September 16, 2021

‘Pre-conditioning’ restores immune tolerance

A treatment targeting T-cell metabolism could reinvigorate immune tolerance mechanisms to combat autoimmune disease and transplant rejection, Vanderbilt researchers discovered.

Systemic lupus erythematosus (SLE) is an autoimmune disease that can cause kidney damage. Immunosuppressive drugs are only partially effective in suppressing activation of immune T cells and production of autoantibodies that attack the kidneys. 

Reporting last month in JCI Insight, Christopher Wilson, PhD, Daniel Moore, MD, PhD, and colleagues report that in an animal model of SLE, abnormally high T-cell metabolism enables activated T cells to resist immune regulation. This suggests that abnormal T-cell metabolism is a barrier to immune therapy. 

The researchers found that when the animals were treated for two weeks with two metabolism-lowering compounds, 2-deoxyglucose and metformin, in combination with anti-CD45RB, a monoclonal antibody that blocks T-cell activation, deposition of autoantibodies in the kidneys was blocked for six months and immune tolerance to tissue transplants was restored. 

“These findings indicate that metabolic therapy thus may be applied as a powerful preconditioning to reinvigorate tolerance mechanisms in autoimmune and transplant settings that resist current therapies,” the researchers concluded. 

The research was supported by a Thomas J. Beatson Jr. Foundation grant, a Juvenile Diabetes Research Foundation Career Development Award, a Mayo Metabolomics Pilot and Feasibility Award and by National Institutes of Health grants DK100469, DK107321, HL128040, DK121438 and AI124190.