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Induction of mucosal immunity, particularly to subunit vaccines, has been problematic. The primary hurdle to successful mucosal vaccination is the effective delivery of vaccine antigen (Ag) to the mucosal associated lymphoid tissue. Physical and chemical barriers restrict Ag access and moreover, immune responses induced in the mucosa can be biased towards tolerance or non-reactivity. We proposed that these difficulties could be circumvented by targeting Ag to the gastrointestinal associated lymphoid tissue (GALT) via systemic (parenteral) rather than alimentary routes, using antibodies specific for the mucosal addressin cellular adhesion molecule-1 (MAdCAM). After i.v. or i.m. injection of such rat antibodies in mice, we found a greatly enhanced (up to 3 logs) anti-rat Ab response (Fig. 1). MAdCAM-targeting induces a rapid IgA Ab response in the gut (Fig. 1a) and vastly improves the systemic Ab response (Fig. 1c). Targeting also enhanced T cell proliferation (Fig. 2a) and cytokine responses (Fig. 2b). Parenteral targeting of mucosal addressins may represent a generic technique for bypassing mucosal barriers and eliminating the need for adjuvants in the induction of proximal and systemic immunity.
Figure 2: a) MAdCAM-targeting enhances T cell cytokine and proliferative responses. Mice (5 per group) were immunized i.v. and boosted i.p. at day 18 with 100µg of GL117 in CFA. Ten days after, splenocytes and MLN T cells were purified and 2 X 105 T cells cultured with 2 X 105 irradiated splenocytes in a standard 5 day 3H-thymidine uptake protocol. The mean stimulation index (SI) was calculated as the c.p.m of cells with antigen divided by c.p.m of cells alone. b) MAdCAM-targeting enhances T cell cytokine and proliferative responses. Mice (5 per group) were immunized i.v. and boosted i.p. at day 18 with 100µg of GL117 in CFA. Cytokine levels in the supernatant (from 100 µg antigen recall) were evaluated by sandwich ELISA . |
 Figure 1: Targeting MAdCAM via the systemic route stimulates both potent mucosal and systemic Ab responses. Mice were immunized intravenously with 100 µg of either anti-MAdCAM mAb MECA-367 or isotype control mAb GL117 in saline. Rat IgG2a specific Ab responses for fecal IgA (b), serum IgA (c), and serum IgG (d) were measured by ELISA. Representative data from 3 experiments (Means ± SD of the log titer) are shown. |
