A primary assumption that guides current approaches to in utero hematopoietic cellular transplantation (IUHCT) is that the early-gestation fetus has an immature immune system that is incapable of rejecting a donor cell transplant. For this reason, transplanting the cells prior to the maturation of the adaptive immune system leads to recognition of the donor cells as """"""""self"""""""" rather than """"""""foreign"""""""". However, repeated failures in clinical cases of IUHCT that do not involve an immunodeficiency disease force a re-examination of this model of the fetal immune system. A survey of both clinical and laboratory reports of IUHCT reveal enhanced success when the immunodeficient host is also natural killer (NK) cell deficient. Preliminary studies in mice reveal that NK cells act as an early immune barrier to IUHCT. In order to establish NK cell tolerance and ensure successful engraftment, a minimum level of hematopoietic chimerism must be achieved prior to NK cell maturation. Below this """"""""chimerism threshold"""""""", the host NK cells predictably reject the graft. In this way, the chimerism threshold offers a logical explanation for past failures of clinical IUHCT. Fortunately, the identification of the chimerism threshold greatly facilitates study of the mechanisms linking the chimerism level to the emergence of NK cell tolerance following IUHCT. This concept drives the central hypothesis that the chimerism threshold provides the minimum amount of donor ligand recognition necessary for the selection of """"""""friendly"""""""" NK cell phenotypes and repression of """"""""hostile"""""""" ones. To challenge this hypothesis, the experiment in this proposal will determine the impact of the chimerism threshold on alloreactive NK cell: 1) selection;2) cytotoxicity;and 3) memory. The expected outcome for the experiments in this proposal is the delineation of the mechanisms linking the chimerism level to the emergence of NK cell tolerance following IUHCT. This knowledge will have a dramatic impact on the field of IUHCT as it establishes a new paradigm for the early fetal immune response to allotransplantation. This directly affects the development of strategies to enhance the success of IUHCT such as donor cell dose, donor selection, booster transplants and therapeutic targeting of the host immune response. On a broader scale, these findings will guide further mechanistic study of fetal NK cell education.
The current proposal aims to provide new information in the field of in utero hematopoietic cellular transplantation. The results of these experiments will guide future clinical use of in utero hematopoietic cellular transplantation for the treatment of hereditary disease in infants and children.
|Strong, Beverly S I; Newkold, Tess J; Lee, Amanda E et al. (2016) Extrinsic allospecific signals of hematopoietic origin dictate iNKT cell lineage-fate decisions during development. Sci Rep 6:28837|
|Kinder, Jeremy M; Jiang, Tony T; Ertelt, James M et al. (2015) Cross-Generational Reproductive Fitness Enforced by Microchimeric Maternal Cells. Cell 162:505-15|
|Alhajjat, Amir M; Strong, Beverly S; Lee, Amanda E et al. (2015) Prenatal Allospecific NK Cell Tolerance Hinges on Instructive Allorecognition through the Activating Receptor during Development. J Immunol 195:1506-16|
|Kinder, Jeremy M; Jiang, Tony T; Ertelt, James M et al. (2015) Tolerance to noninherited maternal antigens, reproductive microchimerism and regulatory T cell memory: 60 years after 'Evidence for actively acquired tolerance to Rh antigens'. Chimerism 6:8-20|
|Alhajjat, Amir M; Lee, Amanda E; Strong, Beverly S et al. (2015) NK cell tolerance as the final endorsement of prenatal tolerance after in utero hematopoietic cellular transplantation. Front Pharmacol 6:51|
|Strong, Beverly S I; Ryken, Katherine O; Lee, Amanda E et al. (2015) Prenatal Allogeneic Tolerance in Mice Remains Stable Despite Potent Viral Immune Activation. J Immunol 195:4001-9|
|Balaji, Swathi; Moles, Chad M; Bhattacharya, Sukanta S et al. (2014) Comparison of interleukin 10 homologs on dermal wound healing using a novel human skin ex vivo organ culture model. J Surg Res 190:358-66|
|Elahi, Shokrollah; Ertelt, James M; Kinder, Jeremy M et al. (2013) Immunosuppressive CD71+ erythroid cells compromise neonatal host defence against infection. Nature 504:158-62|
|Alhajjat, Amir M; Strong, Beverly S; Durkin, Emily T et al. (2013) Trogocytosis as a mechanistic link between chimerism and prenatal tolerance. Chimerism 4:126-31|
|King, Alice; Balaji, Swathi; Marsh, Emily et al. (2013) Interleukin-10 regulates the fetal hyaluronan-rich extracellular matrix via a STAT3-dependent mechanism. J Surg Res 184:671-7|