The Biophysics of Lymphatic Transport: Engineering Tools and Immunological Consequences

O’Melia, Meghan J.; Lund, Amanda W.; Thomas, Susan N.

doi:10.1016/j.isci.2019.11.005

Cited by 38 publications

(40 citation statements)

References 155 publications

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“…NPs of 30 nm have been shown to clear by lymphatic drainage, and we target NPs of this size for this study. 28 − 32 Moreover, recent studies of TLR7/8a-functional macromolecular constructs indicate that mannose functionalization can increase recognition and internalization by mannose-binding C-type lectins. 14 , 33 We therefore hypothesized that introduction of mannose to the NP surface alongside TLR7/8a may improve NP uptake and therefore receptor activation.…”

Section: Results and Discussionmentioning

confidence: 99%

“…Since the TLR7/8a molecule on its own is small, it can rapidly enter systemic circulation, whereas the TLR7/8a NPs are in a size regime, approximately 30 nm, that has been shown to drain passively to lymph nodes. 28 − 32 , 41 In these assays, we assessed toxicity by conducting Luminex analysis of cytokines in mouse serum 2 h after the initial treatment and by measuring mouse body mass over the course of treatment ( Figure 4 A).…”

Section: Results and Discussionmentioning

confidence: 99%

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Nanoparticles Presenting Potent TLR7/8 Agonists Enhance Anti-PD-L1 Immunotherapy in Cancer Treatment

et al. 2020

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Cancer immunotherapy can be augmented with toll-like receptor agonist (TLRa) adjuvants, which interact with immune cells to elicit potent immune activation. Despite their potential, use of many TLRa compounds has been limited clinically due to their extreme potency and lack of pharmacokinetic control, causing systemic toxicity from unregulated systemic cytokine release. Herein, we overcome these shortcomings by generating poly(ethylene glycol)–poly(lactic acid) (PEG–PLA) nanoparticles (NPs) presenting potent TLR7/8a moieties on their surface. The NP platform allows precise control of TLR7/8a valency and resulting surface presentation through self-assembly using nanoprecipitation. We hypothesize that the pharmacokinetic profile of the NPs minimizes systemic toxicity, localizing TLR7/8a presentation to the tumor bed and tumor-draining lymph nodes. In conjunction with antiprogrammed death-ligand 1 (anti-PD-L1) checkpoint blockade, peritumoral injection of TLR7/8a NPs slows tumor growth, extends survival, and decreases systemic toxicity in comparison to the free TLR7/8a in a murine colon adenocarcinoma model. These NPs constitute a modular platform for controlling pharmacokinetics of immunostimulatory molecules, resulting in increased potency and decreased toxicity.

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Section: Results and Discussionmentioning

confidence: 99%

Section: Results and Discussionmentioning

confidence: 99%

Nanoparticles Presenting Potent TLR7/8 Agonists Enhance Anti-PD-L1 Immunotherapy in Cancer Treatment

et al. 2020

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“…It is likely that neolymphogenesis is beneficial in the early phases of disease to maintain tissue homeostasis, but if become uncontrolled during the disease progression, may lead to pathological maladaptation. Persistent local inflammation impairs lymphatic contraction causing altered fluid transport ( 85 ). In addition, accumulation of collagen and fibrogenic molecules produced by smooth muscle cells and fibroblasts into the perilymphatic space causes capillary fibrosis and impairs vascular function ( 86 ).…”

Section: Mechanisms Of Mitral Valve Diseasementioning

confidence: 99%

Rheumatic Heart Valve Disease Pathophysiology and Underlying Mechanisms

Passos

Nunes

Aïkawa

2021

Front. Cardiovasc. Med.

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Rheumatic heart valve disease (RHVD) is a post-infectious sequel of acute rheumatic fever resulting from an abnormal immune response to a streptococcal pharyngitis that triggers valvular damage. RHVD is the leading cause of cardiovascular death in children and young adults, mainly in women from low and middle-income countries. It is known that long-term inflammation and high degree of fibrosis leads to valve dysfunction due to anatomic disruption of the valve apparatus. However, since public and private investments in RHVD studies are practically inexistent the number of publications is scarce. This disease shows different natural history and clinical presentations as compared to other degenerative heart valve diseases. Although more than five decades passed after the pioneering studies on the pathogenesis of RHVD, it is still unclear how self-tolerance mechanisms fail in this disease, and how humoral and cellular inflammatory responses are interconnected. Despite that pathological mechanisms have been already proposed for RHVD, none of them are able to explain the preferential involvement of the mitral valve. This review focuses on pathophysiology and underlying mechanisms of RHVD.

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“…The graph models which we make publicly available, provide an important step towards a quantitative analysis of transport phenomena in the whole lymphatic system. This is a problem of a paramount importance for systems immunology, pharmacokinetics and medicine [1,2,28].…”

Section: Discussionmentioning

confidence: 99%

Graph Theory for Modeling and Analysis of the Human Lymphatic System

et al. 2020

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The human lymphatic system (HLS) is a complex network of lymphatic organs linked through the lymphatic vessels. We present a graph theory-based approach to model and analyze the human lymphatic network. Two different methods of building a graph are considered: the method using anatomical data directly and the method based on a system of rules derived from structural analysis of HLS. A simple anatomical data-based graph is converted to an oriented graph by quantifying the steady-state fluid balance in the lymphatic network with the use of the Poiseuille equation in vessels and the mass conservation at vessel junctions. A computational algorithm for the generation of the rule-based random graph is developed and implemented. Some fundamental characteristics of the two types of HLS graph models are analyzed using different metrics such as graph energy, clustering, robustness, etc.

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The Biophysics of Lymphatic Transport: Engineering Tools and Immunological Consequences

Cited by 38 publications

References 155 publications

Nanoparticles Presenting Potent TLR7/8 Agonists Enhance Anti-PD-L1 Immunotherapy in Cancer Treatment

Nanoparticles Presenting Potent TLR7/8 Agonists Enhance Anti-PD-L1 Immunotherapy in Cancer Treatment

Rheumatic Heart Valve Disease Pathophysiology and Underlying Mechanisms

Graph Theory for Modeling and Analysis of the Human Lymphatic System

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