The role of lymphoid tissue SPARC in the pathogenesis and response to treatment of multiple myeloma.

BACKGROUND: Despite the significant progress in the treatment of multiple myeloma (MM), the disease remains untreatable and its cure is still an unmet clinical need. Neoplastic transformation in MM is initiated in the germinal centers (GCs) of secondary lymphoid tissue (SLT) where B cells experience extensive somatic hypermutation induced by follicular dendritic cells (FDCs) and T-cell signals. OBJECTIVE: We reason that secreted protein acidic and rich in cysteine (SPARC), a common stromal motif expressed by FDCs at the origin (SLTs) and the destination (BM) of MM, plays a role in the pathogenesis of MM, and, here, we sought to investigate this role. METHODS: There were 107 BM biopsies from 57 MM patients (taken at different time points) together with 13 control specimens assessed for SPARC gene and protein expression and compared with tonsillar tissues. In addition, regulation of myeloma-promoting genes by SPARC-secreting FDCs was assessed in in vitro GC reactions (GCRs). RESULTS: SPARC gene expression was confirmed in both human primary (BM) and secondary (tonsils) lymphoid tissues, and the expression was significantly higher in the BM. Sparc was detectable in the BM and tonsillar lysates, co-localized with the FDC markers in both tissues, and stimulation of FDCs in vitro induced significantly higher levels of SPARC expression than unstimulated controls. In addition, SPARC inversely correlated with BM PC infiltration, ISS staging, and ECOG performance of the MM patients, and in vitro addition of FDCs to lymphocytes inhibited the expression of several oncogenes associated with malignant transformation of PCs. CONCLUSION: FDC-SPARC inhibits several myelomagenic gene expression and inversely correlates with PC infiltration and MM progression. Therapeutic induction of SPARC expression through combinations of the current MM drugs, repositioning of non-MM drugs, or novel drug discovery could pave the way to better control MM in clinically severe and drug-resistant patients

Interferon regulatory factor 8-deficiency determines massive neutrophil recruitment but T cell defect in fast growing granulomas during tuberculosis

Following Mycobacterium tuberculosis (Mtb) infection, immune cell recruitment in lungs is pivotal in establishing protective immunity through granuloma formation and neogenesis of lymphoid structures (LS). Interferon regulatory factor-8 (IRF-8) plays an important role in host defense against Mtb, although the mechanisms driving anti-mycobacterial immunity remain unclear. In this study, IRF-8 deficient mice (IRF-8−/−) were aerogenously infected with a low-dose Mtb Erdman virulent strain and the course of infection was compared with that induced in wild-type (WT-B6) counterparts. Tuberculosis (TB) progression was examined in both groups using pathological, microbiological and immunological parameters. Following Mtb exposure, the bacterial load in lungs and spleens progressed comparably in the two groups for two weeks, after which IRF-8−/− mice developed a fatal acute TB whereas in WT-B6 the disease reached a chronic stage. In lungs of IRF-8−/−, uncontrolled growth of pulmonary granulomas and impaired development of LS were observed, associated with unbalanced homeostatic chemokines, progressive loss of infiltrating T lymphocytes and massive prevalence of neutrophils at late infection stages. Our data define IRF-8 as an essential factor for the maintenance of proper immune cell recruitment in granulomas and LS required to restrain Mtb infection. Moreover, IRF-8−/− mice, relying on a common human and mouse genetic mutation linked to susceptibility/severity of mycobacterial diseases, represent a valuable model of acute TB for comparative studies with chronically-infected congenic WT-B6 for dissecting protective and pathological immune reactions

Improved monitoring of clinical response in Systemic Lupus Erythematosus by longitudinal trend in soluble vascular cell adhesion molecule-1

This work was funded by Arthritis Research UK. MJL holds an Arthritis Research UK Clinician Scientist Fellowship (19631), and was previously supported by the St Thomas’ Lupus Trust. The study received support from the National Institute for Health Research (NIHR)-funded Flow Cytometry Core Facility and the Biomedical Research Centre based at Guy’s & St. Thomas’ National Health Service (NHS) Foundation Trust, in partnership with King’s College London

Impaired immunological synapse in sperm associated antigen 6 (SPAG6) deficient mice

This work is supported by grant RO1AI18697 from NIAID/NIH, American Asthma Foundation 11-0094 AAF, VCU School of Medicine Bridge grant, NIH HD076257, and VCU Massey Cancer Award. Flow cytometry is supported by the Massey Cancer Center Core P30 CA16059. Microscopy was performed at the VCU Department of Neurobiology and Anatomy Facility, supported in part with funding from NIH-NINDS center core grant 5P30N5S047463

Isolation and Characterization of Mouse and Human Follicular Dendritic Cells.

Follicular dendritic cells (FDCs) reside in the B cell follicles of secondary and tertiary lymphoid tissues where they play key roles in the development and maintenance of lymphoid tissue architecture and function. FDCs trap native antigens for extended periods of time in the form of immune complexes which critcally regulate germinal center reactions in health and disease. Here, we describe how to isolate and characterize FDCs from murine and human lymphoid tissues

Symmetric molecules with 1,4-triazole moieties as potent inhibitors of tumour-associated lactate dehydrogenase-A.

A series of symmetric molecules incorporating aryl or pyridyl moieties as central core and 1,4-substituted triazoles as a side bridge was synthesised. The new compounds were investigated as lactate dehydro-genase (LDH, EC 1.1.1.27) inhibitors. The cancer associated LDHA isoform was inhibited with IC50 = 117-174 µM. Seven compounds exhibited better LDHA inhibition (IC50 117-136 µM) compared to known LDH inhibitor - galloflavin (IC50 157 µM).This project was supported by the National Plan of Science, Technology and Innovation [Grant No. 12-MED2980–54], Prince Sattam bin Abdulaziz University, Alkharj, PO Box 173, 11942

SYNOVIAL MAST CELLS CORRELATE WITH LOCAL AND SYSTEMIC INFLAMMATION AND ARE FUNCTIONALLY ASSOCIATED WITH ECTOPIC LYMPHOID STRUCTURES IN PATIENTS WITH EARLY RHEUMATOID ARTHRITIS

Meeting AbstractThe research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007–2013) under REA grant agreement n° 60876

SYNOVIAL MAST CELLS CORRELATE WITH LOCAL AND SYSTEMIC INFLAMMATION AND ARE FUNCTIONALLY ASSOCIATED WITH ECTOPIC LYMPHOID STRUCTURES IN PATIENTS WITH EARLY RHEUMATOID ARTHRITIS

Meeting AbstractThe research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007–2013) under REA grant agreement n° 60876