Abstract
Background and AimChronic 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.MethodsWe investigated the effect of iNKT stimulation by liposomal α‐GC just after transplant on the subsequent immune reconstitution and the development of sclerodermatous cGVHD.ResultsOur 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.ConclusionsThese 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.
Highlights
Chronic graft‐versus‐host disease is a major cause of nonrelapse morbidity and mortality following hematopoietic stem cell transplantation (HSCT),[1] while effective prophylaxis and therapies for cGVHD are still lacking.[2]
It has been reported that adoptive transfer of donor‐type regulatory T cell (Treg) could prevent the onset of acute GVHD in murine bone marrow transplantation (BMT) models and human clinical trials,[4] and the administration of low‐dose interleukin‐2 (IL‐2) to patients with active cGVHD increased the levels of peripheral Tregs and ameliorated the clinical symptoms.[5,6]
To clarify the mechanism of the preventive effect of lipo α‐GC against cGVHD in an early phase after BMT, we examined the dynamics of invariant natural killer T (iNKT) cells and Tregs by flow cytometric analysis of spleen cells on Day 7 (Figure 3)
Summary
Chronic graft‐versus‐host disease (cGVHD) is a major cause of nonrelapse morbidity and mortality following hematopoietic stem cell transplantation (HSCT),[1] while effective prophylaxis and therapies for cGVHD are still lacking.[2] CD4+CD25+Foxp3+ regulatory T cells (Tregs) play an indispensable role in the maintenance of tolerance after allogeneic HSCT.[3] It has been reported that adoptive transfer of donor‐type Tregs could prevent the onset of acute GVHD in murine bone marrow transplantation (BMT) models and human clinical trials,[4] and the administration of low‐dose interleukin‐2 (IL‐2) to patients with active cGVHD increased the levels of peripheral Tregs and ameliorated the clinical symptoms.[5,6] These results suggest that in vivo modulation of Tregs is a promising strategy to control aggressive GVHD after allogeneic HSCT. Tregs and T follicular regulatory cells were shown to suppress Tfh‐cell activation and germinal center formation, which could control humoral immunity in mice after vaccination.[23] Adoptive transfer of donor Tregs allowed their infiltration into the germinal center and modulated B‐cell differentiation, resulting in amelioration of murine cGVHD in a CXCR5‐dependent manner.[24]. We investigated the clinical effects and immune mechanisms of lipo α‐GC in a murine sclerodermatous cGVHD model
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