RESUMO
Peripheral neuropathy is a common aging-related degenerative disorder that interferes with daily activities and leads to increased risk of falls and injury in the elderly. The etiology of most aging-related peripheral neuropathy is unknown. Inherited defects in several genome maintenance mechanisms cause tissue-specific accelerated aging, including neurodegeneration. We tested the hypothesis that a murine model of XFE progeroid syndrome, caused by reduced expression of ERCC1-XPF DNA repair endonuclease, develops peripheral neuropathy. Nerve conduction studies revealed normal nerve function in young adult (8 week) Ercc1(-/Δ) mice, but significant abnormalities in 20 week-old animals. Morphologic and ultrastructural analysis of the sciatic nerve from mutant mice revealed significant alterations at 20 but not 8 weeks of age. We conclude that Ercc1(-/Δ) mice have accelerated spontaneous peripheral neurodegeneration that mimics aging-related disease. This provides strong evidence that DNA damage can drive peripheral neuropathy and offers a rapid and novel model to test therapies.
Assuntos
Envelhecimento/metabolismo , Dano ao DNA , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Endonucleases/metabolismo , Doenças do Sistema Nervoso Periférico/enzimologia , Progéria/enzimologia , Envelhecimento/genética , Envelhecimento/patologia , Animais , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Masculino , Camundongos , Camundongos Knockout , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/patologia , Progéria/genética , Progéria/patologiaRESUMO
Dendritic cells (DCs) are the most effective antigen-presenting cells (APCs) and are used in a variety of immunotherapeutic approaches. Adoptive cellular immunotherapy (ACI) of cancer using DCs has attracted much interest due to their capacity to promote immunity in prophylactic and therapeutic protocols. As one approach, DCs are injected into patients or tumor-bearing animals, to trigger specific antitumor immunity. In that framework, several approaches to DC delivery have been reported, including direct intratumoral injection; this has yielded positive but variable results. The underlying reasons for this have not been fully determined, but major hypotheses include technical difficulties in delivering cells into tumors and tumor-mediated immunosuppression. Image-guided ACI offers the potential to establish that DCs are efficiently delivered to the tumor site, which might eliminate some of the variability. Therefore, we developed highly sensitive methods for monitoring the injection or trafficking of DCs into tumors using a clinically approved formulation of a gadolinium-based magnetic resonance imaging (MRI) contrast agent, Gd(III)-HP-DO3A (ProHance). We determined the labeling efficiency of DCs with this formulation; that labeling DCs with this agent did not inhibit expression of surface markers important for antigen presentation and activation of naive T cells; that their capacity to interact with natural killer (NK) cells was not reduced; and that their migration was not diminished. Further, we determined that ProHance-labeled DCs can be effectively imaged in vivo in established central nervous system tumors.
