Abstract
The specific eradication of pathogenic T cells for the treatment of allograft rejections and autoimmune disorders without impairment of overall immune function is a fundamental goal. Here, cell-sized poly(lactic-co-glycolic acid) microparticles (PLGA MPs) were prepared as a scaffold to co-display the peptide/major histocompatibility complex (pMHC, target antigen) and anti-Fas monoclonal antibody (apoptosis-inducing molecule) for the generation of biodegradable killer MPs. Ovalbumin (OVA) antigen-targeted killer MPs significantly depleted OVA-specific CD8+ T cells in an antigen-specific manner, both in vitro and in OT-1 mice. After intravenous administration, the killer MPs predominantly accumulated in the liver, lungs, and gut of OT-1 mice with a retention time of up to 48 hours. The killing effects exerted by killer MPs persisted for 4 days after two injections. Moreover, the H-2Kb alloantigen-targeted killer MPs were able to eliminate low-frequency alloreactive T cells and prolong alloskin graft survival for 41.5 days in bm1 mice. Our data indicate that PLGA-based killer MPs are capable of specifically depleting pathogenic T cells, which highlights their therapeutic potential for treating allograft rejection and autoimmune disorders.
Highlights
Immunosuppressive therapies for allograft rejection and autoimmune diseases are currently being pursued in order to inactivate the entire T cell repertoire, which could lead to overall immune impairment [1,2,3]
These results demonstrated the strong ability of MPs to couple protein and monoclonal antibody (mAb)
The H-2Kb alloantigen-targeted killer MPs were able to eliminate lowfrequency alloreactive T cells in bm1 mice and markedly prolong alloskin graft survival. These results demonstrate www.impactjournals.com/oncotarget the therapeutic potential of killer Polylactic-co-glycolic acid (PLGA) MPs for allograft rejections and autoimmune disorders
Summary
Immunosuppressive therapies for allograft rejection and autoimmune diseases are currently being pursued in order to inactivate the entire T cell repertoire, which could lead to overall immune impairment [1,2,3]. One proposed treatment is based on the use of FasLtransfected dendritic cells (DCs) or monocytes to induce peripheral antigen-specific apoptosis of T cells, which are referred to as killer antigen-presenting cells (KAPCs) [68]. Despite promising results in the treatment of chronic infections [9, 10], allograft rejection [11], or autoimmune diseases [12], the cell-based KAPCs still suffer from several principal drawbacks: they are time-consuming and cost-intensive when generated on a large scale, and there is batch-to-batch variability in FasL expression. Cellular KAPCs are sensitive to both their in vivo and in vitro environments due to the activity of cytotoxic T cells, which can lead to KAPC depletion or unwanted changes in cell-cell signaling [14, 15]
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