Flagellin, A TLR5 Agonist, Facilitates Production of foxp3+CD4+CD25+ Regulatory T Cells to Maintain Balanced Immune Reconstitution in Allogeneic BMT without GvHD
Year: 2009
Type: article
Abstract: Background: Graft-vs-host disease (GvHD) and lyphopenia are the major clinical problems in allogeneic bone marrow transplantation (BMT). Immunosuppressive drugs are used to control GvHD, but immunosuppression is often incomplete and patients experience drug-related toxicities. Donor foxp3+CD25+CD4+ regulatory T cells are also effective at controlling GvHD, but are expensive and time consuming to produce. Flagellin, a bacterial protein and a TLR5 agonist, can culminate production of proinflammatory cytokines and chemokines. In this study we investigated whether flagellin could facilitate thymic production of donor BM-derived foxp3+CD25+CD4+ regulatory T cells to control GvHD and regulate post BMT immune reconstitution. Methods: Irradiated (11Gy) CB6F1 recipient received 5 × 106 T cell depleted BM and 5 × 106 splenocytes from naive C57BL/6 congenic donors. 50 micro gm flagellin/mouse was administered i.p. 3 hours before irradiation and 24 hours after BMT. Recipients that received no flagellin were used as control. After 70+ days post transplant recipients were infected with 5 × 103 pfu MCMV i.p., sacrificed at different time points and lymphocytes were harvested from spleen and thymus for analysis. Flow cytometry was used to determine immune reconstitution, normal and regulatory T cells. Results: All flagellin-treated recipients survived without GvHD for 66 days post transplant, while only 65% of the control mice survived and had chronic GvHD. The number of splenocytes was significantly increased in flagellin-treated recipients compared to control recipients (p = 0.0006) on day 66-post transplant. Donor spleen- and BM-derived CD4+ and CD8+ T cells were significantly higher in the spleen of flagellin-treated recipients compared to control mice. Flagellin-treated recipients had higher levels of both donor spleen- and BM-derived anti-viral CD8+ T cells in the spleen compared to control recipients. The thymus of flagellin-treated recipients produced donor spleen- and BM-derived T cells and foxp3+CD25+CD4+ regulatory T cells, while thymic functions were severely reduced in control recipients. Conclusion: Flagellin treatment successfully reduced GvHD, improved survival, enhanced donor T-cell engraftment and produced regulatory T cells in allo-BMT. Treated recipients had brisk and persistent cellular immune responses against MCMV infection. Hence, prophylactic use of flagellin is a novel therapeutic approach to treat blood cancer patients with allogeneic BMT.
Institution: Emory University
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,650
OpenAlex ID: W2060834689