Frontiers in immunology
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Frontiers in immunology · Jan 2019
ReviewRegulation of Immune Function by the Lymphatic System in Lymphedema.
The lymphatic vasculature has traditionally been thought to play a passive role in the regulation of immune responses by transporting antigen presenting cells and soluble antigens to regional lymph nodes. However, more recent studies have shown that lymphatic endothelial cells regulate immune responses more directly by modulating entry of immune cells into lymphatic capillaries, presenting antigens on major histocompatibility complex proteins, and modulating antigen presenting cells. Secondary lymphedema is a disease that develops when the lymphatic system is injured during surgical treatment of cancers or is damaged by infections. ⋯ Prolonged T helper 2 biased immune responses in lymphedema regulate the pathology of this disease by promoting tissue fibrosis, inhibiting formation of collateral lymphatics, decreasing lymphatic vessel pumping capacity, and increasing lymphatic leakiness. Treg infiltration following lymphatic injury results from proliferation of natural Tregs and suppresses innate and adaptive immune responses. These studies have broad clinical relevance since understanding how lymphatic injury in lymphedema can modulate immune responses may provide a template with which we can study more subtle forms of lymphatic injury that may occur in physiologic conditions such as aging, obesity, metabolic tumors, and in the tumor microenvironment.
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Frontiers in immunology · Jan 2019
ReviewAnti-complement Treatment for Paroxysmal Nocturnal Hemoglobinuria: Time for Proximal Complement Inhibition? A Position Paper From the SAAWP of the EBMT.
The treatment of paroxysmal nocturnal hemoglobinuria has been revolutionized by the introduction of the anti-C5 agent eculizumab; however, eculizumab is not the cure for Paroxysmal nocturnal hemoglobinuria (PNH), and room for improvement remains. Indeed, the hematological benefit during eculizumab treatment for PNH is very heterogeneous among patients, and different response categories can be identified. Complete normalization of hemoglobin (complete and major hematological response), is seen in no more than one third of patients, while the remaining continue to experience some degree of anemia (good and partial hematological responses), in some cases requiring regular red blood cell transfusions (minor hematological response). ⋯ These agents are available either subcutaneously or orally, and have been investigated in monotherapy or in association with eculizumab in PNH patients. Preliminary data clearly demonstrate that proximal complement inhibition is pharmacologically feasible and apparently safe, and may drastically improve the hematological response to complement inhibition in PNH. Indeed, we envision a new scenario of therapeutic complement inhibition, where proximal inhibitors (either anti-C3, anti-FD or anti-FB) may prove effective for the treatment of PNH, either in monotherapy or in combination with anti-C5 agents, eventually leading to drastic improvement of hematological response.
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Frontiers in immunology · Jan 2019
ReviewCauses and Consequences of Innate Immune Dysfunction in Cirrhosis.
Liver cirrhosis is an increasing health burden and public health concern. Regardless of etiology, patients with cirrhosis are at risk of a range of life-threatening complications, including the development of infections, which are associated with high morbidity and mortality and frequent hospital admissions. The term Cirrhosis-Associated Immune Dysfunction (CAID) refers to a dynamic spectrum of immunological perturbations that develop in patients with cirrhosis, which are intimately linked to the underlying liver disease, and negatively correlated with prognosis. ⋯ Innate immune cells, in particular monocytes/macrophages and neutrophils, are pivotal effector and target cells in CAID. This review focuses on the pathophysiological mechanisms leading to impaired innate immune function in cirrhosis. Knowledge of the phenotypic manifestation and pathophysiological mechanisms of cirrhosis associated immunosuppression may lead to immune targeted therapies to reduce susceptibility to infection in patients with cirrhosis, and better biomarkers for risk stratification, and assessment of efficacy of novel immunotherapies.
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Frontiers in immunology · Jan 2019
ReviewPD-L1 Distribution and Perspective for Cancer Immunotherapy-Blockade, Knockdown, or Inhibition.
Cancer immunotherapy involves blocking the interactions between the PD-1/PD-L1 immune checkpoints with antibodies. This has shown unprecedented positive outcomes in clinics. Particularly, the PD-L1 antibody therapy has shown the efficiency in blocking membrane PD-L1 and efficacy in treating some advanced carcinoma. ⋯ Apart from cancer cells, PD-L1 silencing on host immune cells such as APC and DC can also enhance T cell immunity, leading to tumor clearance. Moreover, the molecular regulation of PD-L1 expression in cells is being elucidated, which helps identify potential therapeutic molecules to target PD-L1 production and improve clinical outcomes. Based on our understandings of PD-L1 distribution, regulation, and function, we prospect that the more effective PD-L1-based cancer immunotherapy will be combination therapies.
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Frontiers in immunology · Jan 2019
ReviewCan Immunogenic Chemotherapies Relieve Cancer Cell Resistance to Immune Checkpoint Inhibitors?
The unprecedented clinical activity of checkpoint blockade in several types of cancers has formally demonstrated that anti-tumor immune responses are crucial in cancer therapy. Durable responses seen in patients treated with immune checkpoint inhibitors (ICI) show that they can trigger the establishment of long-lasting immunologic memory. This beneficial outcome is however achieved for a limited number of patients. ⋯ How can this be prevented through combination therapies? We here review the functions of immune checkpoints, the successes of ICI in treating cancer and their therapeutic limits. We discuss how conventional cancer therapies can be properly selected to set up combinatorial approaches with ICI leading to treatment improvement. We finally summarize clinical data showing the ongoing progress in cancer treatment involving ICI and chemotherapy combination strategies.