期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 13, 期 583, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.abc8980
关键词
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资金
- National Institute of Allergy and Infectious Diseases (NIAID) [UM1AI109565]
- NIH through the National Institute of Diabetes and Digestive and Kidney Diseases
- NIAID
- Eunice Kennedy Shriver National Institute of Child Health and Human Development [U01 DK061034, U01 DK085466, U01 DK085476, 13, U01 DK107014, UC4 DK11700901, U01 DK 106693]
- JDRF [2019-833-S-B]
A single 14-day course of teplizumab treatment in high-risk individuals showed lasting effects on delaying type 1 diabetes diagnosis and improving beta cell function. Changes in CD8(+) T cell subsets indicated that partially exhausted effector cells were associated with clinical response to immune therapy. This trial demonstrated improvements in metabolic responses and diabetes delay with immune therapy.
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 placebotreated 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 IFN gamma and TNF alpha. 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.
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