Alleviation of Acute and Chronic Graft-Versus-Host Disease in a Murine Model Is Associated with Glucocerebroside-Enhanced Natural Killer T Lymphocyte Plasticity

Ilan, Yaron; Ohana, Meir; Pappo, Orit; Margalit, Maya; Lalazar, Gadi; Engelhardt, Dean; Rabbani, Elazar; Nagler, Arnon

doi:10.1097/01.tp.0000252783.66886.f3

Cited by 38 publications

(28 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…iNKTs express a semiinvariant T-cell receptor a chain (Va24Ja18 in human) that recognizes lipids presented by the nonpolymorphic class I-like molecule CD1d. 18 Thus far, the beneficial immunologic effects of iNKTs in the setting of allo-SCT were associated to a decreased incidence of acute GVHD both in experimental models 19,20 and in the clinical setting. Therefore, Chaidos et al reported that PBSC grafts with higher iNKT doses were associated with a significant decrease of aGVHD.…”

Section: Discussionmentioning

confidence: 99%

Larger number of invariant natural killer T cells in PBSC allografts correlates with improved GVHD-free and progression-free survival

Malard

Labopin

Chevallier

et al. 2016

Blood

View full text Add to dashboard Cite

Key Points• Higher dose of invariant NKT cells within PBSC allograft is associated with an improved GPFS.We studied the impact of a set of immune cells contained within granulocyte colonystimulating factor-mobilized peripheral blood stem cell grafts (naïve and memory T-cell subsets, B cells, regulatory T cells, invariant natural killer T cells [iNKTs], NK cells, and dendritic cell subsets) in patients (n 5 80) undergoing allogeneic stem cell transplantation (SCT), using the composite end point of graft-versus-host disease (GVHD)-free and progression-free survival (GPFS) as the primary end point. We observed that GPFS incidences in patients receiving iNKT doses above and below the median were 49% vs 22%, respectively (P 5 .007). In multivariate analysis, the iNKT dose was the only parameter with a significant impact on GPFS (hazard ratio 5 0.48; 95% confidence interval, 0.27-0.85; P 5 .01). The incidences of severe grade III to IV acute GVHD and National Institutes of Health grade 2 to 3 chronic GVHD (12% and 16%, respectively) were low and associated with the use of antithymocyte globulin in 91% of patients. No difference in GVHD incidence was reported according to the iNKT dose. In conclusion, a higher dose of iNKTs within the graft is associated with an improved GPFS. These data may pave the way for prospective and active interventions aiming to manipulate the graft content to improve allo

show abstract

Section: Discussionmentioning

confidence: 99%

Larger number of invariant natural killer T cells in PBSC allografts correlates with improved GVHD-free and progression-free survival

Malard

Labopin

Chevallier

et al. 2016

Blood

View full text Add to dashboard Cite

show abstract

“…GC has been shown to function as a 'finetuning factor' in several mouse models of immune-mediated disorders [10,11]. The administration of GC protects against chronic graft-versus-host disease in mice due to an increase in the intrahepatic CD4/CD8 T cell ratio and decreased CD8 + T cell trapping [12]. In addition, in a colitis animal model, GC treatment alters the expression of the ganglioside GM1, a key marker of cell membrane lipid rafts on CD4 + and CD8 + T cells, and alleviates immune-mediated colitis [13].…”

Section: Introductionmentioning

confidence: 99%

β-Glucosylceramide ameliorates liver inflammation in murine autoimmune cholangitis

