Interplay of DDP4 and IP-10 as a Potential Mechanism for Cell Recruitment to Tuberculosis Lesions.

INTRODUCTION: Mycobacterium tuberculosis is one of the world's most successful pathogens equipped to establish itself within the human host as a subclinical infection without overt disease. Unable to eradicate the bacteria, the immune system contains the infection in a granuloma structure. Th1 cells that are essential for infection control are recruited to the site of infection directed by chemokines, predominantly CXCL10. It has previously been shown that CXCL10 in the plasma of patients chronically infected with hepatitis C virus is present primarily in an antagonist form. This is due to N-terminal truncation by the enzyme DPP4, which results in the antagonist form that is capable of binding its receptor CXCR3, but does not induce signaling. We aimed to explore whether such CXCL10 antagonism may have an impact on the pathogenesis of tuberculosis (TB). RESULTS: We measured plasma levels of agonist and antagonist CXCL10 by Simoa digital ELISA, as well as DPP4 enzyme activity in the plasma of 20 patients with active TB infection, 10 patients with pneumonia infection, and a group of 10 healthy controls. We found higher levels of total and antagonist CXCL10 and reduced DPP4 enzyme activity in the plasma of TB patients compared to controls. We traced the source of CXCL10 secretion using immunohistochemical and confocal analysis to multinucleated giant cells in the TB lesions, and variable expression by macrophages. Interestingly, these cells were associated with DPP4-positive T cells. Moreover, the analysis of lymphocytes at the site of TB infection (bronchoalveolar lavage) showed a reduced frequency of CXCR3+ T cells. INTERPRETATION: Our data suggests that CXCL10 antagonism may be an important regulatory mechanism occurring at the site of TB pathology. CXCL10 can be inactivated shortly after secretion by membrane bound DPP4 (CD26), therefore, reducing its chemotactic potential. Given the importance of Th1 cell functions and IFN-γ-mediated effects in TB, our data suggest a possible unappreciated regulatory role of DPP4 in TB. PERSPECTIVES: DPP4 is the target for a class of enzyme inhibitors used in the treatment of diabetes, and the results from this study suggest that these drugs could be repurposed as an adjunct immunotherapy of patients with TB and MDR-TB.

The technique of endoscopic airway tumor treatment.

More than half of primary lung cancers are not resectable at diagnosis and 40% of deaths may be secondary to loco-regional disease. Many of these patients suffer from symptoms related to airways obstruction. Indications for therapeutic endoscopic treatment are palliation of dyspnea and other obstructive symptoms in advanced cancerous lesions and cure of early lung cancer. Bronchoscopic management is also indicated for all those patients suffering from benign or minimally invasive neoplasm who are not suitable for surgery due to their clinical conditions. Clinicians should select cases, evaluating tumor features (size, location) and patient characteristics (age, lung function impairment) to choose the most appropriate endoscopic technique. Laser therapy, electrocautery, cryotherapy and stenting are well-described techniques for the palliation of symptoms due to airway involvement and local treatment of endobronchial lesions. Newer technologies, with an established role in clinical practice, are endobronchial ultrasound (EBUS), autofluorescence bronchoscopy (AFB), and narrow band imaging (NBI). Other techniques, such as endobronchial intra-tumoral chemotherapy (EITC), EBUS-guided-transbronchial needle injection or bronchoscopy-guided radiofrequency ablation (RFA), are in development for the use within the airways. These endobronchial interventions are important adjuncts in the multimodality management of lung cancer and should become standard considerations in the management of patients with advanced lung cancer, benign or otherwise not approachable central airway lesions. We aimed at revising several endobronchial treatment modalities that can augment standard antitumor therapies for advanced lung cancer, including rigid and flexible bronchoscopy, laser therapy, endobronchial prosthesis, and photodynamic therapy (PDT).