ABSTRACT
Approximately 15-40% of all cancers develop metastases in the central nervous system (CNS), yet few therapeutic options exist to treat them. Cancer therapies based on monoclonal antibodies are widely successful, yet have limited efficacy against CNS metastases, owing to the low levels of the drug reaching the tumour site. Here, we show that the encapsulation of rituximab within a crosslinked zwitterionic polymer layer leads to the sustained release of rituximab as the crosslinkers are gradually hydrolysed, enhancing the CNS levels of the antibody by approximately tenfold with respect to the administration of naked rituximab. When the nanocapsules were functionalized with CXCL13-the ligand for the chemokine receptor CXCR5, which is frequently found on B-cell lymphoma-a single dose led to improved control of CXCR5-expressing metastases in a murine xenograft model of non-Hodgkin lymphoma, and eliminated lymphoma in a xenografted humanized bone marrow-liver-thymus mouse model. Encapsulation and molecular targeting of therapeutic antibodies could become an option for the treatment of cancers with CNS metastases.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Central Nervous System , Drug Delivery Systems/methods , Lymphoma, B-Cell/drug therapy , Molecular Targeted Therapy/methods , Rituximab/pharmacology , Animals , Brain , Chemokine CXCL13/drug effects , Chemokine CXCL13/metabolism , Disease Models, Animal , Lymphatic Metastasis/drug therapy , Lymphoma, Non-Hodgkin/drug therapy , Mice , Nanocapsules , Receptors, CXCR5/drug effects , Receptors, CXCR5/metabolism , Xenograft Model Antitumor AssaysABSTRACT
RATIONALE: The B cell-attracting chemokine CXCL13 is an important mediator in the formation of tertiary lymphoid organs (TLOs). Increased numbers of ectopic lymphoid follicles have been observed in lungs of patients with severe chronic obstructive pulmonary disease (COPD). However, the role of these TLOs in the pathogenesis of COPD remains unknown. OBJECTIVES: By neutralizing CXCL13 in a mouse model of chronic cigarette smoke (CS) exposure, we aimed at interrogating the link between lymphoid follicles and development of pulmonary inflammation, emphysema, and airway wall remodeling. METHODS: We first quantified and localized CXCL13 in lungs of air- or CS-exposed mice and in lungs of never smokers, smokers without airflow obstruction, and patients with COPD by reverse transcriptase-polymerase chain reaction, ELISA, and immunohistochemistry. Next, CXCL13 signaling was blocked by prophylactic or therapeutic administration of anti-CXCL13 antibodies in mice exposed to air or CS for 24 weeks, and several hallmarks of COPD were evaluated. MEASUREMENTS AND MAIN RESULTS: Both mRNA and protein levels of CXCL13 were increased in lungs of CS-exposed mice and patients with COPD. Importantly, expression of CXCL13 was observed within B-cell areas of lymphoid follicles. Prophylactic and therapeutic administration of anti-CXCL13 antibodies completely prevented the CS-induced formation of pulmonary lymphoid follicles in mice. Interestingly, absence of TLOs attenuated destruction of alveolar walls and inflammation in bronchoalveolar lavage but did not affect airway wall remodeling. CONCLUSIONS: CXCL13 is produced within lymphoid follicles of patients with COPD and is crucial for the formation of TLOs. Neutralization of CXCL13 partially protects mice against CS-induced inflammation in bronchoalveolar lavage and alveolar wall destruction.
Subject(s)
Chemokine CXCL13/genetics , Gene Expression Regulation , Nicotiana , Pulmonary Disease, Chronic Obstructive/complications , RNA, Messenger/genetics , Smoke/adverse effects , Smoking/adverse effects , Aged , Airway Remodeling/drug effects , Animals , Bronchoalveolar Lavage Fluid/chemistry , Chemokine CXCL13/biosynthesis , Chemokine CXCL13/drug effects , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Female , Humans , Immunohistochemistry , Male , Mice , Mice, Inbred C57BL , Middle Aged , Polymerase Chain Reaction , Pulmonary Disease, Chronic Obstructive/genetics , Pulmonary Disease, Chronic Obstructive/physiopathology , Smoking/genetics , Smoking/metabolismABSTRACT
OBJECTIVE: Sjögren's syndrome is a chronic autoimmune disorder characterized by progressive lymphocytic infiltration within the salivary and lacrimal glands. This study was undertaken to investigate the effects of innate immunity activation on sialoadenitis in a mouse strain genetically susceptible for development of SS-like disease. METHODS: Female New Zealand Black X New Zealand White F1 mice were repeatedly treated with toll-like 3 receptor agonist poly(I:C). Submandibular glands were investigated at different time points for sialoadenitis by immunohistochemistry and for gene expression of different chemokines by quantitative PCR. Submandibular gland-infiltrating cells were characterized by flow cytometry. RESULTS: Poly(I:C) treatment significantly upregulated the expression of multiple chemokines within the submandibular glands. The severity and incidence of sialoadenitis was considerably higher in poly(I:C)-treated mice. There was a preponderance of dendritic cells and NK cells in the initial inflammatory cell infiltrates, and these were followed by CD4+ T cells. CONCLUSIONS: Our data clearly demonstrate that systemic activation of innate immunity accelerates sialoadenitis in a mouse model for SS-like disease. These findings suggest that chronic activation of innate immunity can influence certain features of SS.
