Small-molecule inhibitors of the CD40–CD40L costimulatory interaction are effective in pancreatic islet transplantation and prevention of type 1 diabetes models
As part of our work to develop small-molecule inhibitors (SMIs) of the CD40-CD40L(CD154) costimulatory protein-protein interaction, here, we describe the ability of two of our most promising SMIs, DRI-C21041 and DRI-C21095, to prolong the survival and function of islet allografts in two murine model...
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Frontiers Media S.A.
2024-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1484425/full |
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| author | Sung-Ting Chuang Oscar Alcazar Brandon Watts Midhat H. Abdulreda Midhat H. Abdulreda Midhat H. Abdulreda Midhat H. Abdulreda Peter Buchwald Peter Buchwald |
| author_facet | Sung-Ting Chuang Oscar Alcazar Brandon Watts Midhat H. Abdulreda Midhat H. Abdulreda Midhat H. Abdulreda Midhat H. Abdulreda Peter Buchwald Peter Buchwald |
| author_sort | Sung-Ting Chuang |
| collection | DOAJ |
| description | As part of our work to develop small-molecule inhibitors (SMIs) of the CD40-CD40L(CD154) costimulatory protein-protein interaction, here, we describe the ability of two of our most promising SMIs, DRI-C21041 and DRI-C21095, to prolong the survival and function of islet allografts in two murine models of islet transplantation (under the kidney capsule and in the anterior chamber of the eye) and to prevent autoimmune type 1 diabetes (T1D) onset in NOD mice. In both transplant models, a significant portion of islet allografts (50%-80%) remained intact and functional long after terminating treatment, suggesting the possibility of inducing operational immune tolerance via inhibition of the CD40-CD40L axis. SMI-treated mice maintained the structural integrity and function of their islet allografts with concomitant reduction in immune cell infiltration as evidenced by direct longitudinal imaging in situ. Furthermore, in female NODs, three-month SMI treatment reduced the incidence of diabetes from 80% to 60% (DRI-C21041) and 25% (DRI-C21095). These results (i) demonstrate the susceptibility of this TNF superfamily protein-protein interaction to small-molecule inhibition, (ii) confirm the in vivo therapeutic potential of these SMIs of a critical immune checkpoint, and (iii) reaffirm the therapeutic promise of CD40-CD40L blockade in islet transplantation and T1D prevention. Thus, CD40L-targeting SMIs could ultimately lead to alternative immunomodulatory therapeutics for transplant recipients and prevention of autoimmune diseases that are safer, less immunogenic, more controllable (shorter half-lives), and more patient-friendly (i.e., suitable for oral administration, which makes them easier to administer) than corresponding antibody-based interventions. |
| format | Article |
| id | doaj-art-b9934ccfe1794acfa9cccb4774a29d1d |
| institution | OA Journals |
| issn | 1664-3224 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-b9934ccfe1794acfa9cccb4774a29d1d2025-08-20T02:14:57ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-11-011510.3389/fimmu.2024.14844251484425Small-molecule inhibitors of the CD40–CD40L costimulatory interaction are effective in pancreatic islet transplantation and prevention of type 1 diabetes modelsSung-Ting Chuang0Oscar Alcazar1Brandon Watts2Midhat H. Abdulreda3Midhat H. Abdulreda4Midhat H. Abdulreda5Midhat H. Abdulreda6Peter Buchwald7Peter Buchwald8Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL, United StatesDiabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL, United StatesDiabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL, United StatesDiabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL, United StatesDepartment of Surgery, Miller School of Medicine, University of Miami, Miami, FL, United StatesDepartment of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, United StatesDepartment of Ophthalmology, Miller School of Medicine, University of Miami, Miami, FL, United StatesDiabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL, United StatesDepartment of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, FL, United StatesAs part of our work to develop small-molecule inhibitors (SMIs) of the CD40-CD40L(CD154) costimulatory protein-protein interaction, here, we describe the ability of two of our most promising SMIs, DRI-C21041 and DRI-C21095, to prolong the survival and function of islet allografts in two murine models of islet transplantation (under the kidney capsule and in the anterior chamber of the eye) and to prevent autoimmune type 1 diabetes (T1D) onset in NOD mice. In both transplant models, a significant portion of islet allografts (50%-80%) remained intact and functional long after terminating treatment, suggesting the possibility of inducing operational immune tolerance via inhibition of the CD40-CD40L axis. SMI-treated mice maintained the structural integrity and function of their islet allografts with concomitant reduction in immune cell infiltration as evidenced by direct longitudinal imaging in situ. Furthermore, in female NODs, three-month SMI treatment reduced the incidence of diabetes from 80% to 60% (DRI-C21041) and 25% (DRI-C21095). These results (i) demonstrate the susceptibility of this TNF superfamily protein-protein interaction to small-molecule inhibition, (ii) confirm the in vivo therapeutic potential of these SMIs of a critical immune checkpoint, and (iii) reaffirm the therapeutic promise of CD40-CD40L blockade in islet transplantation and T1D prevention. Thus, CD40L-targeting SMIs could ultimately lead to alternative immunomodulatory therapeutics for transplant recipients and prevention of autoimmune diseases that are safer, less immunogenic, more controllable (shorter half-lives), and more patient-friendly (i.e., suitable for oral administration, which makes them easier to administer) than corresponding antibody-based interventions.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1484425/fullCD154costimulatory inhibitionimmune checkpointimmunosuppressionislet transplantationprotein-protein interaction |
| spellingShingle | Sung-Ting Chuang Oscar Alcazar Brandon Watts Midhat H. Abdulreda Midhat H. Abdulreda Midhat H. Abdulreda Midhat H. Abdulreda Peter Buchwald Peter Buchwald Small-molecule inhibitors of the CD40–CD40L costimulatory interaction are effective in pancreatic islet transplantation and prevention of type 1 diabetes models Frontiers in Immunology CD154 costimulatory inhibition immune checkpoint immunosuppression islet transplantation protein-protein interaction |
| title | Small-molecule inhibitors of the CD40–CD40L costimulatory interaction are effective in pancreatic islet transplantation and prevention of type 1 diabetes models |
| title_full | Small-molecule inhibitors of the CD40–CD40L costimulatory interaction are effective in pancreatic islet transplantation and prevention of type 1 diabetes models |
| title_fullStr | Small-molecule inhibitors of the CD40–CD40L costimulatory interaction are effective in pancreatic islet transplantation and prevention of type 1 diabetes models |
| title_full_unstemmed | Small-molecule inhibitors of the CD40–CD40L costimulatory interaction are effective in pancreatic islet transplantation and prevention of type 1 diabetes models |
| title_short | Small-molecule inhibitors of the CD40–CD40L costimulatory interaction are effective in pancreatic islet transplantation and prevention of type 1 diabetes models |
| title_sort | small molecule inhibitors of the cd40 cd40l costimulatory interaction are effective in pancreatic islet transplantation and prevention of type 1 diabetes models |
| topic | CD154 costimulatory inhibition immune checkpoint immunosuppression islet transplantation protein-protein interaction |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1484425/full |
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