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A novel anti-EMMPRIN function-blocking antibody reduces T cell proliferation and neurotoxicity: relevance to multiple
Smriti M Agrawal1, Claudia Silva, Janet Wang
1Departments of Clinical Neurosciences and Oncology, Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada.
Background:
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).
Methods:
To improve upon EMMPRIN blockade, and to help unravel the biological functions of EMMPRIN in inflammatory disorders, we have developed several anti-EMMPRIN monoclonal antibodies.
Results:
Of 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.
Conclusions:
We 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.
Insights
A novel monoclonal antibody targeting EMMPRIN (extracellular matrix metalloproteinase inducer) effectively reduced T cell activity and disease severity in a multiple sclerosis model. This antibody shows potential for treating neuroinflammatory conditions like MS.
Area of Science:
- Immunology
- Neuroscience
- Molecular Biology
Background:
- Extracellular matrix metalloproteinase inducer (EMMPRIN) promotes matrix metalloproteinase expression.
- EMMPRIN blockade previously reduced neuroinflammation and disease severity in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS).
Purpose of the Study:
- To develop improved EMMPRIN-blocking agents.
- To investigate EMMPRIN's role in inflammatory disorders through novel monoclonal antibodies.
Main Methods:
- Development and characterization of anti-EMMPRIN monoclonal antibodies, including specificity and binding assays.
- Assessment of antibody effects on activated human T cell proliferation, matrix metalloproteinase-9 (MMP-9) production, and neuronal cytotoxicity in vitro.
- Evaluation of in vivo efficacy using the EAE mouse model.
Main Results:
- Clone 10, a novel anti-EMMPRIN antibody, demonstrated specific binding to mouse and human cells.
- Clone 10 inhibited activated human T cell proliferation, MMP-9 production, and T cell-mediated neuronal toxicity.
- In vivo, clone 10 treatment significantly reduced disease scores in EAE mice compared to isotype control.
Conclusions:
- A novel anti-EMMPRIN monoclonal antibody (clone 10) was developed, demonstrating broad activity against T cell functions.
- EMMPRIN plays multiple roles in T cell biology, making it a viable therapeutic target.
- Clone 10's efficacy in EAE and activity on human cells suggest potential for treating MS and other neuroinflammatory diseases.
