white bars), and IgM (hatched bars) ASC and ISC.

FIG. 4

Maximal S. typhi-specific antibody responses in tears (a), nasal secretion (b), saliva (c), rectal fluid (d), and vaginal fluid (e) after oral (n = 5) or rectal (n = 11) immunization with S. typhi Ty21a. The data are expressed as percentages (geometric means ± SEM) of preimmune levels of specific antibodies relative to the corresponding isotype. Significant increases in proportions of specific antibodies are indicated with asterisks. Numbers of responders (at least 1.5-fold increase in the proportion of specific antibodies) are indicated below each postimmune bar.

FIG. 5

S. typhi-specific antibodies in serum after oral (n = 5) or rectal (n = 11) immunization with S. typhi Ty21a. The bars indicate geometric mean concentrations (±SEM) of specific IgA, IgG, or IgM antibodies (ab) in serum before and after immunization. Significant increases from preimmune levels are indicated with asterisks.