RESUMO
Accompanying the increasing translational impact of immunotherapeutic strategies to treat and prevent disease has been a broadening interest across both bioscience and bioengineering in the lymphatic system. Herein, the lymphatic system physiology, ranging from its tissue structures to immune functions and effects, is described. Design principles and engineering approaches to analyze and manipulate this tissue system in nanoparticle-based drug delivery applications are also elaborated.
Assuntos
Bioengenharia , Sistemas de Liberação de Medicamentos , Humanos , Nanotecnologia , Sistema LinfáticoAssuntos
Citocromo P-450 CYP3A/genética , Genótipo , Hispânico ou Latino , Proteínas Associadas aos Microtúbulos/genética , Síndromes Neurotóxicas/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras , Vincristina , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Testes Farmacogenômicos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Vincristina/administração & dosagem , Vincristina/efeitos adversosRESUMO
Neurons are the longest-lived cells in our bodies and lack DNA replication, which makes them reliant on a limited repertoire of DNA repair mechanisms to maintain genome fidelity. These repair mechanisms decline with age, but we have limited knowledge of how genome instability emerges and what strategies neurons and other long-lived cells may have evolved to protect their genomes over the human life span. A targeted sequencing approach in human embryonic stem cell-induced neurons shows that, in neurons, DNA repair is enriched at well-defined hotspots that protect essential genes. These hotspots are enriched with histone H2A isoforms and RNA binding proteins and are associated with evolutionarily conserved elements of the human genome. These findings provide a basis for understanding genome integrity as it relates to aging and disease in the nervous system.
Assuntos
Reparo do DNA , Genoma Humano , Instabilidade Genômica , Neurônios/metabolismo , Envelhecimento/genética , Dano ao DNA , DNA Intergênico , Desoxiuridina/análogos & derivados , Desoxiuridina/metabolismo , Células-Tronco Embrionárias , Histonas/metabolismo , Humanos , Mitose , Mutação , Doenças do Sistema Nervoso/genética , Neurônios/citologia , Regiões Promotoras Genéticas , Proteínas de Ligação a RNA/metabolismo , Análise de Sequência de DNA , Transcrição GênicaRESUMO
Antibody-mediated immune checkpoint blockade is a transformative immunotherapy for cancer. These same mechanisms can be repurposed for the control of destructive alloreactive immune responses in the transplantation setting. Here, we implement a synthetic biomaterial platform for the local delivery of a chimeric streptavidin/programmed cell death-1 (SA-PD-L1) protein to direct "reprogramming" of local immune responses to transplanted pancreatic islets. Controlled presentation of SA-PD-L1 on the surface of poly(ethylene glycol) microgels improves local retention of the immunomodulatory agent over 3 weeks in vivo. Furthermore, local induction of allograft acceptance is achieved in a murine model of diabetes only when receiving the SA-PD-L1-presenting biomaterial in combination with a brief rapamycin treatment. Immune characterization revealed an increase in T regulatory and anergic cells after SA-PD-L1-microgel delivery, which was distinct from naïve and biomaterial alone microenvironments. Engineering the local microenvironment via biomaterial delivery of checkpoint proteins has the potential to advance cell-based therapies, avoiding the need for systemic chronic immunosuppression.