We have established a model of in utero hematopoietic stem cell (HSC) transplantation into fetal rhesus monkeys. Using T cell depleted bone marrow from sires we have shown that the engraftment rate in fetal offspring is ~75%. Unfortunately, the percent donor cells is low, (<0.1%) And would be insufficient to correct most inherited diseases that could be treated with in utero transplantation. We are interested in determining whether this low level of engraftment can tolerize the recipient so that boosts of donor HSC could be given to increase their presence in the recipient. In a mouse model we found that <0.01% Donor cells are sufficient to induce tolerance to mismatched HSC. This past year we measured the in vitro reactivity of recipient lymphocytes to donor stimulator cells in a mixed lymphocyte culture (MLC). The majority of engrafted animals had a significantly reduced response to donor cells versus third party stimulators consistent with but not conclusive of tolerance. We also began a study of renal transplantation to measure in vivo tolerance induction in these animals. In two separate control experiments (unrelated donor kidney to recipient and sire kidney to female offspring) the kidneys were acutely rejected within 5-7 days. However, in a sire to daughter transplant in which the recipient was engrafted in utero with parental HSC, the kidney was only mildly rejected after 4-5 weeks post transplant, indicating a state of tolerance. For the coming year we will measure T cell cytotoxicity in engrafted animals and perform a second kidney transplant. These studies should help us understand the requirements for tolerance induction and provide a basis for future attempts at increasing donor cell numbers post in utero hsc transplantation.
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