Anti-CD3 Preconditioning Separates GVL from GVHD Via Modulating Host Dendritic and Donor T Cell Migration in TBI-Conditioned Recipients

Host dendritic cells (DCs) play a critical role in initiating graft versus host disease (GVHD) and graft versus leukemia (GVL), and separation of GVL from GVHD remains a major challenge in the treatment of hematological malignancies by allogeneic hematopoietic cell transplantation (HCT). Here, we show that preconditioning with anti- CD3 mAb before conditioning with total body irradiation prevents GVHD but retains GVL in a HCT model of MHC-mismatched C57BL/6 donor to BALB/c host. Prevention of GVHD is associated with inhibition of donor T expression of homing and chemokine receptors and inhibition of GVHD target tissue expression of chemokines. Furthermore, inhibition of donor T expression of gut homing a4b7 and chemokine receptor CCR9 by anti-CD3 preconditioning results from reduction of CD103⁺ DCs in draining mesenteric lymph nodes, which is associated with downregulation of DC expression of CCR7, a receptor required for tissue DC migration to draining LN. These results indicate that anti-CD3 preconditioning reduces not only tissue release of chemokines but also prevents tissue DC migration to draining LN and subsequently reduces draining LN DC’s capacity in imprinting donor T tissue tropism. Therefore, modulation of host DCs by anti-CD3 preconditioning before HCT represents a new approach for separating GVL from GVHD. (Li and Chen contribute equally.