Allogeneic HCT is very effective in curing patients with hematologic diseases. Outcomes are, however, significantly reduced by GvHD. One of the key factors in the initiation and perpetuation of GvHD is tissue damage, for example of the intestines. ILC are key regulators of tissue integrity and repair. We have demonstrated that ILC reconstitution after transplantation is often delayed, which poses patients at risk to develop GvHD. In this project we confirmed this observation in a second, independent cohort of patients. We demonstrated that the capacity of adult HSPC to develop into mature ILC is much less than that of fetal or umbilical cord blood HSPC. ILC reconstitution after allogeneic HCT is probably to a large extend dependent on expansion of mature ILC present in the graft, similar as T and B cell reconstitution. Indeed, we demonstrated that adult HCT grafts do contain mature ILC. One of the key findings of the project was that patients who received a transplant with higher than median proportions of ILC showed better ILC recovery and had a significantly reduced risk to develop GvHD. This further strengthened our hypothesis that adoptive transfer of ILC shortly after allogeneic HCT may be a way to improve ILC reconstitution, to better restoration of tissue damage and to prevent GvHD. We developed a protocol to culture ILC from HPC in a clinical grade setting (stroma-free, animal component free) and successfully generated functional ILC3 in quantities that are probably sufficient for adoptive transfer in allogeneic HCT recipients.
Taken together, our data suggest that ILC reconstitution for a large part depends on mature ILC present in the HCT graft which is associated with the risk to develop GvHD. The better understanding of ILC reconstitution and the successful development of a protocol to generate ILC from HSPC are critical steps that bring us much closer to our ultimate goal to investigate ex vivo generated ILC as adoptive therapy to prevent GvHD in the clinic.