Alpha-galactosylceramide-driven immunotherapy for allergy

Abstract

We report here that the delivery of both alpha-galactosylceramide (alphaGalCer), a representative ligand for invariant natural killer T (iNKT) cells, and an antigenic polypeptide to marginal zone B cells induces the differentiation of regulatory cells in vivo, and suppresses the secondary antibody responses in mice. Splenic CD21+ CD23- B cells of mice treated with alphaGalCer-liposomes produce IL-10 when co-cultured with iNKT cells, whereas the cells treated with aqueous alphaGalCer fail to do so. Adoptive transfer of the B cells into syngenic mice leads to the expansion of splenic CD11c(low) CD45RB(high) cells, which convert naive CD4+ T cells from RAG2-deficient DO11.10 mice to CD4+ CD25(high) Foxp3+ T cells in the presence of OVA323-339 peptide. Administration of alphaGalCer-OVA-liposomes into OVA-primed mice causes the development of CD4+ CD25(high) Foxp3+ T cells that produce both IL-10 and IFN-gamma, and induced the antigen-specific suppression of the secondary antibody responses when boosted with OVA alone. These results indicate that antigen-containing alphaGalCer-liposomes can facilitate the development of tolerogenic antigen-presenting cells and inducible regulatory T cells that are involved in the suppression of immune responses to antigens.

Clonal Deletion Established via Invariant NKT Cell Activation and Costimulatory Blockade Requires In Vivo Expansion of Regulatory T Cells

“…It was also considered that thymic DCs generate Tregs in thymus (46). We previously reported augmentation of pDCs, which can develop Tregs in the periphery (6,47,48), after lipo-aGC administration (8,10). We confirmed that pDCs augmented by lipo-aGC stimulation…”

“…conventional T cells in vitro (8). Hence, we presumed that the early Treg expansion observed in our model is mainly induced in the periphery.…”

Invariant natural killer T cells in hematopoietic stem cell transplantation: killer choice for natural suppression

“…92 Studies have shown that aqueous αGC when presented by DCs activates iNKTs, whereas liposomal αGC that is usually presented by B cells triggers IL-10 production by iNKT and B cells, resulting in expansion of tolerogenic DCs and generation of Tregs. 93,94 In line with these observations, administration of the liposomal formulation of αGC (RGI-2001) prevents GvHD in mice (via expansion of nTregs) but retains the GvL effect. 95 The safety and efficacy of this pharmacological approach is currently under investigation in HSCT patients with hematologic malignancies in a multi-center phase 1/2 clinical trial (NCT013729209).…”

Selective quantitation of the incorporation of the immunomodulator α-galactosylceramide in liposomes using LC–MS/MS

“…The bilayer can accommodate hydrophobic portions of molecules such as α-GalCer, which subsequently become surrounded by the fatty tails of the liposome phospholipids, while allowing the hydrophilic portions of α-GalCer to interact with the aqueous continuous phase and the phospholipid head groups [7]. This results in increased aqueous solubility of α-GalCer as the liposomes act as a solubilising vehicle and in addition may modify activity through such mechanisms as increased uptake by certain cells [1]. Other components such as cholesterol can also be incorporated into the bilayer to promote aspects such as stability [8].…”

“…Introduction α-Galactosylceramide (α-GalCer) is a synthetic glycosphingolipid that exhibits potent immunomodulatory effects through a well-defined mechanism of action. This mechanism involves presentation of α-GalCer on CD1d molecules of antigen presenting cells to invariant natural killer T (iNKT) cells, which causes a rapid release of immunomodulatory cytokines [1]. The therapeutic effects of iNKT cell activation have been demonstrated as important in various pathological conditions such as atopy [1], cancer [2], infections [3] and autoimmune diseases [4].…”