PROJECT
HEAD-Treg: Human Engineered
Anti-Autoimmune-Disease Regulatory T Cells System
Abstract
FOXP3 + regulatory T cells (Treg) are a class of T lymphocyte subsets that play an immunosuppressive and regulatory function.
The dysfunction of FOXP3+ Treg is closely related to the development of autoimmune diseases, such as rheumatoid arthritis. FOXP3,
a transcription factor in Forkhead family, whose functional stability is regulated by post-translational modification enzymes, is a
key transcription factor for Treg cells’ specific expression. The ubiquitinase USP7 was able to specifically modify the FOXP3
protein by specific ubiquitination to enhance the functional stability of FOXP3, thereby enhancing the immunosuppressive function
of Treg cells.
In patients with rheumatoid arthritis, the balance between Th17 and Treg is usually broken, and inflammatory cells such as Th17
predominate in the human body. A quantity of inflammatory cytokines, such as IL-17A, IL-6 and TNF-α and so on, secreted by Th17 and
other inflammatory cells enhance the inflammation of the lesion, which causes the local enrichment of effector cells such as CD20+
B lymphocytes in the focus and deprives the normal function of Treg cells, resulting in further decline in immunosuppressive
capacity. Based on these facts, we hope that our cell therapy program that is to isolate and obtain primary regulatory T cells from
rheumatoid arthritis patients and then infute engineered Treg cells again to the human body, can have a promising effect in the
treatment of rheumatism.
In our design, first, we designed a SynNotch system that contains a modified Notch protein capable of specifically activating the gene expression of USP7 in inflammatory conditions with the presence of IL17A. USP7 proteins can lead to de-ubiquitination of the FOXP3 protein, so that it can enhance the stability of FOXP3 protein in the inflammation environment by protecting FOXP3 from degradation via ubiquitination. As a result, Treg cells can maintain their immunosuppressive function. Meantime, we designed a CAR system that enables
Treg cells to target CD20+ B lymph Cell specifically to play an immunosuppressive function and thus take an anti-inflammatory effect.
Given our design and purpose, we call the system a Human Engineered Anti-Autoimmune Disease Regulatory T Cells System (HEAD-Treg).
Introduction and Background
People are exposed to billions of pathogens every day. In the meantime, billions of cells within our body undergo a complicated process
from generation, aging to apoptosis, together with injuries and mutations. Our immune system identifies and eliminates the threat from inside and outside of our body with precision and efficacy, just like an elaborated network.
In accordance with the Chinese Yin-Yang theory and the western critical thinking, our immune system is under a dynamic equilibrium
at all times. The immune network consisting of immune organs, immune tissues and immune cells rely on each other and promote each other,
which is a both unified and varying state which called as immune homeostasis, with immune response and immune tolerance as two most
critical features. On one hand, immune response helps us get rid of antigens, and eradicate harmful factors against human body; on
the other hand, immune tolerance helps us distinguishing the enemies from our own, avoiding any harm from overreaction and indiscriminate
destruction. Thus, the immune homeostasis is a prerequisite for our healthy life, once the balance is no longer maintained a series of
diseases will occur and physical functions may fail. If immune tolerance shows more potency than immune response, the human body will be
in an immune inhibited state, where pathogens and cancer cells are left uncontrolled leading to the onset of severe infection and malignancy.
If immune response gains the upper hand over immune tolerance, normal cells will be targeted for elimination leading to diseases we call as
autoimmune diseases, for example rheumatoid arthritis(RA), systematic lupus erythromatosis, autoimmune type I diabetes, etc. In this way,
finding a way to recover the immune homeostasis becomes an essential strategy in dealing with these two types of diseases.
An imbalance in immune cell’s function is often found in them. Sometime the immune system cannot recognize the target cell, sometime a
certain type of immune cell may proliferate. Thus, remodeling the function of a crucial type of immune cell turns into a key point.
Cytotherapy has, therefore, become a rising star against these diseases, with CAR-T and TCR-T as the representatives in this technology.
The trick in these therapies lies in transforming T cells with synthetic biology approaches, inserting and expressing artificial genes of
chimeric antigen receptor into T cell genome and enabling them to recognize and eradicate target cells precisely. Obviously, such strategy
has achieved a certain success. This year, the CAR-T product from Novartis was officially approved by FDA to treat acute lymphoblastic
leukemia(ALL) in enfants and young adults, which has shown high efficacy in the treatment of non-solid tumors.
Two subtypes of immune cells are of great significance with respect to the onset of autoimmune diseases like RA, one is the incendiary
of inflammation which is called Th17 cell, and one is the firefighter of inflammation which is called regulatory T cell(Treg). In normal
human body, the ratio of Th17 to Treg is in a dynamic equilibrium, while in rheumatoid arthritis patients Th17 greatly outnumbers Treg in
the focus of a lesion. Inflammatory cytokines secreted by Th17, including IL-17, IL-6, TNF-α, will trigger a cascade of reaction causing
severe inflammation locally together with B lymphocytes which may further lead to organ dysfunction and could be fatal.
(cited from:Chen X, Oppenheim JJ. Th17 cells and Tregs: unlikely allies. J Leukoc Biol. 2014 May;95(5):723-731. Epub 2014 Feb 21.)