400: Resident Human Myeloid Dendritic Cell Activation and Local Allogeneic T Cell Responses in the Bone Marrow of Humanized NOD/SCID Mice

Resident human dendritic cells (DC) in vascularized lymphoid organs such as bone marrow (BM) and spleen (SP) may contribute significant T cell responses to the overall systemic immune responses. To address this possibility in vivo, we developed humanized (hu)NOD/SCID mice, which contain human resident DC in the BM and SP derived from engrafted cord blood CD34+ cells. When huNOD/SCID mice were injected with polyinosinic:polycytidylic acid [poly(I:C)], activation of the resident human myeloid (M)DC occurred concurrently, in the BM and SP, within 2–8 h of injection. Poly(I:C) activated human MDC in the BM and SP increased the proportions of CD86+MDC and their production of IL-6, IL-10 and IL-12. The presence of activated resident human MDC, prior to human allogeneic naïve T cell transplantation was associated with subsequent donor T cell activation, proliferation and effector cell generation in the BM and SP of recipient mice. However, the division kinetics of donor T cells appeared to be tissue-specific, with those in the BM undergoing six to eight divisions, whereas in the SP, the majority of donor T cells that entered a first division did not undergo subsequent division. Thus, human resident MDC in both BM and SP undergo rapid activation in response to systemic activator and contribute, according to their location, to distinctly different division kinetics of the locally recruited donor T cells. The findings in this humanized mouse model highlight the contribution of activated resident MDC in controlling local donor T cell responses and have direct application to investigations on the contribution of conditioning and DC activation to the pathogenesis of acute graft versus host disease following clinical allogeneic haematopoietic stem cell transplantation. Resident human dendritic cells (DC) in vascularized lymphoid organs such as bone marrow (BM) and spleen (SP) may contribute significant T cell responses to the overall systemic immune responses. To address this possibility in vivo, we developed humanized (hu)NOD/SCID mice, which contain human resident DC in the BM and SP derived from engrafted cord blood CD34+ cells. When huNOD/SCID mice were injected with polyinosinic:polycytidylic acid [poly(I:C)], activation of the resident human myeloid (M)DC occurred concurrently, in the BM and SP, within 2–8 h of injection. Poly(I:C) activated human MDC in the BM and SP increased the proportions of CD86+MDC and their production of IL-6, IL-10 and IL-12. The presence of activated resident human MDC, prior to human allogeneic naïve T cell transplantation was associated with subsequent donor T cell activation, proliferation and effector cell generation in the BM and SP of recipient mice. However, the division kinetics of donor T cells appeared to be tissue-specific, with those in the BM undergoing six to eight divisions, whereas in the SP, the majority of donor T cells that entered a first division did not undergo subsequent division. Thus, human resident MDC in both BM and SP undergo rapid activation in response to systemic activator and contribute, according to their location, to distinctly different division kinetics of the locally recruited donor T cells. The findings in this humanized mouse model highlight the contribution of activated resident MDC in controlling local donor T cell responses and have direct application to investigations on the contribution of conditioning and DC activation to the pathogenesis of acute graft versus host disease following clinical allogeneic haematopoietic stem cell transplantation.