Abstract
BackgroundIn a quest for a needle-free vaccine administration strategy, we evaluated the ocular conjunctiva as an alternative mucosal immunization route by profiling and comparing the local and systemic immune responses to the subcutaneous or conjunctival administration of tetanus toxoid (TTd), a model antigen.Materials and methodsBALB/c and C57BL/6 mice were immunized either subcutaneously with TTd alone or via the conjunctiva with TTd alone, TTd mixed with 2% glycerol or TTd with merthiolate-inactivated whole-cell B. pertussis (wBP) as adjuvants. Mice were immunized on days 0, 7 and 14 via both routes, and an evaluation of the local and systemic immune responses was performed two weeks after the last immunization. Four weeks after the last immunization, the mice were challenged with a lethal dose (2 × LD50) of tetanus toxin.ResultsThe conjunctival application of TTd in BALB/c mice induced TTd-specific secretory IgA production and skewed the TTd-specific immune response toward a Th1/Th17 profile, as determined by the stimulation of IFNγ and IL-17A secretion and/or the concurrent pronounced reduction of IL-4 secretion, irrespective of the adjuvant. In conjunctivaly immunized C57BL/6 mice, only TTd administered with wBP promoted the establishment of a mixed Th1/Th17 TTd-specific immune response, whereas TTd alone or TTd in conjunction with glycerol initiated a dominant Th1 response against TTd. Immunization via the conjunctiva with TTd plus wBP adjuvant resulted in a 33% survival rate of challenged mice compared to a 0% survival rate in non-immunized animals (p<0.05).ConclusionConjunctival immunization with TTd alone or with various adjuvants induced TTd-specific local and systemic immune responses, predominantly of the Th1 type. The strongest immune responses developed in mice that received TTd together with wBP, which implies that this alternative route might tailor the immune response to fight intracellular bacteria or viruses more effectively.
Highlights
The conjunctiva, which lines the ocular surface from the corneal rim to the lid margin [1], and its underlying structures are recognized as a part of the mucosa-associated lymphoid tissue (MALT), annotated as conjunctiva-associated lymphoid tissue (CALT) or eye-associated lymphoid tissue (EALT) [2]
The strongest immune responses developed in mice that received tetanus toxoid (TTd) together with whole-cell B. pertussis (wBP), which implies that this alternative route might tailor the immune response to fight intracellular bacteria or viruses more effectively
Immunization through the conjunctival route resulted in levels of TTd-specific Secretory IgA (SIgA) in both mouse strains that were significantly higher than those found in the tears of syngeneic control mice as well as mice that were subcutaneously immunized with TTd (Fig. 1)
Summary
The conjunctiva, which lines the ocular surface from the corneal rim to the lid margin [1], and its underlying structures are recognized as a part of the mucosa-associated lymphoid tissue (MALT), annotated as conjunctiva-associated lymphoid tissue (CALT) or eye-associated lymphoid tissue (EALT) [2]. CALT can detect antigens from the ocular surface, present the antigens and generate protective effector cells; together, these properties signify the presence of a mucosal immune system at the conjunctiva [3], [4], [5], [6]. The conjunctiva is an attractive choice for mucosal immunization, against ocular infections, as eye drops are administered; drop-count dosing is feasible; and as the conjunctiva is interconnected with the nasal mucosa via the tear ducts, the administration of antigens to the conjunctival sac would drain to the nasal-associated lymphoid tissue (NALT). In a quest for a needle-free vaccine administration strategy, we evaluated the ocular conjunctiva as an alternative mucosal immunization route by profiling and comparing the local and systemic immune responses to the subcutaneous or conjunctival administration of tetanus toxoid (TTd), a model antigen
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