Objective
The objectives of this proposal are to 1) define how islet-reactive B cells interfere with the development and function of islet-protective Tregs, which B cells perform this negative function, and where they do so during Treg development and 2) to identify approaches to prevent these negative interactions to enhance immune therapy for T1D and determine how to B cell directed therapies and other therapies can be combined to fully correct immune function to prevent and reverse disease..
Background Rationale
General Audience Summary - Background/Rationale
The immune system becomes activated when the factors stimulating its function exceed the factors regulating or inhibiting its activation. In T1D, the immune system has become activated against islets years to decades before there is enough islet loss to cause insulin deficiency that leads to the symptoms of hyperglycemia. During this progressive process, immune activation must be sustained, suggesting that stimulating factors must persist or that regulatory factors must not recover. The traditional model of immune activation and beta cell loss in T1D is that there are persistent activation signals. It is thought that many of these activation signals occur through interactions between the T cells that destroy islets and B cells that can activate these T cells and produce the autoantibodies we detect. Our work indicates that B lymphocytes also work to impede and prevent immune regulation; thus these cells present an ongoing barrier to successful immune therapy. It is for this reason, we believe, that powerful therapies that suppress immune activation do not produce long-term effects in T1D--the effects do not persist because the needed immune regulation never recovers. Our data indicates that B lymphocytes contribute significantly to "regulate the regulators". This proposal will uncover the mechanisms of these interactions and will identify and assess new approaches to enable the recovery of a properly regulated immune system. We will add to our understanding of immune activation and beta cell loss in T1D and develop a new understanding of T1D pathogenesis and rational approaches for treatment.
Description of Project
The very first sign of Type 1 diabetes is the presence of autoantibodies in the blood. The appearance of these markers of immune disease can proceed beta cell failure by years to decades, but they also guarantee that type 1 diabetes is underway and that person will eventually need insulin. These autoantibodies are produced by B lymphocytes and their presence indicates that B cells and T cells have interacted with each other. This interaction leads to the activation of the cells that ultimately destroy the insulin-producing beta cells and leave an individual dependent on insulin. The activation of the T cells that destroy islets is opposed by regulatory T cells that protect islets from destruction by inhibiting T cell activation and destructive function. It has traditionally been thought that the B cells that drive T1D do so by directly stimulating the T cells that kill islets. However, work by our lab and others have shown that T cells don't need B cells to become activated even though B cells are needed for the disease to progress. We have investigated this puzzle and have determined that B cells cause disease by inhibiting regulatory cells. By "inhibiting the inhibitors", B cells create an environment in which islet-destroying T cells are unrestrained. Because regulatory T cells are the only long-lived protective cell in the immune system, their loss creates a lifelong risk for diabetes and other autoimmune diseases; in addition their loss makes it difficult to permanently repair the immune system. These newly defined interactions between B cells and Tregs are a likely key contributor to the inability for any immune therapy to date to produce a permanent effect for T1D. In this proposal we will define how B cells impede regulatory T cells and how this process can be repaired to enable permanent treatments for T1D.
Anticipated Outcome
Completion of this study will reveal 1) the mechanisms by which B cells deplete Tregs and limit their function; 2) the identity of the B cells that prevent immune regulation; 3) when during Treg development these interactions occur; 4) how B cell directed therapies can combine with other therapies to improve outcomes; and 5) new models to understand clinical immune therapy including new concepts to apply to ongoing clinical trials (such as treatment of new onset T1D with rituximab and abatacept).
Relevance to T1D
Healthy individuals do not develop autoimmune diseases like T1D because they have internal regulatory processes that prevent the immune system from harming the body's own tissues. These processes fail in T1D as first shown by the identification of autoantibodies in the blood. To achieve long-term treatment of immune T1D and prevention of further islet loss, these endogenous processes need to be identified and repaired. We have identified a previously unrecognized process that may be critical to successful long-term treatment of T1D. While it is well established that the presence of autoantibodies indicates that T1D is underway and progressing toward islet failure, it has traditionally been thought that the presence of autoantibodies reflects direct interactions between autoantibody-producing B lymphocytes and islet-killing T lymphocytes. Our data suggest that there is also a critical contribution from an indirect process in which these B cells impede the function of islet-protective Tregs. By limiting Treg function, B lymphocytes permanently alter the immune landscape to favor autoimmune disease. Although islet-destructive activated T cells can be inhibited by immune therapy, when therapy is stopped islet destruction recurs because the underlying immune protection delivered by Tregs has been eroded. If we can halt this erosion of immune regulation by B lymphocytes, we may be able to enhance immune therapies and develop strategies to restore long-term islet protection to prevent and reverse T1D.