Project 457612

Hematopoietic Stem Cell Transplantation (HSCT), the infusion of a donors immune system into a recipient, is an important immune-based therapy for patients with high-risk and recurring blood cancers. However, HSCT is attributed to an increased risk of health complications, the most severe being chronic graft-versus-host-disease (cGvHD), in which foreign donor immune cells attack the recipient's tissues. cGvHD occurs in 25% of pediatric and 60% of adult HSCT survivors. It is known to cause long-term, and often irreversible organ damage and has a 10-25% mortality rate. Our team has identified an increased number of certain immune system cells, known as regulatory Natural Killer cells (NKreg)), in transplant patients who failed to develop cGvHD. Further, other researchers have found that the transfer of expanded NK cells potentially decreases blood cancer relapse with no increase in GvHD. Thus, we hypothesize that the transfer of expanded NKreg cells after transplant represents a significant strategy to decrease cGvHD without increasing blood cancer relapse. To address my hypothesis, I will pursue three major aims. First, I will determine the function of NKreg cells associated with successful and failed suppression of cGvHD. Second, I will maximize the expansion of functional NKreg cells appropriate for human clinical trial. Third, I will evaluate the effect of expanded NKreg cells on cGvHD immune populations in both culture and mouse models. In completion of my proposed research, I expect to understand the characteristics of human NKreg cells that associate with no development of cGvHD and establish a method for maximized expansion which is appropriate for clinical trial. These approaches will provide a biological understanding for developing strategies to prepare NKreg cells as a therapy for cGvHD, contributing to the goal of improving the safety and effectiveness of transplant therapy, and increasing the number of quality life years among blood cancer patients.