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Diabetes induced by checkpoint inhibition in nonobese diabetic mice can be prevented or reversed by a JAK1/JAK2 inhibitor
OBJECTIVES: Immune checkpoint inhibitors have achieved clinical success in cancer treatment, but this treatment causes immune‐related adverse events, including type 1 diabetes (T1D). Our aim was to test whether a JAK1/JAK2 inhibitor, effective at treating spontaneous autoimmune diabetes in nonobese...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9618467/ https://www.ncbi.nlm.nih.gov/pubmed/36325490 http://dx.doi.org/10.1002/cti2.1425 |
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author | Ge, Tingting Phung, Amber‐Lee Jhala, Gaurang Trivedi, Prerak Principe, Nicola De George, David J Pappas, Evan G Litwak, Sara Sanz‐Villanueva, Laura Catterall, Tara Fynch, Stacey Boon, Louis Kay, Thomas W Chee, Jonathan Krishnamurthy, Balasubramanian Thomas, Helen E |
author_facet | Ge, Tingting Phung, Amber‐Lee Jhala, Gaurang Trivedi, Prerak Principe, Nicola De George, David J Pappas, Evan G Litwak, Sara Sanz‐Villanueva, Laura Catterall, Tara Fynch, Stacey Boon, Louis Kay, Thomas W Chee, Jonathan Krishnamurthy, Balasubramanian Thomas, Helen E |
author_sort | Ge, Tingting |
collection | PubMed |
description | OBJECTIVES: Immune checkpoint inhibitors have achieved clinical success in cancer treatment, but this treatment causes immune‐related adverse events, including type 1 diabetes (T1D). Our aim was to test whether a JAK1/JAK2 inhibitor, effective at treating spontaneous autoimmune diabetes in nonobese diabetic (NOD) mice, can prevent diabetes secondary to PD‐L1 blockade. METHODS: Anti‐PD‐L1 antibody was injected into NOD mice to induce diabetes, and JAK1/JAK2 inhibitor LN3103801 was administered by oral gavage to prevent diabetes. Flow cytometry was used to study T cells and beta cells. Mesothelioma cells were inoculated into BALB/c mice to induce a transplantable tumour model. RESULTS: Anti‐PD‐L1‐induced diabetes was associated with increased immune cell infiltration in the islets and upregulated MHC class I on islet cells. Anti‐PD‐L1 administration significantly increased islet T cell proliferation and islet‐specific CD8(+) T cell numbers in peripheral lymphoid organs. JAK1/JAK2 inhibitor treatment blocked IFNγ‐mediated MHC class I upregulation on beta cells and T cell proliferation mediated by cytokines that use the common γ chain receptor. As a result, anti‐PD‐L1‐induced diabetes was prevented by JAK1/JAK2 inhibitor administered before or after checkpoint inhibitor therapy. Diabetes was also reversed when the JAK1/JAK2 inhibitor was administered after the onset of anti‐PD‐L1‐induced hyperglycaemia. Furthermore, JAK1/JAK2 inhibitor intervention after checkpoint inhibitors did not reverse or abrogate the antitumour effects in a transplantable tumour model. CONCLUSION: A JAK1/JAK2 inhibitor can prevent and reverse anti‐PD‐L1‐induced diabetes by blocking IFNγ and γc cytokine activities. Our study provides preclinical validation of JAK1/JAK2 inhibitor use in checkpoint inhibitor‐induced diabetes. |
format | Online Article Text |
