Flagellin Reduces GvHD Through Early Immunosuppression Induced by the flagellin-TLR5 Immune Interaction of Host Cells in Allogeneic HSCT Recipients
Year: 2011
Type: article
Abstract: We previously showed that flagellin (Fla) significantly reduced GvHD in H-2K→ H-2b HSCT model and had better long-term survival. Here, we reported the mechanisms by which Fla reduces GvHD using similar HSCT model and also B6 BM → B6TLR5 knock out (KO) and KO BM →B6 radiation chimeras. We hypothesized that flagellin-TLR5 binding in the host gut epithelium will be responsible to reduce GvHD. To determine the flagellin effects on early days of transplant, Fla-treated (50-μg/mouse i.p 3 hrs before irradiation and 24 hrs after transplant) B6 recipients of 3x106 splenocytes and 5x106 TCD BM cells from H-2K donors were sacrificed on day 4 and 10 after post transplant. Splenocytes were analyzed by FACS. Fla-treated recipients had significantly lower numbers of cells per spleen compared to controls [p = 0.002] on day 4 post transplant but not on day 10 [p = 0.43] post-transplant. Accordingly, the numbers of donor spleen-derived CD4 and CD8 T cells per spleen in Fla-treated recipients were significantly lower compared to PBS-treated recipients on day 4 post transplant. The early activation status of donor T cells in the spleen of Fl-treated recipients was also found significantly lower compared to controls. Next, we addressed our hypothesis by doing similar experiments using radiation chimeras. Radiation chimeras were generated by transplanting 10x106 BM cells from B6 and/or KO donors to 11Gy irradiated B6 or KO recipients. B6→KO, KO→B6, B6→B6, KO→KO radiation chimeras were again irradiated with 9.0Gy and transplanted with 3x106 H-2K splenocytes and 5 x 106TCD BM 12 weeks later. Each group received two doses of Fla or PBS i.p. Survival and weight loss were determined. Fla-treated B6→B6 radiation chimeras (TLR5+ donor and host hematopoietic and host epithelial cells) survived 100% with only mild GvHD (12% weight loss at day 79 post transplant). 50% of Fla-treated B6→KO (TLR5+ donor hematopoietic cells) and 40% of KO→ B6 (TLR5+ host hematopoietic and epithelial cells) chimeras survived with 15% and 18% weight loss, respectively. All the Fla-treated KO→ KO recipients died within 65 days post transplant. On the other hand, all 4 groups of PBS-treated control recipients died or were sacrificed due to GvHD-associated weight loss exceeding 25%. Flagellin reduces GvHD by suppressing the activities of donor T cells within 4 days post-transplant. The early immunosuppression may be the result of Fla-TLR5 immune interaction in the host epithelium that reduces GvHD.
Institution: Emory University
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,650
OpenAlex ID: W1969880997