Our immune system is an astonishingly sophisticated, multi-layered series of defenses against harmful agents. In many cases, however, the immune system fails to effectively fight certain diseases, or the activity of the immune system itself causes health problems. In these cases, patients must rely on drugs and other medical treatments to take over where the immune system has failed. Recent biomedical advances make it possible to engineer the immune system to outperform its natural state.
Rebel immune systems: In healthy individuals, regulatory T cells (TRegs) modulate the immune system to tolerate self-antigens. If this system fails, autoimmune diseases arise, and the immune system will attack healthy tissues in the body, causing inflammation and cell death. Treatment of autoimmune diseases usually involves some form of immunosuppression, which makes patients more susceptible to harmful infections. However, using cellular engineering, it is now possible to make antigen-specific TRegs which specifically down-regulate harmful autoimmune responses without globally suppressing immunity2. Using a mouse model, Kim et al. have shown the effectiveness of engineered TRegs designed to express a clonal, patient-derived transgene, which can be expanded ex-vivo and used to downregulate a specific autoimmune response3.
Remote-controlled cells: Chimeric Antigen Receptors (CARs) are recombinant genes that can be used to engineer T cells to recognize and attack cells that express certain antigens, such as cancer cells. Therapeutically, this approach has seemed promising, but has been is plagued by severe toxicity due to high activity of the CAR T cells. Wendell Lim’s group has solved this problem by designing split CARs that are activated by the addition of a small molecule, essentially making the immune response remote controlled1. This pharmacologic regulation allows the activity of the engineered T cells to be precisely titrated, thereby reducing toxicity and other side effects.
Genetic cancer vaccines: The natural induction of a tumor-specific immune response is primarily due to presentation of tumor-associated antigens by dendritic cells (DCs), which activates T cells to attack the cancer. This type of acquired immune response can be stimulated by the use of vaccines, which initiate a DC-mediated presentation of disease-relevant antigens. In order to enhance the specificity of displayed antigens, Moulin et al. have identified DC-associated promoters, and used these elements to express selected vaccine genes specifically within dendritic cells4. This technology will allows expression of vaccine antigens directly by DCs for the induction of specific immune responses, and should also improve vaccine safety.
Cyagen Biosciences can help you harness the experimental power of animal models and cellular engineering in your own research. We provide custom mouse and rat models, including transgenics, knockouts and knockins, CRISPR/Cas9 and TALEN genome editing, as well as custom virus packaging, stem cells, and cell culture reagents. Our VectorBuilder platform provides a wide variety of molecular engineering services. Using our innovative online tools, you can design and order custom DNA constructs specific to your experimental needs. Choose from lentiviruses, AAV vectors, shRNA expression vectors, CRISPR/Cas9 vectors, and more! Design your constructs, we will do the cloning, and you can make discoveries!
- Wu CY, Roybal KT, Puchner EM, Onuffer J, Lim WA. (2015) Remote control of therapeutic T cells through a small molecule-gated chimeric receptor. Science. pii: aab4077.
- Bluestone JA. (2005) Regulatory T-cell therapy: is it ready for the clinic? Nature Reviews Immunology. 5:343-9.
- Kim YC, Zhang AH, Su Y, Rieder SA, Rossi RJ, Ettinger RA, Pratt KP, Shevach EM, Scott DW. (2015) Engineered antigen-specific human regulatory T cells: immunosuppression of FVIII-specific T- and B-cell responses. Blood. 125:1107-15.
- Moulin V, Morgan ME, Eleveld-Trancikova D, Haanen JB, Wielders E, Looman MW, Janssen RA, Figdor CG, Jansen BJ, Adema GJ. (2012) Targeting dendritic cells with antigen via dendritic cell-associated promoters. Cancer Gene Therapy. 19:303-11
Image courtesy of Praisaeng at FreeDigitalPhotos.net