id | pubmed-9618467 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-96184672022-11-01 Diabetes induced by checkpoint inhibition in nonobese diabetic mice can be prevented or reversed by a JAK1/JAK2 inhibitor Ge, Tingting Phung, Amber‐Lee Jhala, Gaurang Trivedi, Prerak Principe, Nicola De George, David J Pappas, Evan G Litwak, Sara Sanz‐Villanueva, Laura Catterall, Tara Fynch, Stacey Boon, Louis Kay, Thomas W Chee, Jonathan Krishnamurthy, Balasubramanian Thomas, Helen E Clin Transl Immunology Original Articles OBJECTIVES: Immune checkpoint inhibitors have achieved clinical success in cancer treatment, but this treatment causes immune‐related adverse events, including type 1 diabetes (T1D). Our aim was to test whether a JAK1/JAK2 inhibitor, effective at treating spontaneous autoimmune diabetes in nonobese diabetic (NOD) mice, can prevent diabetes secondary to PD‐L1 blockade. METHODS: Anti‐PD‐L1 antibody was injected into NOD mice to induce diabetes, and JAK1/JAK2 inhibitor LN3103801 was administered by oral gavage to prevent diabetes. Flow cytometry was used to study T cells and beta cells. Mesothelioma cells were inoculated into BALB/c mice to induce a transplantable tumour model. RESULTS: Anti‐PD‐L1‐induced diabetes was associated with increased immune cell infiltration in the islets and upregulated MHC class I on islet cells. Anti‐PD‐L1 administration significantly increased islet T cell proliferation and islet‐specific CD8(+) T cell numbers in peripheral lymphoid organs. JAK1/JAK2 inhibitor treatment blocked IFNγ‐mediated MHC class I upregulation on beta cells and T cell proliferation mediated by cytokines that use the common γ chain receptor. As a result, anti‐PD‐L1‐induced diabetes was prevented by JAK1/JAK2 inhibitor administered before or after checkpoint inhibitor therapy. Diabetes was also reversed when the JAK1/JAK2 inhibitor was administered after the onset of anti‐PD‐L1‐induced hyperglycaemia. Furthermore, JAK1/JAK2 inhibitor intervention after checkpoint inhibitors did not reverse or abrogate the antitumour effects in a transplantable tumour model. CONCLUSION: A JAK1/JAK2 inhibitor can prevent and reverse anti‐PD‐L1‐induced diabetes by blocking IFNγ and γc cytokine activities. Our study provides preclinical validation of JAK1/JAK2 inhibitor use in checkpoint inhibitor‐induced diabetes. John Wiley and Sons Inc. 2022-10-30 /pmc/articles/PMC9618467/ /pubmed/36325490 http://dx.doi.org/10.1002/cti2.1425 Text en © 2022 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Original Articles Ge, Tingting Phung, Amber‐Lee Jhala, Gaurang Trivedi, Prerak Principe, Nicola De George, David J Pappas, Evan G Litwak, Sara Sanz‐Villanueva, Laura Catterall, Tara Fynch, Stacey Boon, Louis Kay, Thomas W Chee, Jonathan Krishnamurthy, Balasubramanian Thomas, Helen E Diabetes induced by checkpoint inhibition in nonobese diabetic mice can be prevented or reversed by a JAK1/JAK2 inhibitor |
title | Diabetes induced by checkpoint inhibition in nonobese diabetic mice can be prevented or reversed by a JAK1/JAK2 inhibitor |
title_full | Diabetes induced by checkpoint inhibition in nonobese diabetic mice can be prevented or reversed by a JAK1/JAK2 inhibitor |
title_fullStr | Diabetes induced by checkpoint inhibition in nonobese diabetic mice can be prevented or reversed by a JAK1/JAK2 inhibitor |
title_full_unstemmed | Diabetes induced by checkpoint inhibition in nonobese diabetic mice can be prevented or reversed by a JAK1/JAK2 inhibitor |
title_short | Diabetes induced by checkpoint inhibition in nonobese diabetic mice can be prevented or reversed by a JAK1/JAK2 inhibitor |
title_sort | diabetes induced by checkpoint inhibition in nonobese diabetic mice can be prevented or reversed by a jak1/jak2 inhibitor |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9618467/ https://www.ncbi.nlm.nih.gov/pubmed/36325490 http://dx.doi.org/10.1002/cti2.1425 |
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