1 Lab. of Stem Cell Stress, International Res. Center for Med. Sci., Kumamoto Univ.2 Dept. of Hematology, Hokkaido Univ. Grad. Sch. of Med.3 Center for Metabolic Regulation of Healthy Aging, Kumamoto Univ.Irradiation conditioning with head shielding mitigates acute graft-versus-host disease after allogeneic hematopoietic cell transplantation Allogeneic hematopoietic cell transplantation (Allo-HCT) is a curative treatment for hematological malignancies. However, its widespread use is significantly restricted by graft-versus-host disease (GVHD), a severe post-transplant complication where donor T cells target the recipient's tissues. Developing a conditioning regimen that minimizes GVHD without increasing the risk of disease relapse remains an unmet clinical need.This study aimed at optimizing the radiation intensity through selective shielding of body parts to reduce GVHD risk after allo-HCT. Acute GVHD was induced by transplanting 10 x106 splenocytes and 5 x 106 T cell-depleted bone marrow cells from Balb/c into B6J mice lethally irradiated with or without selective shielding. Head shielding conferred a pronounced reduction in acute GVHD morbidity and mortality. Analysis of alloreactive donor T cells in the GVHD target organs at day 7 post allo-HCT revealed the reduced abundance of allo-T cells in the thymus, gut and mesenteric lymph nodes. Notably, head shielding could not affect the systemic inflammation, but diminished the expression of inflammatory cytokines Il6 and Tnfa in the gut. We hypothesized that this protection may be due to sparing the brainstem from radio-damage, thereby preserving its ability to regulate cholinergic anti-inflammatory pathway in the gut via vagus nerve. To prove this, we performed vagotomy/sham on mice and allowed them to recover for 2 weeks before allo-HCT. Vagotomy abrogated the protective effect of head shielding, evidenced by worsened clinical score, increased allo-T cells, and elevated expression of some gut inflammatory cytokines. Collectively, our results show that irradiation conditioning with head shielding mitigates acute GVHD through preserving brainstem function and vagal signaling to control local inflammation in the gut. ○Ismael C Adolf1 Sayuri Nakata1 Takanori Teshima2 Hitoshi Takizawa1,355P 025
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