(433a) Turning Immunity On and Off

The immune system exists in a delicate balance of mounting active, effector responses to fight infection from invading pathogens and to kill mutated cells, while existing in an active state of tolerance to the non-self contents of the gut and on the skin and to self proteins throughout the body. Dysfunction can lead to susceptibility to infection and cancer on the one hand, and to allergy and autoimmunity on the other. Immunotherapies are being developed to tip this balance one way or the other – for example to vaccinate against cancer to create an immune response against mutated self, or to inverse vaccinate against an autoimmune disease to re-establish immunological tolerance to self.

With regard to turning on immunity to, vaccinologists frequently employ molecular signals of danger to enhance immune responses to pathogen or mutated self antigens, termed adjuvants. We are developing adjuvant systems that employ both physical and molecular mechanisms of action. Adaptive immune responses are triggered particularly powerfully in the lymph nodes and in the lymphoid tissues associated with mucosae. We are developing nanomaterials and soluble polymers to exploit interstitial flow from the site of administration to the lymph nodes, using the material vectors to carry both antigen and associated adjuvant biomolecules. We build these material carriers to include biomolecular features of pathogens to enhance targeting of the target cell populations in the lymph nodes, dendritic cells, for example employing the sugar residue mannose. Thus, materials conjugated to signals for cellular targeting and uptake, to signals of danger for activation of those target cells, and of antigen, to which the effector immune response is intended, are being developed as multifunctional vaccines. We are interested in these materials to turn on immunity to pathogens such as malaria, for which there is no highly effective vaccine, and to cancer.

Immunity to tumors is particularly complex. Normal tissues display regulatory biomolecules that attenuate potential immune responses to prevent autoimmunity; cancers exploit these mechanisms to actively resist killing by the immune system once mutated proteins in the tumor have been detected. These regulatory biomolecules, referred to as checkpoints, are promising targets for cancer immunotherapy, to block these inhibitors of anti-cancer immunity. Moreover, immune regulatory biomolecules, cytokines and chemokines, are also promising candidates develop anti-cancer immunity. The difficulty with these drugs and potential drugs is their frequently high toxicity, since they tip the delicate balance described above and can causes anti-self responses. We are exploring means by which to target these powerful immunotherapeutics to tumors, to enhance their efficacy and reduce their toxicity.

In addition to inducing adaptive immune responses, so-called inverse vaccination to induce antigen-specific tolerance is of high interest. We are exploring biological approaches to deliver protein antigens in a tolerogenic manner, including targeting antigen to the surfaces of erythrocytes after injection, based on the premise that aged erythrocytes are cleared tolerogenically, along with exogenous antigen cargo they may carry. We have shown the ability to induce antigen-specific anergy as well as T regulatory responses, working in models of autoimmunity and of immune response to protein drugs. In this work, the liver appears to be a particularly interesting target for antigen delivery, and we are accordingly exploring glycopolymers to target particular receptors in liver cells in autoimmune and protein drug applications.