This study will explore whether innate immune dendritic cells (DCs) in the skin of patients undergoing bone marrow transplantation for leukemia or lymphoma are responsible for initiating not only positive cancer-fighting actions, but also negative “graft-versus-host disease” (GVHD). If so, the findings may lead to ways to minimize their negative role by changing the balance between donor and host DCs in patients. Bone marrow or blood stem cell transplants for patients with the blood cancers leukemia or lymphoma, provide a new source of donor immune cells to fight and potentially cure these cancers. The transplant, however, often precipitates an attack by the transplanted tissue (the graft) on the patients' (host) tissues. This is usually manifested by severe and sometimes deadly inflammation in the skin or intestine. Physicians currently try to suppress these excessive immune responses caused by donor immune cells by giving medications that suppress donor immune cells after transplantation. Although this reduces the risk of GVHD, it also increases the likelihood of infection.
The researchers have found in mice studies, however, that even the most stringent pre-transplant efforts to kill the patients' immune cells fail to eradicate the host's immune DCs in the skin. Importantly, they also found that the hosts' DCs initiate and regulate both the anti-cancer attacks and the GVHD attacks. Moreover, larger host DC levels are associated with greater severity of GVHD.
Based on these surprising animal model findings, the researchers now seek to determine whether the same situation occurs in patients. They also want to determine whether the time it takes to replace the patient's own skin DCs with those originating from the grafted cells might depend on the intensity of the chemotherapy given in preparation for the transplant.
The investigators at the Fred Hutchinson Cancer Research Center (FHCRC) will collect skin, blood, and bone marrow samples from approximately 100 patients with leukemia or lymphoma prior to, and for several months after transplantation. They will then measure the balance between donor and host-derived DCs in blood and marrow, and assess patients' clinical outcomes data (i.e. severity of GVHD). The Mount Sinai investigators will determine, from the skin samples, whether the patients' own DCs persist and renew in the skin, and whether patients with greater numbers of donor DCs, relative to host DCs have better outcomes. If so, the investigators will try to identify specific “chemokines” (molecules that guide the actions of cells) present in the patients' skin. Such chemokines might be capable of shifting the balance of power from the hosts' DCs to the donor DCs, improving cancer outcomes while reducing the severity of GVHD.
Significance: If this research demonstrates that immune DCs in patients with leukemia or lymphoma are responsible for initiating and regulating immune attacks against both the cancer and normal host tissues by transplanted immune cells, the findings could lead to new approaches aimed at changing the balance between donor and host DCs to decrease GVHD while continuing to marshal immune attacks against the cancer.