Abstract
Selectively depleting the pathogenic T cells is a fundamental strategy for the treatment of allograft rejection and autoimmune disease since it retains the overall immune function of host. The concept of killer artificial antigen-presenting cells (KaAPCs) has been developed by co-coupling peptide–major histocompatibility complex (pMHC) multimer and anti-Fas monoclonal antibody (mAb) onto the polymeric microparticles (MPs) to induce the apoptosis of antigen-specific T cells. But little information is available about its in vivo therapeutic potential and mechanism. In this study, polyethylenimine (PEI)-coated poly lactic-co-glycolic acid microparticle (PLGA MP) was fabricated as a cell-sized scaffold to covalently co-couple H-2Kb-Ig dimer and anti-Fas mAb for the generation of alloantigen-presenting and apoptosis-inducing MPs. Intravenous infusions of the biodegradable KaAPCs prolonged the alloskin graft survival for 43 days in a single MHC-mismatched murine model, depleted the most of H-2Kb-alloreactive CD8+ T cells in peripheral blood, spleen, and alloskin graft in an antigen-specific manner and anti-Fas-dependent fashion. The cell-sized KaAPCs circulated throughout vasculature into liver, kidney, spleen, lymph nodes, lung, and heart, but few ones into local allograft at early stage, with a retention time up to 36 h in vivo. They colocalized with CD8+ T cells in secondary lymphoid organs while few ones contacted with CD4+ T cells, B cells, macrophage, and dendritic cells, or internalized by phagocytes. Importantly, the KaAPC treatment did not significantly impair the native T cell repertoire or non-pathogenic immune cells, did not obviously suppress the overall immune function of host, and did not lead to visible organ toxicity. Our results strongly document the high potential of PLGA MP-based KaAPCs as a novel antigen-specific immunotherapy for allograft rejection and autoimmune disorder. The in vivo mechanism of alloinhibition, tissue distribution, and biosafety were also initially characterized, which will facilitate its translational studies from bench to bedside.
Highlights
Depleting antigen-specific T cells is one of the fundamental strategies to treat allograft rejection and autoimmune disorders because it prevents intact immune impairment, the major drawback of current immunosuppressive agents [1,2,3]
The promising results in the treatment of chronic infections [15, 16], allograft rejection [8, 10, 17], or autoimmune diseases [9] in murine or human models, cell-based FasLexpressing Killer antigen-presenting cells (KAPCs) still suffer from several significant problems related to their cellular nature: the risk of infection, tumorigenicity or immunogenicity raised by live cells, the time consuming, and cost-intensive generation when scaled, large batch-to-batch variability of Fas ligand (FasL) expression [18], mature killer dendritic cells (DCs) may highly express B7.1 or B7.2 and weakly express FasL [19], thereby eliciting vigorous T cell responses toward other antigens and massive neutrophil infiltration [20], and the sensitivity to 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 [21]
PEI-coated Poly lactic-co-glycolic acid (PLGA) MPs were employed as cell-sized scaffold to co-present alloantigen and apoptosis-inducing molecule to alloreactive T cells for the treatment of alloskin rejection
Summary
Depleting antigen-specific T cells is one of the fundamental strategies to treat allograft rejection and autoimmune disorders because it prevents intact immune impairment, the major drawback of current immunosuppressive agents [1,2,3]. In 2008, Schutz et al developed the first polymeric KaAPCs by covalently coupling pMHC multimer and apoptosis-inducing anti-Fas monoclonal antibody (mAb) onto cell-sized magnetic beads and documented their ability to selectively deplete antigen-specific T cells in static 96-well plates from T-cell populations with diverse antigen specificities in a Fas/FasL-dependent manner [25]. Their therapeutic potential has been presented by our previous in vivo testing. A biodegradable, non-toxic, and biocompatible platform should be further developed
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