Objective
The objective of this interdisciplinary work is to design biodegradable polymer depots that contain regulatory signals and self-molecules associated with disease in Type 1 Diabetes (T1D). We will test if delivering these particles to lymph nodes – tissues that control immune function – improves disease during stringent models of T1D in a specific manner, and if these effects are underpinned by induction of regulatory immune cells with unique long-lasting properties. Biomaterials allow co-delivery of cargo, controlled release, and targeting, so this approach creates a powerful opportunity to locally control the environment of lymph nodes and learn how the signals delivered to these sites impact the balance between inflammation and immune tolerance. Understanding and controlling this balance could support vaccine-like therapies for T1D that are selective and long-lasting.
Background Rationale
Recent studies show that co-delivering regulatory signals and self-molecules associated with disease can help promote tolerance in autoimmune diseases such as type 1 diabetes (T1D) and multiple sclerosis (MS). While this approach has great potential, there are challenges associated with getting these molecules and signals to the correct immune cells and tissues, and in the correct combinations. Biomaterial science has recently entered into autoimmune research and therapy, because polymers and other biomaterials can be designed to target, deliver, and protect drugs or biological cargo. These features could help tease out how the components of new immunotherapies impact the development of tolerance. In mouse models of T1D, we have discovered that direct lymph node delivery of biomaterials depots prevents T1D with a single treatment by generating regulatory immune cells. This finding and the need for better T1D treatments suggest our approach to locally control the lymph node environment could generate long-lasting tolerance without systemically exposing patients to potent drugs.
Description of Project
Approximately 2 million Americans suffer from type 1 diabetes (T1D). Although insulin replacement therapy has continually improved, no cure exists. Further, existing treatments require a high degree of compliance and lifestyle changes. T1D results when self-reactive T and B cells mistakenly attack insulin-producing beta cells in the pancreas. In contrast to broadly suppressive drugs, new immunotherapies seek to specific options. However, even the newest drugs being explored – such as monoclonal antibodies, cannot differentiate between healthy and dysfunctional cells. Another experimental concept is to direct or modulate immune cell populations toward regulatory functions that control inflammation and specifically suppress self-reactive cells. One exciting prospect for treating T1D in this manner are “vaccine-like” therapies in which self-antigens are used to generate protective regulatory T cells. Here we propose a vaccine strategy that combines biomaterials and nanotechnology to engineer the local function of lymph nodes – the tissues that coordinate immune function. In these sites, T cells and other immune cells with specific reactivity (e.g., fragments of beta cells) receive sets of signals that help them develop and expand toward either inflammatory or regulatory cells. These cells then leave lymph nodes and migrate to sites of infection in the case of healthy immunity, or to the target organs that are attacked in the case of autoimmunity. We have invented a new approach to directly deliver controlled release depots to lymph nodes that locally release regulatory cues to promote regulatory T cells as these T cells become activated in lymph nodes. In mouse models of T1D we have shown these depots prevent disease with a single lymph node treatment when administered early. The goal of the proposed work is to build on these data to test if the therapy can reverse T1D in challenging mouse models and treatment regimens. Additionally, our initial data indicate the helpful regulatory cells we generate might have a long-lasting. Thus, we will also test the hypothesis and the underlying biological mechanisms that may be involved. We will synthesize depots co-loaded with molecules associated with disease in T1D and signals that help reprogram how these cells are processed by the immune system to generate regulatory T cells. We will use these depots to assess efficacy in two challenging treatment models of T1D, and determine if these effects are specific. The latter will be tested by challenging mice that exhibit good therapeutic outcomes with a vaccine to ensure animals can mount normal healthy responses. We will also test the hypothesis that lymph node depots generate specialized regulatory T cells that are durable, and confirm if transfer of regulatory T cells from treated animals can stop disease. This will confirm our hypothesis that these cells play a major part in efficacy. We also hypothesize lymph node depots recondition the local environment of lymph nodes, so we will use specialized research tools to assess this idea. Lastly, B cells also play a role in T1D, so we will determine if depots are also able to stop some of the inflammatory processes these cells contribute too, and further, if we promote helpful regulatory function in B cells. If successful, this study could help engineers, scientists and clinicians understand what components should be included in antigen-specific T1D therapies, and support new immunotherapies that are highly specific and long lasting by controlling the local environment of lymph nodes, without systemic exposure to potent drugs.
Anticipated Outcome
The proposed studies will result in three outcomes: 1) exciting pre-clinical data demonstrating the extent to which lymph node environment can stop and maintain tolerance in several challenging models of T1D, 2) data revealing the mechanisms and durability underpinning efficacy among T and B cells, and 3) new insight into how self antigens and regulatory cues are integrated in and between lymph nodes and systemic immunity. Together, these findings will position this platform for potential translation in development of next generation T1D therapies.
Relevance to T1D
This work is directly relevant to type 1 diabetes (T1D) along several dimensions. First, the proposal will generate a key set of remaining pre-clinical data to support development of this technology as a new T1D therapy. Ultimately, translation of this idea could lead to better treatment options for patients. Second, new fundamental knowledge will be generated that helps improve the design of this and other treatment strategies for T1D, regardless of injection route. Last, since this is a platform technology, further data in the context of T1D would increase the validity of the strategy, supporting translational while opening paths to apply similar ideas to other autoimmune diseases. Thus the proposed research could have a catalytic effect that contributes to better options for T1D patients, while also contributing generally to more rational design of antigen-specific tolerance strategies.