Chimeric antigen receptor (CAR) T cells have been studied since the late 1980s. By genetically modifying T cells from patients with cancer, scientists use CAR T cells to teach the immune system how to eliminate malignant cells. Recently, this technology has delivered some amazing results for blood cancers, and is now being tested in several solid tumor-cancers.
Leveraging this technology, a team from the Department of Dermatology, at the University of Pennsylvania, has modified T cells to treat the antibody-mediated autoimmune disease, pemphigus vulgaris (PV), in mice. This was the first time that only the self-destructive cells were eliminated in a model of an autoimmune disease.
Modified CAAR T Cells Demonstrate Potency and Specific Cytotoxicity
In the case of PV, the immune system produces antibodies against certain proteins called Dsg3, present in the skin and mucus membranes. These autoantibodies are produced by B cells and disrupt the bounds between skin cells giving rise to painful blisters and sores.
Because of the risk of infection, without treatment, this condition can be life-threatening. PV remission is correlated with the disappearance of circulating anti-Dsg3 B cells. Hence, in this study, authors reasoned that by engineering CAR T cells to express Dsg3 as a cell-surface domain, they would lure the B cells that target the Dsg3 protein and kill them. Notably, in their first in vitro study, using chimeric autoantibody receptor T cells (CAAR T cells) they were able to selectively lyse cells that expressed Dsg3.
Engineered Cells Eliminate Dsg3 Target Cells and Alleviate Symptoms of Pemphigus Vulgaris
To test the competency of the engineered cells, researchers injected a mouse model of PV with Dsg3-expressing CAAR T cells. In principle, the modified T cells would bind anti-Dgs3 autoantibodies from B cells, and selectively kill these diseased B cells.
Notably, after transplanting the mice with CAAR T cells, the levels of anti-Dsg3 autoantibody decreased, meaning that the diseased B cells were dying. More importantly, there was an absence of autoantibody binding to keratinocytes, which resulted in stopping the blistering in the treated mice.
In conclusion, this first preclinical study demonstrates the potential of CAAR T cells to treat antibody-mediated autoimmune diseases. It also paves the way for a new set of treatments that avoid the use of constraining immunosuppression.
Image courtesy of pixabay.com
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