HIV and mature dendritic cells: Trojan exosomes riding the Trojan horse?
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ABSTRACT:
SUBMITTER: Izquierdo-Useros N
PROVIDER: S-EPMC2845607 | biostudies-other | 2010 Mar
REPOSITORIES: biostudies-other
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Project description:BackgroundThe olfactory ensheathing cells (OECs) migrate from the peripheral nervous system to the central nervous system (CNS), a critical process for the development of the olfactory system and axonal extension after injury in neural regeneration. Because of their ability to migrate to the injury site and anti-inflammatory properties, OECs were tested against different neurological pathologies, but were never studied in the context of cancer. Here, we evaluated OEC tropism to gliomas and their potential as a "Trojan horse" to deliver therapeutic transgenes through the nasal pathway, their natural route to CNS.MethodsOECs were purified from the mouse olfactory bulb and engineered to express a fusion protein between cytosine deaminase and uracil phosphoribosyltransferase (CU), which convert the prodrug 5-fluorocytosine (5-FC) into cytotoxic metabolite 5-fluorouracil, leading to a bystander killing of tumor cells. These cells were injected into the nasal cavity of mice bearing glioblastoma tumors and OEC-mediated gene therapy was monitored by bioluminescence imaging and confirmed with survival and ex vivo histological analysis. All statistical tests were two-sided.ResultsOECs migrated from the nasal pathway to the primary glioma site, tracked infiltrative glioma stemlike cells, and delivered therapeutic transgene, leading to a slower tumor growth and increased mice survival. At day 28, bioluminescence imaging revealed that mice treated with a single injection of OEC-expressing CU and 5-FC had tumor-associated photons (mean [SD]) of 1.08E + 08 [9.7E + 07] vs 4.1E + 08 [2.3E + 08] for control group (P < .001), with a median survival of 41 days vs 34 days, respectively (ratio = 0.8293, 95% confidence interval = 0.4323 to 1.226, P < .001) (n = 9 mice per group).ConclusionsWe show for the first time that autologous transplantation of OECs can target and deliver therapeutic transgenes to brain tumors upon intranasal delivery, the natural route of OECs to the CNS, which could be extended to other types of cancer.
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Project description:Multicompartment microcapsules, with each compartment protected by a distinct stimuli-responsive shell for versatile controlled release, are highly desired for developing new-generation microcarriers. Although many multicompartmental microcapsules have been created, most cannot combine different release styles to achieve flexible programmed sequential release. Here, one-step template synthesis of controllable Trojan-horse-like stimuli-responsive microcapsules is reported with capsule-in-capsule structures from microfluidic quadruple emulsions for diverse programmed sequential release. The nested inner and outer capsule compartments can separately encapsulate different contents, while their two stimuli-responsive hydrogel shells can individually control the content release from each capsule compartment for versatile sequential release. This is demonstrated by using three types of Trojan-horse-like stimuli-responsive microcapsules, with different combinations of release styles for flexible programmed sequential release. The proposed microcapsules provide novel advanced candidates for developing new-generation microcarriers for diverse, efficient applications.
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Project description:UnlabelledMany attempts to design prophylactic human immunodeficiency virus type 1 (HIV-1) vaccines have focused on the induction of neutralizing antibodies (Abs) that block infection by free virions. Despite the focus on viral particles, virus-infected cells, which can be found within mucosal secretions, are more infectious than free virus both in vitro and in vivo. Furthermore, assessment of human transmission couples suggests infected seminal lymphocytes might be responsible for a proportion of HIV-1 transmissions. Although vaccines that induce neutralizing Abs are sought, only some broadly neutralizing Abs efficiently block cell-to-cell transmission of HIV-1. As HIV-1 vaccines need to elicit immune responses capable of controlling both free and cell-associated virus, we evaluated the potential of natural killer (NK) cells to respond in an Ab-dependent manner to allogeneic T cells bearing HIV-1 antigens. This study presents data measuring Ab-dependent anti-HIV-1 NK cell responses to primary and transformed allogeneic T-cell targets. We found that NK cells are robustly activated in an anti-HIV-1 Ab-dependent manner against allogeneic targets and that tested target cells are subject to Ab-dependent cytolysis. Furthermore, the educated KIR3DL1(+) NK cell subset from HLA-Bw4(+) individuals exhibits an activation advantage over the KIR3DL1(-) subset that contains both NK cells educated through other receptor/ligand combinations and uneducated NK cells. These results are intriguing and important for understanding the regulation of Ab-dependent NK cell responses and are potentially valuable for designing Ab-dependent therapies and/or vaccines.ImportanceNK cell-mediated anti-HIV-1 antibody-dependent functions have been associated with protection from infection and disease progression; however, their role in protecting from infection with allogeneic cells infected with HIV-1 is unknown. We found that HIV-1-specific ADCC antibodies bound to allogeneic cells infected with HIV-1 or coated with HIV-1 gp120 were capable of activating NK cells and/or trigging cytolysis of the allogeneic target cells. This suggests ADCC may be able to assist in preventing infection with cell-associated HIV-1. In order to fully utilize NK cell-mediated Ab-dependent effector functions, it might also be important that educated NK cells, which hold the highest activation potential, can become activated against targets bearing HIV-1 antigens and expressing the ligands for self-inhibitory receptors. Here, we show that with Ab-dependent stimulation, NK cells expressing inhibitory receptors can mediate robust activation against targets expressing the ligands for those receptors.
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