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 tolerance.  Despite 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.

Many current autoimmune disease therapies act through nonspecific suppression of the immune response, resulting in global immunosuppression and deleterious off-target effects. Antigen-specific immunotherapies that target and suppress only offending autoreactive immune cells to restore autoantigenic tolerance would address a pressing need for safer and more effective therapies, yet remain elusive. Endogenous mechanisms for maintaining immunological tolerance and homeostasis suggest however that restoration of immune tolerance is plausible. For example, mucosal tolerance against ingested antigens is maintained through mechanisms of oral tolerance, where antigens are taken up, processed, and presented in gut-associated lymphoid tissues (GALT) in a highly tolerogenic context. Peripheral tolerance is maintained primarily through a state of antigen unresponsiveness called anergy which occurs when lymphocytes (B or T cells) mount an initial response to primary antigenic signal but do not receive sufficient secondary costimulatory signals to sustain activation. B cells in particular, which contribute to autoimmune pathogenesis through antigen presentation and effector functions, have potential for direct antigen-specific targeting through the B cell receptor (BCR) and provide a promising target for tolerogenic immunotherapies. Multivalent nanomaterials (such as soluble antigen arrays, or cSAgAs) that present multiple copies of covalently-conjugated autoantigen can be tailored to induce anergy in autoimmune B cells through high avidity binding of the BCR in the absence of costimulatory signals to modulate BCR signaling. Design and development of effective cell-targeted antigen-specific immunotherapies should take into account appropriate physicochemical properties of delivered antigen in light of known molecular, cellular, and transport mechanisms for inducing peripheral tolerance. This project seeks to build upon endogenous mechanisms of tolerance to design targeted antigen-specific immunotherapies to treat autoimmune diseases.