Abstract
Background:Graft‐versus‐host disease (GvHD) is a common and life threatening complication of allogeneic stem cell transplantations (ASCT), and is thought to be initiated by chemotherapy‐induced tissue damage. Innate lymphoid cells are involved in tissue remodeling and repair and may therefore have a protective role in the development of GvHD. Indeed, in a previous study we observed that relatively high frequencies of activated ILC3 s before and/or after ASCT were associated with a lower risk to develop GvHD. While rapid reconstitution of ILCs thus seems favorable, ILCs in fact recover slowly and do not reach normal levels within 6 months post‐ASCT.Aims:By investigating the composition of stem cell grafts and the ILC‐development potential of graft‐derived multipotent hematopoietic progenitor cells (HPCs), we here aim to gain more insight into how ILCs reconstitute from stem cell grafts.Methods:Peripheral blood‐mobilized stem cell grafts of healthy adult donors were thawed and ILCs were phenotyped by flow cytometry. Lineage− CD34+ CD45RA+ HPCs were FACS‐sorted and cultured for a maximum of 4 weeks on JAG1‐expressing OP9 stromal cells in the presence of IL‐2, IL‐7, stem cell factor and Flt3‐ligand. This method was previously shown to support ILC development.Results:We detected mature ILC1 s, ILC2 s and ILC3 s in all grafts, and the median frequency of total CD127+ ILCs was 0.26% of the lymphocytes. The distribution of the ILC subsets differed substantially between stem cell grafts. HPCs isolated from human fetal liver successfully developed into ILCs within 4 weeks culture, however, HPCs derived from adult stem cell grafts did not have the capacity to develop into ILCs. We are currently investigating whether the age and the source of the isolated HPCs matters by testing the ILC developmental potential of cord‐blood and bone‐marrow derived HPCs. At the same time we are extending our graft and post‐ASCT analyses to be able to correlate our in vitro findings to in vivo ILC reconstitution.Summary/Conclusion:While mature ILCs present in stem cell grafts may be a good source for reconstituting ILCs, the ILC‐developmental potency of (adult) graft‐derived HPCs seems to be poor, possibly reflecting a decline in the potency of stem cells to develop into ILCs with increasing age. These results offer an explanation for the slow reconstitution of ILCs after ASCT.image
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