Host bone marrow-derived IL-12 enhances donor T cell engraftment in a mouse model of bone marrow transplantation

• Type of Material: Article
• Authors: Katarzyna A Darlak, Emory University; Ying Wang, Emory University; Jian-Ming Li, Emory University; Wayne A C Harris, Emory University; Cynthia R Giver, Emory University; Chunzi Huang, Emory University; Edmund K Waller, Emory University
• Language: English
• Date: 2014
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2014 Darlak et al.; licensee BioMed Central Ltd.
• License: Creative Commons Attribution 2.0 Generic
• Final Published Version (URL): http://www.jhoonline.org/content/7/1/16
• Title of Journal or Parent Work: Journal of Hematology & Oncology
• ISSN: 1756-8722
• Volume: 7
• Issue: 16
• Keywords: Interleukin-12; Engraftment; Transplantation; T-cells
• Research Categories: Health Sciences, Oncology

Abstract

Background: Donor cell engraftment is critical for the success of allogeneic bone marrow transplants. Graft failure is a result of donor cells either failing to engraft initially or being eliminated at later time points. Donor cell engraftment is facilitated by donor T cells, which eliminate residual host hemato-lymphoid effector cells such as NK cells and T cells. Methods: We aimed to explore the role of host hematopoietic cell derived IL-12 on donor cell engraftment in a murine model of BMT. We established radiation chimeras by transplanting C57BL6/J (B6) mice with BM from either congenic B6 mice or IL-12p40 KO mice. These WT → WT or IL-12 KO → WT chimeras then underwent a secondary transplant with allogeneic (FVB) BM. Survival, engraftment, donor T cell expansion, cytokine production by donor T cells, as well as expression of stimulatory markers on donor T cells was analyzed. Results: Mice whose residual host hematopoietic cells were capable of producing IL-12 had modestly higher survival, higher donor T cell engraftment, and significantly higher donor erythroid engraftment. We have also found that an increased number of donor T cells in IL-12 KO → WT chimeras have a regulatory phenotype, expressing FoxP3, producing lower levels of TNF-α, higher levels of IL-10, and expressing higher levels of ICOS as well as PD-1 on CD4+ T cells. Conclusions: To our knowledge, this is the first report of a beneficial role of IL-12 production by host cells in the context of bone marrow engraftment in a murine model of BMT. These findings support the clinical use of exogenous IL-12 for use in settings where graft failure is of concern.