Antigen-specific depletion of gluten-reactive T cells for the potential treatment of celiac disease 2257650

Abstract

Abstract Introduction Celiac disease (CeD) is a gluten-triggered chronic inflammatory disease of the small intestine that affects roughly 1.4% of the global population. As a strict gluten-free diet is the only treatment option, the development of novel treatment strategies is necessary to alleviate physical, psychological, and financial burdens associated with CeD. Roughly 95% of CeD patients express the MHCII variant HLA-DQ2.5. In susceptible individuals, pathogenesis is mediated by gluten-specific CD4+ T cell populations, which are activated upon presentation of gluten peptides by HLA-DQ molecules. This homogeneity presents the opportunity to design HLA-DQ2.5-based therapies to target pathogenic T cell populations for the elimination of celiac disease. Methods As a potential treatment modality, we have engineered human T cells expressing novel ‘chimeric, antigen-presenting’ (CAP) constructs consisting of 1) a gluten peptide-linked HLA-DQ2.5 extracellular domain 2) intracellular CD28/CD3z signaling domains routinely utilized in CAR T cell applications, and 3) an engineered “di-sulfide trap” to stabilize peptide:HLA interactions and CAP surface expression. We hypothesize that upon engagement with gluten-reactive T cells, CAP T cells will specifically eliminate gluten-reactive targets, but leave the remainder of the T cell repertoire untouched. To test this hypothesis, we cultured CAP T cells (effectors) with target cells engineered to express patient-derived gluten-reactive T cell receptors. Results Strikingly, CAP T cells eliminated >98% of target cells within 48h. This effect was specific, as non-specific targets cultured with CAP T cells remained untouched. Further, CAP T cells were efficient killers: even at an 8:1 target:effector ratio, there was almost complete ablation of targets within 72h. Conclusion This work provides a proof-of-concept for CAP T cells, and demonstrates their potential as a novel, T cell-based immunotherapeutic strategy for the treatment of Celiac disease. Funding Source The Colton Consortium for Autoimmunity at the University of Pennsylvania Topic Categories Therapeutic Approaches to Autoimmunity (THER)