Abstract

Calcineurin inhibitors (CNIs) constitute the backbone of modern acute graft-versus-host disease (aGVHD) prophylaxis regimens but have limited efficacy in the prevention and treatment of chronic GVHD (cGVHD). We investigated the effect of CNIs on immune tolerance after stem cell transplantation with discovery-based single-cell gene expression and T cell receptor (TCR) assays of clonal immunity in tandem with traditional protein-based approaches and preclinical modeling. While cyclosporin and tacrolimus suppressed the clonal expansion of CD8+ T cells during GVHD, alloreactive CD4+ T cell clusters were preferentially expanded. Moreover, CNIs mediated reversible dose-dependent suppression of T cell activation and all stages of donor T cell exhaustion. Critically, CNIs promoted the expansion of both polyclonal and TCR-specific alloreactive central memory CD4+ T cells (TCM) with high self-renewal capacity that mediated cGVHD following drug withdrawal. In contrast to posttransplant cyclophosp...

Authors	Wang, Y; Ullah, MA; Waltner, OG; Bhise, SS; Ensbey, KS; Schmidt, CR; Legg, SR; Sekiguchi, T; Nelson, EL; Kuns, RD; Nemychenkov, NS; Atilla, E; Yeh, AC; Takahashi, S; Boiko, JR; Varelias, A; Blazar, BR; Koyama, M; Minnie, SA; Clouston, AD; Furlan, SN; Zhang, P; Hill, GR
Journal	THE JOURNAL OF CLINICAL INVESTIGATION
Pages
Volume	134
Date	3/07/2024
Grant ID	KL2 TR002317 | NCATS NIH HHS [TR] (United States); P01 CA018029 | NCI NIH HHS [CA] (United States); R01 HL148164 | NHLBI NIH HHS [HL] (United States)
Funding Body
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1172/JCI170125