Autoimmune Lymphoproliferative Syndrome (ALPS) is a primary immunodeficiency of T cell-dysregulation caused by defective Fas-mediated apoptosis. Many patients with ALPS develop a severe form of the illness with significant lymphadenopathy, splenomegaly, autoimmune disease, and increased risk of malignancy. Unfortunately, most therapies currently used to treat ALPS patients are non-specific, toxic, and ineffective for many patients. We have data showing that targeting the mTOR signaling pathway is a novel and effective treatment strategy for ALPS. We have treated both mice and children with sirolimus, an mTOR inhibitor (MTI), and found rapid, complete, and durable resolution of disease. Our data suggest the presumed effector cells of ALPS, double-negative T cells (DNTs), are especially sensitive to MTIs. Prior to moving this class of agents to the front-line of therapy for ALPS, we need to investigate the mechanism(s) underlying these remarkable results. We hypothesize that MTIs are effective in ALPS because the abnormal lymphocyte populations present in ALPS are uniquely dependent on mTOR and related signaling pathways. We will test our hypothesis using transgenic mouse models of ALPS and in lymphocytes from ALPS patients. We have developed novel in vitro and in vivo systems to support cells collected from children with ALPS. We propose two specific aims to validate our hypothesis. First, we hypothesize that ALPS cells, specifically DNTs, have intrinsic abnormalities in mTOR and related signaling pathways. We have preliminary data strongly supporting this hypothesis and will define mTOR and related signaling pathways in ALPS. We will focus in part on Akt. Akt is serine-threonine kinase that activates mTOR. We have data suggesting Akt is abnormally activated in ALPS and data suggesting targeting Akt is effective in ALPS cells with specific activity against the DNTs. Second, we will delineate the effects of targeting mTOR on lymphocyte biology and cytokine signaling in ALPS. Unlike in non-ALPS patients treated with MTIs, our data suggest MTIs specifically target DNTs in ALPS with relative sparing of normal lymphocytes. We will investigate the activity of MTIs on lymphocyte subsets, comparing changes in number and function between MTI-treated patients with ALPS versus MTI-treated patients with non-ALPS autoimmune cytopenias. In addition, we have data suggesting regulatory T cells (Tregs) are diminished in ALPS patients, potentially leading to autoimmune disease. MTIs have the unique ability to suppress the immune system while increasing Tregs. We will study Tregs in ALPS. Interleukin-10 (IL-10) is hypothesized to be the driving cytokine in ALPS, leading to autoimmune manifestations. We will determine the effects of mTOR inhibition on IL-10 signaling in ALPS. Finally, we will test our hypothesis that MTIs can prevent cancer in ALPS. We anticipate these studies will allow us to revolutionize the treatment of ALPS, improving patient heath and quality of life.

Public Health Relevance

Autoimmune Lymphoproliferative Syndrome (ALPS) remains a challenging childhood disorder, as current treatments are non-specific, toxic, and ineffective for many patients. We have found that treating children with ALPS with sirolimus substantially improves all clinical aspects of the disease, as well as quality of life. This project will lead to a better understanding of the causes of this disease, resulting in better treatments and potentially even a cure for this often devastating childhood illness.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
High Priority, Short Term Project Award (R56)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Bourcier, Katarzyna
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Children's Hospital of Philadelphia
United States
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