Characterization of regulatory dendritic cells that mitigate acute graft-versus-host disease in older mice following allogeneic bone marrow transplantation

• Published in: PloS one 2013-09, Vol.8 (9), p.e75158-e75158
• Main Authors: Scroggins, Sabrina M, Olivier, Alicia K, Meyerholz, David K, Schlueter, Annette J
• Format: Article
• Language: English
• Subjects: Acute Disease; Adoptive Transfer; Aging - immunology; Aging - physiology; Animals; Antigens; B7-H1 Antigen - metabolism; Bone marrow; Bone marrow transplantation; Bone Marrow Transplantation - adverse effects; Cell culture; Cell survival; Comparative analysis; Cytokines; Cytokines - biosynthesis; Dendritic cells; Dendritic Cells - immunology; Disease; Fatalities; Gene Expression Regulation - immunology; Graft vs Host Disease - etiology; Graft vs Host Disease - immunology; Graft vs Host Disease - metabolism; Graft vs Host Disease - physiopathology; Graft-versus-host reaction; Granulocyte-macrophage colony-stimulating factor; Health aspects; Hematopoietic stem cell transplantation; Hematopoietic stem cells; Histocompatibility antigen HLA; HLA antigens; Humans; Immune Tolerance; Immunoglobulins; Immunological tolerance; Immunology; Interdisciplinary aspects; Interleukin 10; Laboratory animals; Leukocytes; Ligands; Lymphocytes; Medicine; Mice; Morbidity; Mortality; Pathology; PD-L1 protein; Pharmacology; Phenotype; Prophylaxis; Receptors, Immunologic - metabolism; Rodents; Stem cell transplantation; Stem cells; Studies; Survival; Syngeneic grafts; T cell receptors; Time Factors; Transforming growth factors; Transplantation; Transplantation, Homologous - adverse effects; Transplants & implants
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0075158

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.