Objective
The overall objective is to examine key translational questions about Treg function and their mode-of-action in curative settings, including important features associated with the durability of Treg-mediated immune tolerance, such as their selection, impact on effector cells, and alteration to the innate compartment given that cells of the innate system are strong regulators of destructive immune responses.
Background Rationale
T1D is a devastating autoimmune disease affecting millions around the globe. T1D results from the autoimmune destruction of insulin producing pancreatic β-cells, which is primarily mediated by infiltrating destructive immune effectors. β-cell loss becomes virtually complete over time and leads to lifelong dependence on insulin injections. Presently there is no known preventative strategies or a cure for T1D. Immune-based therapies have been attempted with promising results; however, disease prevention and lasting diabetes reversal remain to be achieved. Moreover, cellular transplantation with isolated pancreatic islets of Langerhans offers the opportunity to reverse autoimmunity at the onset of disease or to treat established disease, but lifelong immunosuppressive medication to prevent graft rejection is required and has a negative health impact on the patient. Immune therapies that combine targeting the destructive immune effectors along with promoting regulation of these responses with regulatory T cells (Tregs) could inhibit damaging autoimmunity and alleviate the need for this chronic immunosuppression, making islet transplantation a real biological cure for T1D.
Description of Project
T1D is a devastating autoimmune disease affecting millions around the globe. T1D results from the autoimmune destruction of insulin producing pancreatic β-cells, which is primarily mediated by infiltrating damaging immune effectors. β-cell loss becomes virtually complete over time and leads to lifelong dependence on insulin injections. Presently there is no known preventative strategies or a cure for T1D. Immune-based therapies have been attempted with promising results; however, disease prevention and lasting diabetes reversal remain to be achieved. Cellular transplantation with isolated pancreatic islets of Langerhans offers the opportunity to reverse autoimmunity at the onset of disease or to treat established disease, but lifelong immunosuppressive medication to prevent graft rejection is required and has a negative health impact on the patient. Immune therapies that combine targeting the destructive immune effectors along with promoting regulation of these responses with regulatory T cells (Tregs) could inhibit damaging autoimmunity and alleviate the need for this chronic immunosuppression, making islet transplantation a real biological cure for T1D. Our work thus far has shown that combinational therapies with anti-CD3, which has been shown to modify the progression of diabetes in clinical trials, together with disease targeted Tregs leads to long-term diabetes reversal and can promote tolerance to transplanted tissues and cells. We are now poised to ask mechanistic questions as to why our strategy works and gain significant insights into therapeutic efficacy that can expedite advanced immunotherapies in the clinic. The studies here are aimed as first-line investigations into gaining valuable information on the mode-of-action of this Treg-based therapy, including detailed examination of the Tregs themselves and the impact this therapy has on the destructive effector immune response.
Anticipated Outcome
We anticipate that our combinational regimen of anti-CD3 and regulatory T-cells will deplete destructive effector Tcells and that disease targeting Tregs will alter the immune microenvironment leading to long-lasting tolerance and retain intact immunity without the risks related to chronic systemic immunosuppression.
Relevance to T1D
Currently, there is no immunotherapy to treat T1D with lifelong effects, so even finding a treatment for a subset of patients is a major advancement in the field. Destructive effector T-cells in T1D are in part attributed to abnormal peripheral immune regulation. An impaired pool of regulatory T-cells has been linked to T1D. Therefore, therapies targeting these immune responses are aimed at tipping the balance towards regulation and changing the disease-associated effector repertoire. Therefore, we will undertake a comprehensive study of the cellular and molecular mechanisms involved in inhibiting effector responses to advance our understanding of Treg mode-of-action in a curative strategy for autoimmune diabetes. The studies proposed here will provide fundamental knowledge by which a clinically relevant combinatorial therapy can inhibit autoimmunity and alleviate the need for chronic immunosuppression, making islet transplantation a real biological cure for T1D.