Federal Grant Award Summary

The National Institute of Diabetes and Digestive and Kidney Diseases awarded The Leland Stanford Junior University a $5.58 million Project Grant (CFDA 93.847: Diabetes, Digestive, and Kidney Diseases Extramural Research) effective July 10, 2026, through June 30, 2029, to conduct research analyzing immune tolerance mechanisms in Type 1 Diabetes (T1D) patients receiving sequential B cell depletion and T cell costimulatory blockade therapy. The research leverages the TN-25 TrialNet clinical trial comparing sequential rituximab (RTX) and abatacept (ABA) combination therapy to RTX with placebo, providing a unique opportunity to characterize how these treatments may synergistically restore immune tolerance by disrupting pathogenic co-stimulation signals between antigen-presenting B cells and autoreactive T cells.

The project delivers two primary research objectives: (1) determining whether sequential RTX and ABA therapy abrogates B cell-to-T cell co-stimulation signals through tetramer binding assays, single-cell RNA sequencing, and T-cell receptor sequencing to evaluate islet-reactive T cells and novel KIR+CD8+ regulatory T cell populations; and (2) analyzing whether ABA-mediated limitation of T cell help produces more profound B cell tolerance through clonal deletion, including evaluation of recombinant antibodies cloned from autoreactive B cells at various developmental stages. The research is conducted at Stanford's Palo Alto, California facility and contributes to the broader federal objective of improving understanding of disease mechanisms underlying diabetes to support improved prevention, diagnosis, and treatment strategies.