In a new, multi-center study based on retrospective analyses of data collected by the National Marrow Donor Program (NMDP), the sample and data repository for unrelated bone marrow and stem cell transplants in the country, CHORI scientist Elizabeth Trachtenberg, PhD and her colleagues provide conclusive evidence that missing greater than or equal to 1 killer-immunoglobulin receptor (KIR) ligands, versus the presence of all ligands, significantly protects against relapse in early myeloid leukemia patients who undergo unrelated hematopoietic cell transplantation (HCT).
|"We show that missing KIR ligands has complex effects. You have to tease apart all the different aspects of disease type, years post-diagnosis and KIR and HLA genotypes in patients and donors. It is complicated and requires a very thorough analysis."
Killer-immunoglobulin receptors are cell surface receptors expressed on natural killer (NK) cells, which are part of the body's innate immune system. In order for NK cells to do their job, the NK receptor complexes, which include KIR, must signal to the cell to either elicit or inhibit an immune response.
"Inhibitory and stimulatory KIR, in combination with the inhibitory HLA class I KIR ligands, are what help the natural killer cell to either stop an immunologic response or elicit an immunologic response against a cell," Dr. Trachtenberg explains.
Previous papers out of Italy have shown that missing KIR ligands was beneficial in haploidentical HCT, which, unlike other transplantations, requires very severe T cell depletion. Many labs since then have been trying to replicate those results in smaller patient populations, and, until now, the results have been inconclusive.
Dr. Trachtenberg and her colleagues, however, utilizing the largest sample size to date - over 2,000 patients - found significant effects related to missing ligands in the recipient when the results were stratified by disease stage.
"If a patients' leukemia was identified and transplantation occurred within one year of diagnosis, then missing at least one KIR ligand gave strong protection against relapse," says Dr. Trachtenberg. "If however, patients had been diagnosed with leukemia for more than one year before transplantation, the KIR ligand mismatch predicted a greater risk of acute graft versus host disease in patients with chronic myeloid leukemia."
Graft versus host disease (GVHD) occurs as a result of alloreactivity. In HCT, alloreactivity is due either to a reaction of donor cells against recipient cells (GVHD), or to recipient cells against donor cells (host versus graft disease, or HVGD).
|"Alloreactivity of recipient against donor is horrible - it can lead to graft rejection and the patient can die. But a little alloreactivity can be a good thing in some cases - when the reaction is against the recipient's tumor cells. In recipients with leukemia, the cancer cells are the ones being killed. "
While to some extent the study confirms previously known KIR ligand mismatch data and echoes that how long a patient has had the disease is very important, it also provides significant evidence that supports the Italian study for the first time.
"What this study tells is that if we know an early myeloid leukemia patient has at least one KIR ligand mismatch with a potential donor, the odds are that this type will protect against relapse, presumably due to a good graft versus leukemia effect," says Dr. Trachtenberg.
And that, after all, is the long term goal: to utilize NK cell genetics to improve stem cell transplantation outcome.
The current study is only one step along the way to achieving those improved outcomes. Dr. Trachtenberg is now identifying all the KIR genotypes in many thousands of NMDP transplant pairs, and with their previous data on HLA genotypes in this population, she and her colleagues are conducting a series of in depth analyses within disease groups on both matched and mismatched patients to better understand the immunogenetics behind stem cell transplantation.
"It's really the seminal study on the role of NK on stem cell transplantation in the US, and by far the largest data set ever analyzed," says Dr. Trachtenberg.
Monday, May 16, 2011 11:33 PM