Donor Treg expansion by liposomal α‐galactosylceramide modulates Tfh cells and prevents sclerodermatous chronic graft‐versus‐host disease

Abstract

Background and Aim Chronic graft‐versus‐host disease (cGVHD) is a major cause of nonrelapse morbidity and mortality following hematopoietic stem cell transplantation (HSCT). α‐Galactosylceramide (α‐GC) is a synthetic glycolipid that is recognized by the invariant T‐cell receptor of invariant natural killer T (iNKT) cells in a CD1d‐restricted manner. Stimulation of iNKT cells by α‐GC leads to the production of not only immune‐stimulatory cytokines but also immune‐regulatory cytokines followed by regulatory T‐cell (Treg) expansion in vivo. Methods We investigated the effect of iNKT stimulation by liposomal α‐GC just after transplant on the subsequent immune reconstitution and the development of sclerodermatous cGVHD. Results Our study showed that multiple administrations of liposomal α‐GC modulated both host‐ and donor‐derived iNKT cell homeostasis and induced an early expansion of donor Tregs. We also demonstrated that the immune modulation of the acute phase was followed by the decreased levels of CXCL13 in plasma and follicular helper T cells in lymph nodes, which inhibited germinal center formation, resulting in the efficient prevention of sclerodermatous cGVHD. Conclusions These data demonstrated an important coordination of T‐ and B‐cell immunity in the pathogenesis of cGVHD and may provide a novel clinical strategy for the induction of immune tolerance after allogeneic HSCT.

Harnessing Treg Homeostasis to Optimize Posttransplant Immunity: Current Concepts and Future Perspectives

“…In addition, the adoptive transfer of donor iNKT cells ameliorated GVHD by expanding donor Tregs, in turn preserving the GVT effect (115). In addition to the acute GVHD model, our murine study using chronic GVHD models showed that a-GC treatment could ameliorate chronic GVHD symptoms through the early expansion of donor-derived Tregs followed by the suppression of follicular helper T cells and germinal center B cells (116). Based on the data of preclinical models, a phase 2 clinical study evaluated the efficacy of RGI-2001, a novel liposomal formulation of a synthetic derivative of a-GC in patients who underwent HSCT.…”

Impaired thymic iNKT cell differentiation at early precursor stage in murine haploidentical bone marrow transplantation with GvHD

“…The important roles of iNKT cells are well appreciated in allogeneic hematopoietic stem cell transplantation (allo-HSCT) and combined bone marrow (BM) and organ transplantation. iNKT cells from recipients, donors, or third-party can reduce the risk of graftversus-host disease (GvHD) while retaining the graft-versusleukemia/lymphoma (GvL) effect (2)(3)(4)(5)(6)(7). Human CD4 -NKT1 cells, CD4 + IL-4-producing iNKT cells, or murine CD4 + NKT2 cells are effective in this respect (8)(9)(10).…”