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Nature Sep 2020Cancer cells, including melanoma cells, often metastasize regionally through the lymphatic system before metastasizing systemically through the blood; however, the...
Cancer cells, including melanoma cells, often metastasize regionally through the lymphatic system before metastasizing systemically through the blood; however, the reason for this is unclear. Here we show that melanoma cells in lymph experience less oxidative stress and form more metastases than melanoma cells in blood. Immunocompromised mice with melanomas derived from patients, and immunocompetent mice with mouse melanomas, had more melanoma cells per microlitre in tumour-draining lymph than in tumour-draining blood. Cells that metastasized through blood, but not those that metastasized through lymph, became dependent on the ferroptosis inhibitor GPX4. Cells that were pretreated with chemical ferroptosis inhibitors formed more metastases than untreated cells after intravenous, but not intralymphatic, injection. We observed multiple differences between lymph fluid and blood plasma that may contribute to decreased oxidative stress and ferroptosis in lymph, including higher levels of glutathione and oleic acid and less free iron in lymph. Oleic acid protected melanoma cells from ferroptosis in an Acsl3-dependent manner and increased their capacity to form metastatic tumours. Melanoma cells from lymph nodes were more resistant to ferroptosis and formed more metastases after intravenous injection than did melanoma cells from subcutaneous tumours. Exposure to the lymphatic environment thus protects melanoma cells from ferroptosis and increases their ability to survive during subsequent metastasis through the blood.
Topics: Animals; Cell Survival; Coenzyme A Ligases; Female; Ferroptosis; Glutathione; Humans; Iron; Lymph; Male; Melanoma; Mice; Neoplasm Metastasis; Oleic Acid; Oxidative Stress; Phospholipid Hydroperoxide Glutathione Peroxidase; Principal Component Analysis
PubMed: 32814895
DOI: 10.1038/s41586-020-2623-z -
Immunotherapy Advances 2022Allergen immunotherapy (AIT) is the only disease-modifying therapy for allergic disease. Through repeated inoculations of low doses of allergen-either as whole proteins... (Review)
Review
Allergen immunotherapy (AIT) is the only disease-modifying therapy for allergic disease. Through repeated inoculations of low doses of allergen-either as whole proteins or peptides-patients can achieve a homeostatic balance between inflammatory effectors induced and/or associated with allergen contact, and mediators of immunologic non-responsiveness, potentially leading to sustained clinical improvements. AIT for airborne/respiratory tract allergens and insect venoms have traditionally been supplied subcutaneously, but other routes and modalities of administration can also be effective. Despite differences of allergen administration, there are some similarities of immunologic responses across platforms, with a general theme involving the restructuring and polarization of adaptive and innate immune effector cells. Here we review the immunology of AIT across various delivery platforms, including subcutaneous, sublingual, epicutaneous, intradermal, and intralymphatic approaches, emphasizing shared mechanisms associated with achieving immunologic non-responsiveness to allergen.
PubMed: 36530352
DOI: 10.1093/immadv/ltac022 -
Dermatology Practical & Conceptual May 2022
PubMed: 35646472
DOI: 10.5826/dpc.1202a67 -
Immunotherapy Advances 2022Immunotherapy for allergy has been practiced for over 100 years. Low-dose repeated exposure to specific allergen extracts over several months to years can successfully... (Review)
Review
Immunotherapy for allergy has been practiced for over 100 years. Low-dose repeated exposure to specific allergen extracts over several months to years can successfully induce clinical tolerance in patients with allergy to insect venoms, pollen, house dust mite, and domestic animals. Different regimens and routes for immunotherapy include subcutaneous, sublingual, oral, and intralymphatic. Food allergies have been difficult to treat in this way due to high anaphylactic potential and only recently the first immunotherapy for peanut allergy has received regulatory approval. Several clinical trials have indicated high efficacy in desensitisation of peanut-allergic individuals using oral immunotherapy, which allows for safer administration of relatively high allergen concentrations. Still, the risk of adverse events including serious allergic reactions and high anxiety levels for patients remains, demonstrating the need for further optimisation of treatment protocols. Here we discuss the design and outcomes of recent clinical trials with traditional oral immunotherapy, and consider alternative protocols and formulations for safer and more effective oral treatment strategies for peanut allergy.
PubMed: 35919493
DOI: 10.1093/immadv/ltac004 -
The World Allergy Organization Journal 2015Gold Standard allergen-specific immunotherapy is associated with low efficacy because it requires either many subcutaneous injections of allergen or even more numerous...
