Present pharmaceutical agents used to treat chronic, immune-mediated inflammatory diseases associated with significant morbidity and mortality generally do not lead to remission and have serious toxic side effects. This proposal offers a strategy to harness the immune system to treat systemic lupus erythematosus (SLE), a disease of generalized autoimmunity. The product will consist of the patient's own blood T cells stimulated ex-vivo to become therapeutic suppressor cells. In future clinical trials large numbers of this product will be transferred back to the patient as a medicine to ameliorate disease. Proof of concept for phase 1 studies will be to show that na?ve CD4+ cells from healthy donors and subjects with SLE stimulated ex-vivo with a proprietary regulatory composition develop potent suppressive activity and protective effects. endogenous regulatory T cells. Principal developmental milestones will be to show that: 1) the product stably expresses Foxp3;2) the product has significant suppressive activity on autologous T cells both in vitro and in vivo in immunodeficient mice;3) unlike endogenous regulatory T cells, the product will be resistant to the inhibitory effects of proinflammatory cytokines;and 4) the product generated from SLE T cells suppresses both spontaneous polyclonal IgG and autoantibody production by lupus B cells. If this personalized T cell therapy is safe and successful in future clinical trials and can be produced cost effectively, this approach can become the next paradigm for not only the treatment of autoimmune diseases, but also for prevention of allograft rejection in a manner that will minimize the use of toxic anti-inflammatory or immunosuppressive agents.

Public Health Relevance

Present pharmaceutical agents used to treat life-threatening autoimmune diseases do not generally lead to remission and have many toxic side effects. Our approach is to harness the patient's own immune system to treat systemic lupus erythematosus, one of the most severe autoimmune diseases,. Here the product will be the patient's own immune cells stimulated outside the body using a proprietary methodology to acquire the capacity to halt the progression of the disease In future clinical trials large numbers of this product will be transferred back to the patient to use as a medicine to treat the disease instead of the currently used agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
Project #
1R43AI084359-01A2
Application #
8124985
Study Section
Special Emphasis Panel (ZRG1-IMM-G (10))
Program Officer
Prograis, Lawrence J
Project Start
2011-09-23
Project End
2013-08-31
Budget Start
2011-09-23
Budget End
2013-08-31
Support Year
1
Fiscal Year
2011
Total Cost
$245,176
Indirect Cost
Name
Excell Therapeutics, LLC
Department
Type
DUNS #
121816032
City
Santa Monica, CA
State
CA
Country
United States
Zip Code
90402
Zhu, Shang-Ling; Huang, Jian-Lin; Peng, Wei-Xiang et al. (2017) Inhibition of smoothened decreases proliferation of synoviocytes in rheumatoid arthritis. Cell Mol Immunol 14:214-222
Xu, Anping; Liu, Ya; Chen, Weiqian et al. (2016) TGF-?-Induced Regulatory T Cells Directly Suppress B Cell Responses through a Noncytotoxic Mechanism. J Immunol 196:3631-41
Liu, Zhong-Min; Wang, Kun-Peng; Ma, Jilin et al. (2015) The role of all-trans retinoic acid in the biology of Foxp3+ regulatory T cells. Cell Mol Immunol 12:553-7
Li, Ning; Wei, Wei; Yin, Feng et al. (2015) The abnormal expression of CCR4 and CCR6 on Tregs in rheumatoid arthritis. Int J Clin Exp Med 8:15043-53
Gao, Yayi; Tang, Jiayou; Chen, Weiqian et al. (2015) Inflammation negatively regulates FOXP3 and regulatory T-cell function via DBC1. Proc Natl Acad Sci U S A 112:E3246-54
Lin, Shuman; Yang, Xuyan; Liang, Dian et al. (2014) Treg cells: a potential regulator for IL-22 expression? Int J Clin Exp Pathol 7:474-80
Ma, Jilin; Liu, Ya; Li, Yang et al. (2014) Differential role of all-trans retinoic acid in promoting the development of CD4+ and CD8+ regulatory T cells. J Leukoc Biol 95:275-83
Lu, Ling; Lan, Qin; Li, Zhiyuan et al. (2014) Critical role of all-trans retinoic acid in stabilizing human natural regulatory T cells under inflammatory conditions. Proc Natl Acad Sci U S A 111:E3432-40
Chen, Maogen; Lin, Xiaohong; Liu, Ya et al. (2014) The function of BAFF on T helper cells in autoimmunity. Cytokine Growth Factor Rev 25:301-5
Yang, Xuyan; Zheng, Song Guo (2014) Interleukin-22: a likely target for treatment of autoimmune diseases. Autoimmun Rev 13:615-20

Showing the most recent 10 out of 21 publications