Methods for treating autoimmune disease by inducing autoantigen-specific regulatory CD4+ T cells
View Patent ↗Described herein are methods and compositions for the treatment and monitoring the progress of autoimmune diseases. In some embodiments, the methods include the stimulation of regulatory T cells specific to autoantigens associated with the autoimmune disease. A specific embodiment relates to diabetes mellitus, and the prevention or delay of loss of residual β-cell mass, providing a longer remission period and delaying the onset of diabetes related, progressive, complications through immunotherapeutic induction of regulatory T cells specific for human insulin B chain. In addition, the methods described herein can be used to predict whether a subject, e.g., a subject with ongoing anti-insulin autoimmunity, will progress to T1DM, and to evaluate a subject's response to a therapeutic intervention.
1. A method of treating a subject for the development or progression of autoimmune diabetes comprising:
obtaining a blood sample from the subject:
detecting whether insulin autoantigen specific CD8+ cytotoxic T cells are present in the blood sample:
diagnosing the subject as susceptible to the development or progression of autoimmune diabetes when the presence of insulin autoantigen specific CD8+ cytotoxic T cells are detected in the blood sample:
treating the diagnosed subject by parenterally administering to the subject an effective amount of a therapeutic composition comprising insulin β-chain autoantigen in a water-in-oil adjuvant emulsion comprising mannide monooleate, polyoxyl-40-hydrogenated castor oil, squalene and squalane sufficient to stimulate insulin β-chain autoantigen-specific CD4+, CD25+, Foxp3+ regulatory T cells in the subject;
obtaining additional blood samples from the treated subject:
detecting the presence of insulin β-chain autoantigen specific CD4+, CD25+, Foxp3+ regulatory T cells (Tregs) in the additional blood samples of the treated subject; and
parenterally administering one or more subsequent doses of the therapeutic composition sufficient to suppress the function of insulin autoantibody specific CD8+ cytotoxic T cells in the treated subject.
2. A method of treating a mammalian subject to prevent the progression of an autoimmune disease comprising:
obtaining a blood sample from the subject:
detecting the presence of autoantigen specific cytotoxic CD8+ T cells in the subject, wherein the autoantigen is associated with the autoimmune disease in the subject;
diagnosing the subject as susceptible to the autoimmune disease when the presence of auto autoantigen specific cytotoxic CD8+ T cells are detected in the blood sample;
treating the diagnosed subject with an effective amount of a therapeutic composition comprising at least one autoantigen associated with the autoimmune disease in a water-in-oil emulsion comprising mannide monooleate, polyoxyl-40-hydrogenated castor oil, squalene and squalene sufficient to induce regulatory T cells specific to the autoantigen in the subject to create a treated subject;
obtaining additional blood samples from the treated subject:
detecting the presence of autoantigen-specific CD4+, CD25+, Foxp3+ regulatory T cells in the additional blood samples of the treated subject; and
parenterally administering a booster amount of the therapeutic composition to the treated subject sufficient to suppress the function of autoantigen specific CD8+ cytotoxic T cells in the treated subject.
3. The method of claim 2 , wherein the subject is a human, the autoimmune disease is diabetes, and the autoantigen is insulin B chain.
4. The method of claim 3 wherein the regulatory T cells secrete IL-10, TGF-Beta, or both IL-10 and TGF-Beta.
5. The method of claim 2 , wherein the autoimmune disease is diabetes and the autoantigen is GAD65.
6. The method of claim 1 wherein the autoantigen is contained in aqueous globules and the aqueous globules have median diameters in the range from about 100 nanometers to about 1 micron.
7. The method of claim 6 wherein the aqueous globules have an average diameter of about 300 nanometers.
8. A method of treating a subject to inhibit the development or progression of autoimmune diabetes comprising:
obtaining a blood sample from the subject;
detecting whether insulin autoantigen specific CD8+ cytotoxic T cells are present in the blood sample;
diagnosing the subject as susceptible to the development or progression of autoimmune diabetes when the presence of insulin autoantigen specific CD8+ cytotoxic T cells are detected in the blood sample;
treating the diagnosed subject by parenterally administering to the subject an effective amount of a therapeutic composition comprising insulin β-chain autoantigen in a water-in-oil adjuvant emulsion comprising mannide monooleate, polyoxyl-40-hydrogenated castor oil, squalene and squalane sufficient to stimulate insulin β-chain autoantigen-specific CD4+, CD25+, Foxp3+ regulatory T cells in the subject;
obtaining additional blood samples from the treated subject;
detecting the presence of insulin autoantibody specific CD8+ cytotoxic T cells in the additional blood samples of the treated subject; and
parenterally administering one or more subsequent doses of the therapeutic composition sufficient to suppress the function of insulin autoantibody specific CD8+ cytotoxic T cells in the treated subject.
9. The method of claim 2 or 8 , wherein the autoantigen is contained in aqueous globules and the aqueous globules have median diameters in the range from about 100 nanometers to about 1 micron.
10. The method of claim 9 wherein the aqueous globules have an average diameter of about 300 nanometers.