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Targeting of PI3K/AKT/mTOR pathway to inhibit T cell activation and prevent graft-versus-host disease development
| Content Provider | Semantic Scholar |
|---|---|
| Author | Herrero-Sánchez, Mª Carmen Almeida, Julia Segundo, Laura San Inogés, Susana Santos-Briz, Ángel García-Briñón, Jesús Corchete, Luís Antonio Miguel, Jesús Fernando San Cañizo, Consuelo Del Blanco, Belén |
| Copyright Year | 2016 |
| Abstract | BACKGROUND Graft-versus-host disease (GvHD) remains the major obstacle to successful allogeneic hematopoietic stem cell transplantation, despite of the immunosuppressive regimens administered to control T cell alloreactivity. PI3K/AKT/mTOR pathway is crucial in T cell activation and function and, therefore, represents an attractive therapeutic target to prevent GvHD development. Recently, numerous PI3K inhibitors have been developed for cancer therapy. However, few studies have explored their immunosuppressive effect. METHODS The effects of a selective PI3K inhibitor (BKM120) and a dual PI3K/mTOR inhibitor (BEZ235) on human T cell proliferation, expression of activation-related molecules, and phosphorylation of PI3K/AKT/mTOR pathway proteins were analyzed. Besides, the ability of BEZ235 to prevent GvHD development in mice was evaluated. RESULTS Simultaneous inhibition of PI3K and mTOR was efficient at lower concentrations than PI3K specific targeting. Importantly, BEZ235 prevented naïve T cell activation and induced tolerance of alloreactive T cells, while maintaining an adequate response against cytomegalovirus, more efficiently than BKM120. Finally, BEZ235 treatment significantly improved the survival and decreased the GvHD development in mice. CONCLUSIONS These results support the use of PI3K inhibitors to control T cell responses and show the potential utility of the dual PI3K/mTOR inhibitor BEZ235 in GvHD prophylaxis. |
| Starting Page | 4721 |
| Ending Page | 4729 |
| Page Count | 9 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | https://jhoonline.biomedcentral.com/track/pdf/10.1186/s13045-016-0343-5 |
| PubMed reference number | 27765055v1 |
| Volume Number | 9 |
| Journal | Journal of hematology & oncology |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Allogeneic Hematopoietic Stem Cell Transplantation BEZ235 BKM120 Cell Proliferation Cellular Phone Chronic Lymphocytic Leukemia Dual FRAP1 protein, human Graft-vs-Host Disease Hematopoietic stem cells Hemopoietic stem cell transplant Leukemia, B-Cell Natural immunosuppression Neoplasms Proto-Oncogene Proteins c-akt T-Lymphocyte Transplanted tissue cellular targeting mTOR Inhibitor |
| Content Type | Text |
| Resource Type | Article |