Gold Standard allergen-specific immunotherapy is associated with low efficacy because it requires either many subcutaneous injections of allergen or even more numerous sublingual allergen administrations to achieve amelioration of symptoms. Intralymphatic vaccination can maximize immunogenicity and hence efficacy. We and others have demonstrated that as few as three low dose intralymphatic allergen administrations are sufficient to effectively alleviate symptoms. Results of recent prospective and controlled trials suggest that this strategy may be an effective form of allergen immunotherapy.
PubMed: 25780493
DOI: 10.1186/s40413-014-0047-7 -
International Archives of Allergy and... 2019Allergen-specific immunotherapy (AIT) is the only allergy treatment that confers long-term symptom amelioration for patients suffering from allergy. The most frequently... (Review)
Review
Allergen-specific immunotherapy (AIT) is the only allergy treatment that confers long-term symptom amelioration for patients suffering from allergy. The most frequently used allergen application route is subcutaneous injection (SCIT), commonly taken as the gold standard, followed by sublingual (SLIT) or oral (OIT) application of allergen preparations. This is an up-to-date review of the clinical evidence for a novel route of allergen application, i.e., directly into lymph nodes - intralymphatic immunotherapy (ILIT). The major advantages of ILIT over the current AIT approaches are its short duration and the low allergen doses administered. The whole treatment consists of merely 3 ultrasound-guided injections into inguinal lymph nodes 1 month apart. While the number of patients included in randomised controlled trials is still limited, the clinical results for ILIT are encouraging, but more clinical trials are needed, as well as more preclinical work for optimising formulations.
Topics: Allergens; Clinical Trials as Topic; Desensitization, Immunologic; Humans; Hypersensitivity; Injections, Subcutaneous; Lymph Nodes; Sublingual Immunotherapy; Treatment Outcome
PubMed: 30391954
DOI: 10.1159/000493647 -
Immunological Reviews Mar 2022Afferent lymphatics mediate the transport of antigen and leukocytes, especially of dendritic cells (DCs) and T cells, from peripheral tissues to draining lymph nodes... (Review)
Review
Afferent lymphatics mediate the transport of antigen and leukocytes, especially of dendritic cells (DCs) and T cells, from peripheral tissues to draining lymph nodes (dLNs). As such they play important roles in the induction and regulation of adaptive immunity. Over the past 15 years, great advances in our understanding of leukocyte trafficking through afferent lymphatics have been made through time-lapse imaging studies performed in tissue explants and in vivo, allowing to visualize this process with cellular resolution. Intravital imaging has revealed that intralymphatic leukocytes continue to actively migrate once they have entered into lymphatic capillaries, as a consequence of the low flow conditions present in this compartment. In fact, leukocytes spend considerable time migrating, patrolling and interacting with the lymphatic endothelium or with other intralymphatic leukocytes within lymphatic capillaries. Cells typically only start to detach once they arrive in downstream-located collecting vessels, where vessel contractions contribute to enhanced lymph flow. In this review, we will introduce the biology of afferent lymphatic vessels and report on the presumed significance of DC and T cell migration via this route. We will specifically highlight how time-lapse imaging has contributed to the current model of lymphatic trafficking and the emerging notion that - besides transport - lymphatic capillaries exert additional roles in immune modulation.
Topics: Cell Movement; Dendritic Cells; Endothelium, Lymphatic; Humans; Lymph Nodes; Lymphatic Vessels; T-Lymphocytes
PubMed: 34708414
DOI: 10.1111/imr.13030 -
Diagnostics (Basel, Switzerland) Mar 2024Intravascular lymphomas are rare disease conditions that exhibit neoplastic lymphoid cells that are confined mainly to the lumens of small capillaries and medium-sized... (Review)
Review
Intravascular lymphomas are rare disease conditions that exhibit neoplastic lymphoid cells that are confined mainly to the lumens of small capillaries and medium-sized vessels. The majority of the intravascular lymphomas are of B-cell origin, but they can include NK/T-cell and CD30+ immunophenotypes. In the histologic differential diagnosis are benign proliferations such as intralymphatic histiocytosis and intravascular atypical CD30+ T-cell proliferation. In this review, we discuss the clinical, histopathologic, and molecular findings of intravascular B-cell lymphoma, intravascular NK/T-cell lymphoma, intralymphatic histiocytosis, and benign atypical intravascular CD30+ T-cell proliferation.
PubMed: 38611591
DOI: 10.3390/diagnostics14070679