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. To further develop this strategy, we will combine self-molecules with transplant antigen to test whether this approach can be expanded to late stage T1D. Biomaterials allow co-delivery of cargo, controlled release, and targeting, creating 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 tolerance. Understanding and controlling this balance could support therapies for T1D that are selective and long-lasting to ultimately define a target product profile for using in clinical scenarios during both early onset and late stage T1D.
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 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 offers the possibility that inducing tolerance of self-molecules in tandem to islet transplant by locally controlling the lymph node environment might allow selective tolerance important for treating both new onset and established disease.
Description of Project
Approximately 2 million Americans suffer from type 1 diabetes (T1D). Although insulin replacement has continually improved, no cure exist for T1D. Further, existing treatments require a high degree of compliance and lifestyle changes. Thus, there exists a need for the development of new potent, long-lasting therapies. T1D results when self-reactive T and B cells mistakenly attack insulin-producing cells in the pancreas. In contrast to broadly suppressive drugs, emerging immunotherapies seek to target specific, self-reactive cells. However, even the newest drugs – such as monoclonal antibodies, cannot differentiate between healthy and dysfunctional cells. One experimental concept is to direct or modulate immune cell populations toward regulatory functions that control inflammation and specifically suppress self-reactive cells. Here, we propose a strategy that uses biomaterials to engineer the local function of lymph nodes – the tissues the coordinate immune function. In these sites, T cells and other immune cells with specific, unwanted reactivity (e.g., against fragments of insulin-producing beta cells) receive signals that help them develop and expand toward either inflammatory or regulatory cells. These cells then leave the 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 modulatory cues to promote regulatory T cells. With Breakthrough T1D support, we have shown in mouse models of T1D that depots containing a single antigen cue can prevent disease following one treatment when administered before disease onset. Additionally, our initial data indicate the helpful regulatory cells we generate might have a therapeutic effect that is systemic, but cell specific. The goal of this proposed work is to build on these data to test whether inclusion of multiple antigens during lymph node immunotherapy can further enhance the effect and reverse T1D in challenging mouse models and treatment regimens. We will synthesize depots co-loaded with several 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 by studying the underlying biological mechanisms that may be involved. One way we will test specificity is by challenging mice that exhibit good therapeutic outcomes with a vaccine to ensure animals can mount normal healthy responses. In addition, B cells also play a role in T1D, so we will determine if depots are also able to stop of some the inflammatory processes these cells contribute too, and further, if we promote helpful regulatory function in B cells. Lastly, we will combine our approach that tolerizes immune responses to self-reactive antigens with molecules that regulate transplant rejection. In this scenario, we will test whether our strategy can support transplant of insulin-producing cells to address late-stage disease – a clinically relevant scenario for many T1D patients. If successful, these studies 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) expand exciting pre-clinical data demonstrating the extent to which lymph node environment can stop and maintain tolerance in several challenging models of T1D in combination with transplant, 2) generate data revealing the immune cell mechanisms underpinning the efficacy of lymph node targeted immunotherapy, and 3) support development of a target product profile for IND-enabling studies. 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. Successful translation of this idea – including the three clinically-relevant scenarios proposed –could help support transformative options for patients with new onset disease, as well as those with established disease. 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 disease. 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.