Abstract
BackgroundExtracellular matrix metalloproteinase inducer (EMMPRIN; CD147, basigin) is an inducer of the expression of several matrix metalloproteinases (MMPs). We reported previously that blocking EMMPRIN activity reduced neuroinflammation and severity of disease in an animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE).MethodsTo improve upon EMMPRIN blockade, and to help unravel the biological functions of EMMPRIN in inflammatory disorders, we have developed several anti-EMMPRIN monoclonal antibodies.ResultsOf these monoclonal antibodies, a particular one, clone 10, was efficient in binding mouse and human cells using several methods of detection. The specificity of clone 10 was demonstrated by its lack of staining of EMMPRIN-null embryos compared to heterozygous and wild-type mouse samples. Functionally, human T cells activated with anti-CD3 and anti-CD28 elevated their expression of EMMPRIN and the treatment of these T cells with clone 10 resulted in decreased proliferation and matrix metalloproteinase- 9 (MMP-9) production. Activated human T cells were toxic to human neurons in culture and clone 10 pretreatment reduced T cell cytotoxicity correspondent with decrease of granzyme B levels within T cells. In vivo, EAE mice treated with clone 10 had a markedly reduced disease score compared to mice treated with IgM isotype control.ConclusionsWe have produced a novel anti-EMMPRIN monoclonal antibody that blocks several aspects of T cell activity, thus highlighting the multiple roles of EMMPRIN in T cell biology. Moreover, clone 10 reduces EAE scores in mice compared to controls, and has activity on human cells, potentially allowing for the testing of anti-EMMPRIN treatment not only in EAE, but conceivably also in MS.
Highlights
Extracellular matrix metalloproteinase inducer (EMMPRIN; CD147, basigin) is an inducer of the expression of several matrix metalloproteinases (MMPs)
We describe our development of a novel anti-EMMPRIN function blocking monoclonal IgM antibody named clone 10 that detects and affects EMMPRIN activity on both murine and human cells
Western blot analyses suggest that clone 10 detects EMMPRIN in murine and human brain homogenates In preliminary screenings, the conditioned media from several hybridoma clones were found to be immunoreactive to EMMPRIN peptide (40-55) (Figure 1) in ELISA assays
Summary
Extracellular matrix metalloproteinase inducer (EMMPRIN; CD147, basigin) is an inducer of the expression of several matrix metalloproteinases (MMPs). We reported previously that blocking EMMPRIN activity reduced neuroinflammation and severity of disease in an animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). Extracellular matrix metalloproteinase inducer (EMMPRIN; basigin, CD147) is a member of the immunoglobulin (Ig) superfamily It is a cell surface glycoprotein expressed on numerous cell types [1,2,3,4], with many binding partners including CD98, monocarboxylate transporters (MCT-1), cyclophilin, CD44, and hyaluronan to name but a few [5,6,7], and a long list of acronyms including tumor collagenase stimulatory factor (TCSF) [8]), M6 (in human cells) [3], EMMPRIN-null mice have abnormalities of body size, memory function [15], female reproduction, spermatogenesis [16,17], lung and liver tissue structure, blood–brain barrier integrity [18], T cell cycling in the thymus [19] and retinal function [20,21]. We described that a commercially available function-blocking anti-mouse EMMPRIN antibody reduced MMP activity in the CNS resulting in lowered EAE clinical severity and decreased leukocyte infiltration into the CNS [25]
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