Over the last 30 years of NAPRTCS registry data, we have been fortunate to witness the dramatic decline in the rates of early first AR (within 12 months post-transplant) in each more recent cohort. 1 These early AR improvements, coupled with nearly parallel cumulative incidence slopes of late first AR (beyond 12 months post-transplant), led to significant drops in the cumulative 48-month first AR rate. The reasons for these reductions are multi-factorial: more potent immunosuppression, improvements in surgical techniques, better donor selection, and immunological matching.However, the data from the most recent cohorts revealed a disturbing trend. Chua et al showed a higher cumulative incidence of late first AR (defined as first AR after 12 months post-transplant) that made the 48-month cumulative first AR rate higher in the 2012-2017 living donor cohort than the last two living donor cohorts of
Aim We assessed the safety of ustekinumab (a monoclonal antibody used in psoriasis to target the IL-12 and IL-23 pathways) in a small cohort of recent-onset (<100 days of diagnosis) adults with type 1 diabetes (T1D) by conducting a pilot open-label dose-finding and mechanistic study (NCT02117765) at the University of British Columbia. Methods We sequentially enrolled 20 participants into four subcutaneous dosing cohorts: i) 45mg loading-weeks 0/4/16, ii) 45mg maintenance-weeks 0/4/16/28/40, iii) 90mg loading-weeks 0/4/16 and iv) 90mg maintenance-weeks 0/4/16/28/40. The primary endpoint was safety as assessed by an independent data and safety monitoring board (DSMB) but we also measured mixed meal tolerance test C-peptide, insulin use/kg, and HbA1c. Immunophenotyping was performed to assess immune cell subsets and islet antigen-specific T cell responses. Results Although several adverse events were reported, only two (bacterial vaginosis and hallucinations) were thought to be possibly related to drug administration by the study investigators. At 1 year, the 90mg maintenance dosing cohort had the smallest mean decline in C-peptide AUC (0.1pmol/mL). Immunophenotyping showed that ustekinumab reduced the percentage of circulating Th17, Th1 and Th17.1 cells and proinsulin-specific T cells that secreted IFN-γ and IL-17A. Conclusion Ustekinumab was deemed safe to progress to efficacy studies by the DSMB at doses used to treat psoriasis in adults with T1D. A 90mg maintenance dosing schedule reduced proinsulin-specific IFN-γ and IL-17A-producing T cells. Further studies are warranted to determine if ustekinumab can prevent C-peptide AUC decline and induce a clinical response.
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