Abstract
Despite improvements in human leukocyte antigen matching and pharmacologic prophylaxis, acute graft-versus-host disease (GVHD) is often a fatal complication following hematopoietic stem cell transplant (HSCT). Older HSCT recipients experience significantly increased morbidity and mortality compared to young recipients. Prophylaxis with syngeneic regulatory dendritic cells (DCreg) in young bone marrow transplanted (BMT) mice has been shown to decrease GVHD-associated mortality. To evaluate this approach in older BMT recipients, young (3–4 months) and older (14–18 months) DCreg were generated using GM-CSF, IL-10, and TGFβ. Analysis of young versus older DCreg following culture revealed no differences in phenotype. The efficacy of DCreg treatment in older BMT mice was evaluated in a BALB/c→C57Bl/6 model of GVHD; on day 2 post-BMT (d +2), mice received syngeneic, age-matched DCreg. Although older DCreg-treated BMT mice showed decreased morbidity and mortality compared to untreated BMT mice (all of which died), there was a small but significant decrease in the survival of older DCreg-treated BMT mice (75% survival) compared to young DCreg-treated BMT mice (90% survival). To investigate differences between dendritic cells (DC) in young and older DCreg-treated BMT mice that may play a role in DCreg function in vivo, DC phenotypes were assessed following DCreg adoptive transfer. Transferred DCreg identified in older DCreg-treated BMT mice at d +3 showed significantly lower expression of PD-L1 and PIR B compared to DCreg from young DCreg-treated BMT mice. In addition, donor DC identified in d +21 DCreg-treated BMT mice displayed increased inhibitory molecule and decreased co-stimulatory molecule expression compared to d +3, suggesting induction of a regulatory phenotype on the donor DC. In conclusion, these data indicate DCreg treatment is effective in the modulation of GVHD in older BMT recipients and provide evidence for inhibitory pathways that DCreg and donor DC may utilize to induce and maintain tolerance to GVHD.
Highlights
Allogeneic hematopoietic stem cell transplant (HSCT) remains the only curative treatment modality for many hematopoietic disorders and malignancies
The results demonstrate that DCreg treatment is effective in alleviating graft-versushost disease (GVHD) in older bone marrow transplanted (BMT) mice; these mice still experience mildly increased severity of GVHD compared to young DCregtreated BMT mice, and slightly higher mortality
DCreg treatment is effective in preventing GVHD mortality while maintaining graft-versus tumor (GVT) responses in young BMT mice [22,30]
Summary
Allogeneic hematopoietic stem cell transplant (HSCT) remains the only curative treatment modality for many hematopoietic disorders and malignancies. Acute graft-versushost disease (GVHD) is an immune mediated disease whereby donor T cells are primed against recipient histocompatibility antigens resulting in expansion and differentiation of alloreactive T cells, the release of pro-inflammatory cytokines, and the recruitment of additional effector cell populations. This leads to damage of many tissues, most commonly skin, gastrointestinal tract, and liver. GVHD occurs in 20-40% of young and up to 70% of older allogeneic transplant recipients, and is fatal in approximately 30% of those patients [1,2] In both humans and mice, older recipient age is an independent risk factor for increased incidence and severity of GVHD [3,4,5,6,7]. The number of older individuals undergoing HSCT is steadily growing [8], increasing the need for evaluation of therapies for GVHD in older transplant recipients
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
