Search

Prolonged prevention of autoimmune diabetes: Teplizumab was previously shown in a clinical trial to delay onset of type 1 diabetes (T1D) in high-risk relatives of individuals with T1D. Now, Sims et al. extend the follow-up analysis of this trial by 12 months, finding that efficacy of the initial 2-week treatment course persisted, with an extended time to T1D diagnosis in the teplizumab-treated group. Clinical benefits associated with reversed C-peptide decline improved beta cell function and partial exhaustion in CD8+ T cells in the treated patients. HbA1c did not differ between placebo and treatment groups. This follow-up study further supports the use of anti-CD3 treatment for the prevention of T1D. We analyzed the effects of a single 14-day course of teplizumab treatment on metabolic function and immune cells among participants in a previously reported randomized controlled trial of nondiabetic relatives at high risk for type 1 diabetes (T1D). In an extended follow-up (923-day median) of a previous report of teplizumab treatment, we found that the median times to diagnosis were 59.6 and 27.1 months for teplizumab- and placebo-treated participants, respectively (HR = 0.457, P = 0.01). Fifty percent of teplizumab-treated but only 22% of the placebo-treated remained diabetes-free. Glucose tolerance, C-peptide area under the curve (AUC), and insulin secretory rates were calculated, and relationships to T cell subsets and function were analyzed. Teplizumab treatment improved beta cell function, reflected by average on-study C-peptide AUC (1.94 versus 1.72 pmol/ml; P = 0.006). Drug treatment reversed a decline in insulin secretion before enrollment, followed by stabilization of the declining C-peptide AUC seen with placebo treatment. Proinsulin:C-peptide ratios after drug treatment were similar between the treatment groups. The changes in C-peptide with teplizumab treatment were associated with increases in partially exhausted memory KLRG1+TIGIT+CD8+ T cells (r = 0.44, P = 0.014) that showed reduced secretion of IFNγ and TNFα. A single course of teplizumab had lasting effects on delay of T1D diagnosis and improved beta cell function in high-risk individuals. Changes in CD8+ T cell subsets indicated that partially exhausted effector cells were associated with clinical response. Thus, this trial showed improvement in metabolic responses and delay of diabetes with immune therapy. [ABSTRACT FROM AUTHOR]