Controlling Our Immune System — 10

TOWARD TOLERANCE IN SPECIFIC CONDITIONS

It is a sign of the revolutionary time we live in that the first drug to delay the onset of an autoimmune disease was proved to work and approved by the FDA in 2022. The disease was our nemesis, type 1 diabetes. Since 1999, researchers have been studying how to interrupt T cell attack of beta islet cells of the pancreas, and achieve tolerance. Their drug of focus has been teplizumab, a monoclonal antibody that binds to the surface CD3 receptor specific to T cells. By 2021, a fourteen-day course of the antibody for high-risk relatives was shown, in a randomized trial of seventy-six participants, to significantly delay the onset of diabetes (sixty months versus twenty-seven months for the antibody vs. placebo, respectively) and improve beta cell function. Some individuals had true interruption, without ever developing type 1 diabetes. The FDA approved teplizumab for prevention of type 1 diabetes for people who had two or more autoantibodies and abnormal glucose metabolism in 2022. Later, in 2023, a phase 3 trial of 217 children and teens newly diagnosed with the disease (in contrast to the high-risk previous trial), given two twelve-day courses of the antibody, had significant improvement of stimulated C-peptide levels, a key metric indicating preserved beta cell function. The mechanism for teplizumab’s durable effects appears to be related to promoting CD8+ T cell exhaustion.

That opens the door for more effective or complementary means of preventing this type of diabetes. One direction is toward more specificity of antibodies to T cells that attack insulin-producing cells instead of targeting all effector T cells. An antiviral approach with the combination of pleconaril and ribavirin for new-onset cases was assessed in a randomized trial with success for preserving β-cell function as reflected by C-peptide production. Baricitinib, a potent anti-inflammatory used in rheumatoid arthritis and severe COVID, was tested in a randomized trial also of new-onset cases, and preserved β-cell function. In people aged twelve to twenty-four years with a specific HLA type (DR3-DQ2) associated with type 1 diabetes, autoantibodies (GAD65), and recent onset of the disease, a randomized trial of an intralymphatic autoantigen called GAD-Alum compared with placebo led to improved glycemic control.

Avaccine against Coxsackie, a virus that is strongly associated as a risk factor for type 1 diabetes, has been developed and needs to be evaluated. Promoting tolerance with use of oral, powdered insulin to promote Tregs has some promise. Giving Treg cells failed in a clinical trial of new-onset cases, but the results suggested it was the quality of the cells rather than quantity that was important. The gut microbiome is clearly influential; microbiome manipulation, such as with single strain introduction of Bifidobacterium longum, is one of many strategies being assessed. Preventing childhood obesity, another risk factor, is essential. The potential benefit of GLP-1 drugs to help preserve β-cell function, as has been seen with semaglutide in a small group of new-onset diabetes, needs further exploration. Stem cell–derived pancreatic islet cells have successfully eliminated the need to inject insulin in a clinical trial, but the participants had to take immunosuppressant drugs to prevent rejection. Transplantation of stem cell–derived β-cells that are genome edited to avoid rejection would be a more attractive route and is being pursued for a potential cure. In sum, there is no question that the multiprong strategy for both prevention and “building a bridge to a cure for type 1 diabetes” is underway.