Zhang

Moritoki

Tsuneyama

et al. 2009

Clinical and Experimental Immunology

View full text Add to dashboard Cite

SummaryWe have demonstrated spontaneous development of autoimmune cholangitis, similar to human primary biliary cirrhosis, in mice expressing a dominant negative form of the transforming growth factor-b receptor (dnTGFbRII) restricted to T cells. The autoimmune cholangitis appears to be mediated by autoreactive CD8 + T lymphocytes that home to the portal tracts and biliary system. Because the liver pathology is primarily secondary to CD8+ T cells, we have determined herein whether administration of b-glucosylceramide (GC), a naturally occurring plant glycosphingolipid, alters the natural history of disease in this model. We chose GC because previous work has demonstrated its ability to alter CD8 + T cell responses and to down-regulate tissue inflammation. Accordingly, dnTGF-bRII mice were treated with either GC or control for a period of 18 weeks beginning at 6 weeks of age. Importantly, in mice that received GC, there was a significant decrease in the frequency and absolute number of autoreactive liverinfiltrating CD8 + T cells, accompanied by a significant decrease in activated CD44 high CD8 + T cell populations. Further, there was a significant reduction in portal inflammation in GC-treated mice. Interestingly, there were no changes in anti-mitochondrial antibodies, CD4 + T cells, CD19 + B cells or natural killer (NK) T cell populations, indicating further that the beneficial effects of GC on liver inflammation were targeted specifically to liverinfiltrating CD8 + T cells. These data suggest that further work on GC in models of CD8 + T-mediated inflammation are needed and point to a new therapeutic venue for potentially treating and/or modulating autoimmune disease.

show abstract

“…Solid malignant disorders 49,172 171 Ob/Ob mice 76 Cohen rats 77 Sand rats 78 Autoimmune disorders Acute and chronic graft versus host disease 73 …”

Section: Malignancymentioning

confidence: 99%

“…These data suggest that GC can ameliorate GVHD in both Th1-and Th2-mediated murine models and that it is able to differentially affect the immune system. 73 …”

Section: Graft-versus-host Diseasementioning

confidence: 99%

“…Alternatively, stimuli that were originally identical may reach NKT cells through different pathways through presentation by different APCs. 73,83 Furthermore, NKT cells are a heterogeneous population of cells that differ from one another in their CD1d reactivity and CD expression, which may contribute to their plasticity. Apart from the inherent heterogeneity between different NKT cell populations, changes in the properties of lipid rafts may affect raft-bound receptors, such as CD1d, and may add to the variety of responses.…”

Section: Gc As a Metabolic Intermediate In Insulin Resistance Pathwaysmentioning

confidence: 99%

See 1 more Smart Citation

Glucocerebroside: an evolutionary advantage for patients with Gaucher disease and a new immunomodulatory agent

2009

Self Cite

View full text Add to dashboard Cite

Gaucher disease (GD) is caused by the reduced activity of a lysosomal enzyme, glucocerebrosidase, leading to the accumulation of glucocerebroside (GC). The relatively high prevalence of this disease within an ethnic group is believed to reflect a selective advantage. Treatment with enzyme replacement therapy (ERT) is safe and effective in ameliorating the primary symptoms of the disease, yet there have been reports that some patients on ERT have developed type 2 diabetes or metabolic syndrome, malignancies and central nervous system disorders. A series of animal studies suggest that these complications may be related to the reduction of GC levels by the enzyme administered. GC has been shown to have an immunomodulatory effect through the promotion of dendritic cells, natural killer T cells, and regulatory T cells. The break down of GC to ceramide can underline part of these findings. Clinical trials suggested a beneficial effect of GC in type 2 diabetes or nonalcoholic steatohepatitis. This review of the data from animal models and humans proposes that the increased level of GC may provide an evolutionary advantage for patients with GD. Indirectly, these data support treating symptomatic patients with mild/moderate GD with lowdose ERT and re-evaluating the use of ERT in asymptomatic patients.

show abstract

Alleviation of Acute and Chronic Graft-Versus-Host Disease in a Murine Model Is Associated with Glucocerebroside-Enhanced Natural Killer T Lymphocyte Plasticity

Abstract: GC ameliorates GVHD in both Th1- and Th2-mediated murine models, suggesting it is able to differentially affect the immune system. GC may alleviate immunologically incongruous disorders, and may be associated with "fine tuning" of immune responses.

Cited by 38 publications

References 40 publications

Larger number of invariant natural killer T cells in PBSC allografts correlates with improved GVHD-free and progression-free survival

Larger number of invariant natural killer T cells in PBSC allografts correlates with improved GVHD-free and progression-free survival

β-Glucosylceramide ameliorates liver inflammation in murine autoimmune cholangitis

Glucocerebroside: an evolutionary advantage for patients with Gaucher disease and a new immunomodulatory agent

Contact Info

Product

Resources

About