Tuning Immunity Through the Mucosa

Delivery of vaccines (antigen + adjuvant) to mucosal surfaces is known to be an effective strategy to promote protective immunity at barrier tissues through initiation of immune responses in underlying mucosa-associated lymphoid tissues (MALT). MALT includes the nasal-associated lymphoid tissue (NALT), bronchial-associated lymphoid tissue (BALT), and gut-associated lymphoid tissue (GALT). These tissues play a critical role in the resulting immune response (analogous to lymph nodes in the periphery) as sites where antigen-specific immune responses are orchestrated against mucosally-encountered antigens. Delivery of antigens to the MALT can drive programming of mucosa-specific lymphocyte function and mucosal tissue homing. Yet although well-motivated by the biology of mucosal immunity, delivery of vaccine components across mucosal barriers has presented a major challenge for mucosal vaccine development. 

At the same time, certain mucosal sites such as the gut and lungs are inherently predisposed to induce tolerance upon antigen exposure in the absence of costimulatory signals (i.e. adjuvant), making these tissue sites an attractive target for antigen delivery to treat autoimmunity. Oral antigen delivery to GALT, for instance, preferentially induces systemic tolerance through a specialized mechanism known as oral toleranceDespite a long history of using oral tolerance to treat animal models of autoimmunity, this approach has yet to successfully translate into humans. Like mucosal vaccination, a major barrier to clinical translation has been the high dose of antigen required to overcome limited uptake across mucosal barriers in the gut. Mucosal antigen delivery systems that avoid degradation and clearance while achieving efficient uptake at lower doses may address a need for safe and efficacious antigen-specific immunotherapies to treat autoimmunity.

Our lab uses delivery platforms that we have developed for efficient transmucosal uptake, such as albumin-hitchhiking amphiphile vaccines, as tools to explore strategies for 'tuning immunity through the mucosa'. The location of antigen exposure and orchestration of the immune response can be tailored by varying route of administration (i.e., intranasal / intrapulmonary / oral), while the context of antigen presentation can be tailored by varying costimulatory signals (i.e., +/- adjuvant) and microbial background (i.e. dirty vs. specific pathogen free mice). Through these projects we aim to elucidate mechanisms that drive immune activation versus tolerance in the mucosal immune compartment, providing insights that may be used to guide the design of mucosal vaccines and antigen-specific immunotherapies.

Tuning immunity through the mucosa by tailoring location of antigen exposure (in terms of mucosal barrier tissue and the underlying mucosa-associated lymphoid tissue) and context of antigen presentation (in terms of microbial background and costimulatory cues).

Supporting publications:

Hartwell BL*, Martin JT*, Kumarapperuma S*, Melo MB, Carnathan DG, Cossette BJ, Adams J, Gong S, Zhang W, Tokatlian T, Menis S, Schiffner T, Franklin CG, Goins B, Fox PT, Silvestri G, Schief WR, Ruprecht RM, Irvine DJ. “Combined PET and whole-tissue imaging of lymphatic-targeting vaccines in non-human primates.” Biomaterials. 2021; 275:120868. DOI: 10.1016/j.biomaterials.2021.120868

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