Partial and transient modulation of the CD3-T-cell receptor complex, elicited by low-dose regimens of monoclonal anti-CD3, is sufficient to induce disease remission in non-obese diabetic mice.
It has been established that a total of 250 microg of monoclonal anti-mouse CD3 F(ab')(2) fragments, administered daily (50 microg per dose), induces remission of diabetes in the non-obese diabetic (NOD) mouse model of autoimmune diabetes by preventing beta cells from undergoing further autoimm...
| Main Authors: | , , , |
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| Format: | Journal article |
| Language: | English |
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2010
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| _version_ | 1797059982686945280 |
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| author | Mehta, D Christmas, R Waldmann, H Rosenzweig, M |
| author_facet | Mehta, D Christmas, R Waldmann, H Rosenzweig, M |
| author_sort | Mehta, D |
| collection | OXFORD |
| description | It has been established that a total of 250 microg of monoclonal anti-mouse CD3 F(ab')(2) fragments, administered daily (50 microg per dose), induces remission of diabetes in the non-obese diabetic (NOD) mouse model of autoimmune diabetes by preventing beta cells from undergoing further autoimmune attack. We evaluated lower-dose regimens of monoclonal anti-CD3 F(ab')(2) in diabetic NOD mice for their efficacy and associated pharmacodynamic (PD) effects, including CD3-T-cell receptor (TCR) complex modulation, complete blood counts and proportions of circulating CD4(+), CD8(+) and CD4(+) FoxP3(+) T cells. Four doses of 2 microg (total dose 8 microg) induced 53% remission of diabetes, similarly to the 250 microg dose regimen, whereas four doses of 1 microg induced only 16% remission. While the 250 microg dose regimen produced nearly complete and sustained modulation of the CD3 -TCR complex, lower doses, spaced 3 days apart, which induced similar remission rates, elicited patterns of transient and partial modulation. In treated mice, the proportions of circulating CD4(+) and CD8(+) T cells decreased, whereas the proportions of CD4(+) FoxP3(+) T cells increased; these effects were transient. Mice with greater residual beta-cell function, estimated using blood glucose and C-peptide levels at the initiation of treatment, were more likely to enter remission than mice with more advanced disease. Thus, lower doses of monoclonal anti-CD3 that produced only partial and transient modulation of the CD3-TCR complex induced remission rates comparable to higher doses of monoclonal anti-CD3. Accordingly, in a clinical setting, lower-dose regimens may be efficacious and may also improve the safety profile of therapy with monoclonal anti-CD3, potentially including reductions in cytokine release-related syndromes and maintenance of pathogen-specific immunosurveillance during treatment. |
| first_indexed | 2024-03-06T20:11:20Z |
| format | Journal article |
| id | oxford-uuid:2aa746fa-6758-4847-b90a-998492be87de |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:11:20Z |
| publishDate | 2010 |
| record_format | dspace |
| spelling | oxford-uuid:2aa746fa-6758-4847-b90a-998492be87de2022-03-26T12:26:21ZPartial and transient modulation of the CD3-T-cell receptor complex, elicited by low-dose regimens of monoclonal anti-CD3, is sufficient to induce disease remission in non-obese diabetic mice.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:2aa746fa-6758-4847-b90a-998492be87deEnglishSymplectic Elements at Oxford2010Mehta, DChristmas, RWaldmann, HRosenzweig, MIt has been established that a total of 250 microg of monoclonal anti-mouse CD3 F(ab')(2) fragments, administered daily (50 microg per dose), induces remission of diabetes in the non-obese diabetic (NOD) mouse model of autoimmune diabetes by preventing beta cells from undergoing further autoimmune attack. We evaluated lower-dose regimens of monoclonal anti-CD3 F(ab')(2) in diabetic NOD mice for their efficacy and associated pharmacodynamic (PD) effects, including CD3-T-cell receptor (TCR) complex modulation, complete blood counts and proportions of circulating CD4(+), CD8(+) and CD4(+) FoxP3(+) T cells. Four doses of 2 microg (total dose 8 microg) induced 53% remission of diabetes, similarly to the 250 microg dose regimen, whereas four doses of 1 microg induced only 16% remission. While the 250 microg dose regimen produced nearly complete and sustained modulation of the CD3 -TCR complex, lower doses, spaced 3 days apart, which induced similar remission rates, elicited patterns of transient and partial modulation. In treated mice, the proportions of circulating CD4(+) and CD8(+) T cells decreased, whereas the proportions of CD4(+) FoxP3(+) T cells increased; these effects were transient. Mice with greater residual beta-cell function, estimated using blood glucose and C-peptide levels at the initiation of treatment, were more likely to enter remission than mice with more advanced disease. Thus, lower doses of monoclonal anti-CD3 that produced only partial and transient modulation of the CD3-TCR complex induced remission rates comparable to higher doses of monoclonal anti-CD3. Accordingly, in a clinical setting, lower-dose regimens may be efficacious and may also improve the safety profile of therapy with monoclonal anti-CD3, potentially including reductions in cytokine release-related syndromes and maintenance of pathogen-specific immunosurveillance during treatment. |
| spellingShingle | Mehta, D Christmas, R Waldmann, H Rosenzweig, M Partial and transient modulation of the CD3-T-cell receptor complex, elicited by low-dose regimens of monoclonal anti-CD3, is sufficient to induce disease remission in non-obese diabetic mice. |
| title | Partial and transient modulation of the CD3-T-cell receptor complex, elicited by low-dose regimens of monoclonal anti-CD3, is sufficient to induce disease remission in non-obese diabetic mice. |
| title_full | Partial and transient modulation of the CD3-T-cell receptor complex, elicited by low-dose regimens of monoclonal anti-CD3, is sufficient to induce disease remission in non-obese diabetic mice. |
| title_fullStr | Partial and transient modulation of the CD3-T-cell receptor complex, elicited by low-dose regimens of monoclonal anti-CD3, is sufficient to induce disease remission in non-obese diabetic mice. |
| title_full_unstemmed | Partial and transient modulation of the CD3-T-cell receptor complex, elicited by low-dose regimens of monoclonal anti-CD3, is sufficient to induce disease remission in non-obese diabetic mice. |
| title_short | Partial and transient modulation of the CD3-T-cell receptor complex, elicited by low-dose regimens of monoclonal anti-CD3, is sufficient to induce disease remission in non-obese diabetic mice. |
| title_sort | partial and transient modulation of the cd3 t cell receptor complex elicited by low dose regimens of monoclonal anti cd3 is sufficient to induce disease remission in non obese diabetic mice |
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