Microchimerism as AlloImmunity

Fred Hutchinson Cancer Research Center, Seattle WA

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Abstract

DESCRIPTION (provided by applicant): MICROCHIMERISM AS ALLO-IMMUNITY Umbilical cord blood (CB) has become an accepted source of hematopoietic stem cells for allogeneic transplantation in children and adults. In addition to ready availability, advantages of CB include better tolerance for donor-recipient HLA-mismatches and reduced incidence/severity of chronic graft-versus-host disease. Moreover, a significantly decreased risk of relapse in patients undergoing CB transplant (CBT) for hematologic malignancy was recently reported. CB is a resource that has the potential to generate insight into maternal-fetal immunology in humans and within the context of CBT presents a powerful opportunity for translational insight and benefit. CB derives from the fetal circulation. However, some maternal cells are known to traffic to the fetus during pregnancy, referred to as maternal microchimerism (MMc). The significantly reduced relapse rate of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) after CBT strongly implicated CB MMc because benefit was observed specifically when HLA alleles of the fetus (CB), that the CB mother did not have (paternally-inherited) were shared with the CBT recipient. MMc, however, was not examined directly. In previous years we have studied pregnancy immunology and autoimmune disease. As a result we and others have begun to elucidate biological consequences of microchimerism (Mc) originating from maternal-fetal exchange. Substantial evidence has now been garnered for Mc effects on human health, both detrimental and beneficial depending on a number of factors, especially HLA alleles. The potential to impart anti-cancer benefit brings a new dimension to elucidating consequences of maternal-fetal exchange and the competing renewal will focus on this compelling subject. Our hypothesis is that MMc is at least in part responsible for the reduced relapse rate of AML and ALL after CBT. Having developed the necessary techniques and acquired broad-based expertise in Mc we are uniquely positioned to directly address this novel investigative horizon, with direct translational applications to human health and immediate implications for patients undergoing allogeneic transplantation. The first Aim will establish essential information regarding the prevalence, quantities and phenotypes of MMc in CB. The second Aim will investigate CB MMc in vivo in AML and ALL patients undergoing CBT in peripheral blood and bone marrow pre and post-transplant. Results will be evaluated for correlation with patient outcome, especially relapse. CB could potentially contain other sources of Mc, for example from prior births of the mother, and the third Aim will test for any alternative CB Mc sources. The fourth Aim will examine AML and ALL patients who have not undergone transplantation to determine the frequency of patient-mother shared HLA alleles; MMc will also be assayed at diagnosis and after achieving first remission. CB MMc functionality and HLA target specificity will be evaluated in the fifth Aim. Overall these studies examine a new horizon in potential maternal-fetal benefit as hematologic malignancy prevention and exploit the unique opportunity for insight into natural and iatrogenic chimerism afforded by CBT.