“…TGF-β of T lymphocyte, monocyte/macrophage or granulocyte origin is typically detected at sites of inflammation. 39 Among the three isoforms of TGF-β, TGF-β1 exhibits the broadest spectrum of biological activities. Notably, TGF-β1 promotes early dendritic cell development in vitro and suppression of immature dendritic cell activation and maturation.…”
Section: Immunoregulation Of Dendritic Cells By Il-10mentioning
The paradigm of tolerogenic/immature versus inflammatory/mature dendritic cells has dominated the recent literature regarding the role of these antigen-presenting cells in mediating immune homeostasis or self-tolerance and response to pathogens, respectively. This issue is further complicated by the identification of distinct subtypes of dendritic cells that exhibit different antigen-presenting cell effector functions. The discovery of pathogen-associated molecular patterns and toll-like receptors provides the mechanistic basis for dendritic cell recognition of specific pathogens and induction of appropriate innate and adaptive immune responses. Only recently has insight been gained into how dendritic cells contribute to establishing and/or maintaining immunological tolerance to self. Soluble and cellular mediators have been reported to effectively regulate the function of dendritic cells by inducing several outcomes ranging from non-inflammatory dendritic cells that lack the ability to induce T lymphocyte activation to dendritic cells that actively suppress T lymphocyte responses. A thorough discussion of these stimuli and their outcomes is essential to understanding the potential for modulating dendritic cell function in the treatment of inflammatory disease conditions.
“…TGF-β of T lymphocyte, monocyte/macrophage or granulocyte origin is typically detected at sites of inflammation. 39 Among the three isoforms of TGF-β, TGF-β1 exhibits the broadest spectrum of biological activities. Notably, TGF-β1 promotes early dendritic cell development in vitro and suppression of immature dendritic cell activation and maturation.…”
Section: Immunoregulation Of Dendritic Cells By Il-10mentioning
The paradigm of tolerogenic/immature versus inflammatory/mature dendritic cells has dominated the recent literature regarding the role of these antigen-presenting cells in mediating immune homeostasis or self-tolerance and response to pathogens, respectively. This issue is further complicated by the identification of distinct subtypes of dendritic cells that exhibit different antigen-presenting cell effector functions. The discovery of pathogen-associated molecular patterns and toll-like receptors provides the mechanistic basis for dendritic cell recognition of specific pathogens and induction of appropriate innate and adaptive immune responses. Only recently has insight been gained into how dendritic cells contribute to establishing and/or maintaining immunological tolerance to self. Soluble and cellular mediators have been reported to effectively regulate the function of dendritic cells by inducing several outcomes ranging from non-inflammatory dendritic cells that lack the ability to induce T lymphocyte activation to dendritic cells that actively suppress T lymphocyte responses. A thorough discussion of these stimuli and their outcomes is essential to understanding the potential for modulating dendritic cell function in the treatment of inflammatory disease conditions.
“…Intravenous administration of myeloid iDCs generated in vitro with GM-CSF can prolong the survival of pancreatic islet or heart allografts [106,107]. A theoretical drawback of this approach is the possibility that, following injection, iDCs differentiate in vivo into mDCs with the ability to stimulate anti-donor T-cell responses and accelerate allograft rejection.…”
Section: In Vivo Treatment Of Autoimmune Diseases With Treg Cells Andmentioning
“…Allograft survival can be prolonged by infusion of tDCs derived from the marrows, spleens, and solid organs of donor mice. [13][14][15][16][17] Moreover, indirect alloantigen presentation by recipient tDCs has also been shown to promote tolerance to allografts as well as amelioration of graft versus host disease. [18][19][20][21] tDCs can be enriched and expanded in vitro under a variety of culture conditions.…”
Current methods for eradicating clinically significant inhibitory antibodies to human factor VIII (hFVIII) in patients with hemophilia A rely on repeated delivery of high doses of factor concentrates for a minimum of many months. We hypothesize that tolerance can be induced more efficiently and reliably through hFVIII antigen presentation by tolerogenic dendritic cells (tDCs). In this study, we generated tDCs from hemophilia A mice and modified them with a foamy virus vector expressing a bioengineered hFVIII transgene. Naive and preimmunized mice infused with hFVIII expressing tDCs showed suppression of the T cell and inhibitor responses to recombinant hFVIII (rhFVIII). Treatment with hFVIII expressing tDCs was also associated with a higher percentage of splenocytes demonstrating a regulatory T cell phenotype in immunized mice. Furthermore, CD4(+) T cells harvested from recipients of hFVIII expression vector-modified tDCs were able to mediate antigen-specific immune suppression in naive secondary recipients. We also demonstrated a trend for improved suppression of inhibitor formation by coexpressing interleukin-10 (IL-10) and hFVIII from a bicistronic vector. These preclinical results demonstrate the potential for employing vector modified ex vivo generated tDCs to treat high titer inhibitors in patients with hemophilia A.
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