Collaborative Project #5: Harnessing biomaterials to study the link between local lymph node function and systemic tolerance
Collaborating Investigator: Christopher Jewell
Affiliation: University of Maryland
Funding Source: NIH
Grant Number: R01EB026896
Project Period: 04/03/18-12/31/21
Project Status: New
During autoimmune disease, the body incorrectly identifies “self” molecules as foreign and mounts a chronic immune attack. Conventional therapies employ broad immunosuppression, which has provided significant benefits to patients, but can leave these individuals immunocompromised. This limitation, along with the lack of cures for most autoimmune diseases, has sparked intense interest in strategies that could control autoimmunity with vaccine-like specificity, leaving the rest of the immune system intact. Several pre-clinical reports and clinical trials have investigated this theory to combat multiple sclerosis (MS), a neurodegenerative disease in which myelin in the central nervous system (CNS) is attacked by the immune system. An important finding from these studies is that co-administration of myelin peptide and tolerizing immune signals can promote the development of regulatory T cells (TREGS) that ameliorate disease. New knowledge of how signal integration in lymph nodes (LNs) drives tolerance could help address limitations associated with current therapies, such as incomplete control of disease and non-specific suppression. This proposal will study these fundamental questions in disease using a new platform that combines direct intraLN (i.LN.) injection with controlled release biomaterial depots. This work will generate insight that informs design of new therapies that aim to promote tolerogenic function in an antigen-specific manner during autoimmune diseases such as MS, Type 1 diabetes, and rheumatoid arthritis.
Aim 1: Determine how local signals in LNs polarize T cell function and program systemic tolerance
Aim 2: Decipher the impact of signal location, delivery route, and kinetics on T cell polarization
Aim 3: Compare the local structure and function of depot-treated LNs to distal LNs, spleen, and CNS
Aim 4: Test if the link between local function and systemic tolerance is generalizable to other self-antigens
CP: TolAPC nanoimmunomaterials developed as part of TR&D2 will be utilized for intra-LN delivery to increase expansion of regulatory T cells and tolerogenic function.
We will combine controlled release depots with TolAPC particles and explore direct injection to lymph nodes, the tissues that orchestrate immune function. We hypothesize that controlled release of signals plus TolAPCs will generate TREGS and be helpful to ameliorate multiple autoimmune diseases.
There is a need for advanced therapeutics to generate immune tolerance against a specific antigen to treat autoimmune diseases. TR&D2 generates new materials with high efficacy at expanding regulatory T cells that can be leveraged by the Jewell lab and their intralymph node injection of biomolecules approach. These materials can accelerate the accomplishment of the aims to generate tolerance (push) and the collaboration guides the design and evaluation of the next generation of materials (pull). Another area of collaboration between the Jewell lab and TR&D2 is in investigation of non-viral nanoparticles for use as genetic vaccines. TR&D2 generates new polymers with high efficacy at transfecting dendritic cells that can be leveraged by the Jewell lab and their intralymph node cancer vaccination approach. These materials can accelerate the accomplishment of those aims as well (push) and the collaboration guides the design and evaluation of the next generation of BEAQ transfection materials (pull). Broadly, the Jewell lab develops in vitro and in vivo tools to study immunomaterials (pull) and TR&D2 produces ideal materials for these studies (push). This enables back and forth collaborative interplay to advance both the design and synthesis of improved NIMs as well as evaluation and demonstration of their function.