Tolerizing PS-liposomes
Tolerogenics ToleroPrime technology
Tolerogenics ToleroPrime technology
Dendritic cells (DCs) are widely recognized as the most professional antigen-presenting cells (APCs). Moreover, they are indispensable in the regulation of the delicate balance between immunity and tolerance. By interacting with other cells of the immune system through cell-cell contact or the production of cytokines, DCs induce an appropriate answer to a specific antigen.
Immature DCs, characterized by low expression of MHC II and costimmulatory molecules induce tolerance.
Exposure of DCs to antigen in the presence of immune stimulatory molecules such as LPS leads to maturation of DCs and subsequent immune responses.
However, in the absence of immune stimmulatory molecules DCs develop a tolerogenic phenoype upon antigen exposure (tolDCs). Recent investigations have shown that antigen-specific tolerance can be induced in vivo via vaccination with antigen-pulsed in vitro generated DCs. The development of tolDCs can be enforced by exposure to NF-κB inhibitors, such as vitamin D3 derivates or tolerance-promoting cytokines. Such tolDCs are phenotypically immature DCs characterized by a low expression of MHC-II as well as co-stimulatory molecules such as CD40, CD80, CD86, and a reduced production of pro-inflammatory IL-12 and increased secretion of anti-inflammatory IL-10 (for reviews, see Thomas 2013, Arthritis Res Ther 15:204-14; Gross and Wiendl 2013, Curr Opin Rheumatol 25:268-74; Van Brussel et al. 2014, Autoimmun Rev 13:138-50; Mackern-Oberti et al. 2015, Autoimmun Rev 14:127-39).
Dependent on the modulation of DCs by NF-κB inhibitors or tolerance-promoting cytokines, different subsets of Tregs are generated. However, all Treg subsets are tolerance-promoting. In principle, tolerizing DC immunotherapy poses the same serious limitations as therapeutic applications of adoptive transfer of antigen- or allergen-specific Tregs. Most important is the identification of a maturation-resistant subtype of DCs. Using current methods for the in vitro generation of tolDCs, phenotypically immature DCs are produced. However, that does not guarantee stability of the tolerogenic properties, especially after vaccination. Given the risk of in vivo reactivation, this is particularly of importance in any pathological state with an underlying inflammatory microenvironment.
The potential problems are
In an attempt to avoid many of the problems associated with therapeutic in vitro modifications of Tregs or DCs, liposomes were formulated to generate tolDCs under in vivo conditions. Phosphatidylcholine (PC) liposomes were loaded with antigen and a lipophilic NF-κB inhibitor and injected into mice with antigen-induced inflammatory arthritis. As demonstrated in this study, the PC-liposomes targeted antigen-presenting cells and inducing antigen-specific Tregs. Thereby, effector T-cell responses and the clinical signs of full-blown antigen-induced arthritis could be suppressed (Capini et al. 2009, J. Immunol. 182: 3556-3565).
Principle:
Technique:
Advantage:
Therapeutic efficacy-enhancing mechanisms:
Subcutaneous injection of small amounts of tolerizing liposomes can avoid the risk of global tolerance via bystander suppression in various organs of the reticuloendothelial system. However, the uptake of tolerizing liposomes by phagocytes in subcutaneous tissues is not very effective. Therefore, this approach requires several repeated injections, a procedure that is not acceptable for physicians and patients.
Tolerogenic is solving these problems by utilizing hydrogel-embedded phosphatidylserine-presenting liposomes (PS-liposomes) loaded with allergen and the NF-κB inhibitors dexamethasone phosphate and/or vitamin D3 derivatives. Tolerizing PS-liposomes target antigen presenting cells since PS-liposomes mimic apoptotic cells and are phagocytosed mainly by macrophages and dendritic cells. As a result, the liposomal NF-κB inhibitors effectively generate tolerogenic DCs and, thereby, effectively induce tolerance promoting Tregs and minimizing side reactions. Furthermore, phagocytosis of PS-liposome-encapsulated allergen-derived peptides by DCs and macrophages guarantees effective presentation of the allergens and effective induction of tolerogenic Tregs.
Hydrogel-embedded tolerizing PS-liposomes mimic the anti-inflammatory effect of apoptotic cells and target directly APCs including dendritic cells (DCs) and macrophages. Phagocytosis of tolerizing PS-liposomes guarantees also most efficient inhibition of the pro-inflammatory transcription factor NF-κB in DCs by liposome-encapsulated NF-κB inhibitors, leading to the development of tolerogenic DCs (tolDCs) which are capable of inducing tolerance via tolerogenic regulatory T cells (Tregs).
The hydrogel technology serves as depot and provides for a sustained release of tolerizing PS-liposomes for a period of at least 3 days. PLGA-PEG-PLGA hydrogels are biodegradable and provide also the important advantage in that neither Th1-type nor Th2-type immune responses are triggered.
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