VEGF-A from Granuloma Macrophages Regulates Granulomatous Inflammation by a Non-angiogenic Pathway during Mycobacterial Infection.

Many autoimmune and infectious diseases are characterized by the formation of granulomas which are inflammatory lesions that consist of spatially organized immune cells. These sites protect the host and control pathogens like Mycobacterium tuberculosis (Mtb), but are highly inflammatory and cause pathology. Using bacille Calmette-Guerin (BCG) and Mtb infection in mice that induce sarcoid or caseating granulomas, we show that a subpopulation of granuloma macrophages produces vascular endothelial growth factor (VEGF-A), which recruits immune cells to the granuloma by a non-angiogenic pathway. Selective blockade of VEGF-A in myeloid cells, combined with granuloma transplantation, shows that granuloma VEGF-A regulates granulomatous inflammation. The severity of granuloma-related inflammation can be ameliorated by pharmaceutical or genetic inhibition of VEGF-A, which improves survival of mice infected with virulent Mtb without altering host protection. These data show that VEGF-A inhibitors could be used as a host-directed therapy against granulomatous diseases like tuberculosis and sarcoidosis, thereby expanding the value of already existing and approved anti-VEGF-A drugs.

Impact of Elimination or Reduction of Dietary Animal Proteins on Cancer Progression and Survival: Protocol of an Online Pilot Cohort Study.

BACKGROUND: Current evidence suggests that the incidence of cancer is low in vegan populations, and experimental studies have revealed a significant role of dietary proteins in cancer development and progression. However, little data currently exists regarding the effect of a plant-based diet on the progression of diagnosed cancer. OBJECTIVE: The main objective of this study is to determine if a reduction or total elimination of animal protein from the diet can positively influence the outcome of an existing cancer and, in addition to standard oncological therapies, increase remission rates. METHODS: The primary aim of this online study is to test the effect on remission rates in cancer patients (primary outcome) with distinct self-selected dietary patterns (omnivore, lacto-ovo-vegetarian, vegan), and allow for an estimation of the effect size. Secondary outcomes are tumor behavior, relapse-free interval, therapies, therapy tolerability and side-effects, comorbidities, medication, quality of life, acceptance, and feasibility of the selected diet. Safety concerns exist for vegan diets (especially in cancer patients) and the study will carefully monitor for deterioration of health, tumor progression, or malnutrition. Furthermore, the study will evaluate the online portal as a study platform (technical and safety aspects, and sequence of displayed questionnaires) as well as the validity of self-reported and online-generated data. RESULTS: The study was performed between April, 2015 and June, 2016, and a preliminary evaluation of safety aspects was undertaken after June, 2016. Primary and secondary outcomes will be evaluated when the final patients complete the study in December, 2016. CONCLUSIONS: This study will reveal information about the effects of dietary patterns on cancer disease and progression. The methodology of the study addresses several aspects and limitations of nutrition studies in cancer patients, such as precision of nutrition data, acceptance criteria, online methodology, and safety aspects. CLINICALTRIAL: Clinicaltrials.gov NCT02437474; https://clinicaltrials.gov/ct2/show/NCT02437474 (Archived by WebCite at http://www.webcitation.org/6jL7UUCVq).

Lymphangiogenesis is induced by mycobacterial granulomas via vascular endothelial growth factor receptor-3 and supports systemic T-cell responses against mycobacterial antigen.

Granulomatous inflammation is characteristic of many autoimmune and infectious diseases. The lymphatic drainage of these inflammatory sites remains poorly understood, despite an expanding understanding of lymphatic role in inflammation and disease. Here, we show that the lymph vessel growth factor Vegf-c is up-regulated in Bacillus Calmette-Guerin- and Mycobacterium tuberculosis-induced granulomas, and that infection results in lymph vessel sprouting and increased lymphatic area in granulomatous tissue. The observed lymphangiogenesis during infection was reduced by inhibition of vascular endothelial growth factor receptor 3. By using a model of chronic granulomatous infection, we also show that lymphatic remodeling of tissue persists despite resolution of acute infection and a 10- to 100-fold reduction in the number of bacteria and tissue-infiltrating leukocytes. Inhibition of vascular endothelial growth factor receptor 3 decreased the growth of new vessels, but also reduced the proliferation of antigen-specific T cells. Together, our data show that granuloma-up-regulated factors increase granuloma access to secondary lymph organs by lymphangiogenesis, and that this process facilitates the generation of systemic T-cell responses to granuloma-contained antigens.