A Novel In Vitro Human Granuloma Model of Sarcoidosis and Latent Tuberculosis Infection
| Autor: | Larry S. Schlesinger, Audrey C. Papp, Landon W. Locke, Elliott D. Crouser, Peter White, Mark W. Julian, Evelyn Guirado Caceres, Wolfgang Sadee |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Pulmonary and Respiratory Medicine Purified protein derivative Granuloma formation Granuloma Respiratory Tract Clinical Biochemistry 03 medical and health sciences Human disease Sarcoidosis Pulmonary Latent Tuberculosis medicine Humans Tuberculosis Pulmonary Molecular Biology Original Research Latent tuberculosis business.industry Models Immunological Cell Biology Th1 Cells medicine.disease In vitro 030104 developmental biology Granuloma Immunology Female Sarcoidosis business human activities |
| Zdroj: | American Journal of Respiratory Cell and Molecular Biology. 57:487-498 |
| ISSN: | 1535-4989 1044-1549 0185-7401 |
| Popis: | Many aspects of pathogenic granuloma formation are poorly understood, requiring new relevant laboratory models that represent the complexity (genetics and diversity) of human disease. To address this need, we developed an in vitro model of granuloma formation using human peripheral blood mononuclear cells (PBMCs) derived from patients with active sarcoidosis, latent tuberculosis (TB) infection (LTBI), or normal healthy control subjects. PBMCs were incubated for 7 days with uncoated polystyrene beads or beads coated with purified protein derivative (PPD) or human serum albumin. In response to PPD-coated beads, PBMCs from donors with sarcoidosis and LTBI formed robust multicellular aggregates resembling granulomas, displaying a typical T-helper cell type 1 immune response, as assessed by cytokine analyses. In contrast, minimal PBMC aggregation occurred when control PBMCs were incubated with PPD-coated beads, whereas the response to uncoated beads was negligible in all groups. Sarcoidosis PBMCs responded to human serum albumin-coated beads with modest cellular aggregation and inflammatory cytokine release. Whereas the granuloma-like aggregates formed in response to PPD-coated beads were similar for sarcoidosis and LTBI, molecular profiles differed significantly. mRNA expression patterns revealed distinct pathways engaged in early granuloma formation in sarcoidosis and LTBI, and they resemble molecular patterns reported in diseased human tissues. This novel in vitro human granuloma model is proposed as a tool to investigate mechanisms of early granuloma formation and for preclinical drug discovery research of human granulomatous disorders. Clinical trial registered with www.clinicaltrials.gov (NCT01857401). |
| Databáze: | OpenAIRE |
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