Diabetes and other autoimmune endocrine diseases
We previously reported that co-stimulation blockade by Abatacept, over a two-year period, significantly reduces the decline of beta-cell function and the frequency of peripheral blood CD4+ central memory (CD45RO+/CD62L+) T (TCM) cells in individuals with recent onset type 1 diabetes (T1D). In the placebo group of the clinical trial, we found a significant association between the increase in CD4+ TCM cells at a preceding visit and the decline of beta-cell function at a subsequent visit.
To extend and refine these findings, we used cryopreserved PBMCs from the original TrialNet (TN009) study and polychromatic flow and mass cytometry to characterise CD4+ and CD8+ naïve and memory T-cell subpopulations at greater resolution.
In the placebo group we successfully reproduced our original finding of a significant association between alterations in TCM and changes in beta-cell function, and extended this to several other T-cell subpopulations. Furthermore, we found that Abatacept treatment significantly alters the frequencies of a majority of CD4+, CD4+ regulatory and CD8+ T-cell subpopulations; in general, populations with antigen-inexperience increase, and those with antigen-experience decrease. Importantly, Abatacept also uncouples the relationship between changes in T-cell subpopulations and beta-cell function: in every case, rendering it no longer statistically significant.
These data are indicative of an immunological marker (monitoring of specific naïve/memory T-cell subpopulations) for predicting change in beta-cell function during the natural progression of T1D. Abatacept blunts this relationship, pointing to a novel mechanism of action for this successful immunotherapy that may guide other disease-modifying approaches for T1D.