In utero allotransplantation of retrovirally transduced fetal hepatocytes in primates: Feasibility and short-term follow-up

Objective: Because intrauterine transplantation of fetal hepatocytes could become an effective approach for treating severe genetic disorders of the liver, the objective of this study was to demonstrate the feasibility of in utero allotransplantation of fetal hepatocytes in a nonhuman primate model using direct intraparenchymal administration of donor cells. Methods: Fetal primary hepatocytes were isolated from 3 fetal primates (Macaca mulatta) at 89–120 days of gestation, and cryopreserved. When a recipient was available, the cells were thawed and transduced by a β-galactosidase-expressing retrovirus (3 cases) or labelled with a fluorescent dye (4 cases). Hepatocytes were infused directly into the fetal liver under surgical visual control. Engraftment was assessed by surgical liver biopsies taken 8–60 days following transplantation. Results: Six recipients survived until liver biopsy, and 1 died during the surgical procedure. There was no evidence of engraftment in the 3 fetuses that received genetically marked hepatocytes. All 3 monkeys who received 20–25 × 10⁶ hepatocytes from an 89-day-old donor labelled with fluorescent dye had positive liver biopsies 8–11 days following intrauterine transplantation. Conclusions: In utero allotransplantation of fetal hepatocytes is feasible in the nonhuman primate, and direct intraparenchymal administration enables short-term detection of persisting donor hepatocytes.

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“…Intrahepatic injection also has the advantage of allowing administration of a greater number of cells [12]. Under our conditions, at least 3 !…”

Section: Discussionmentioning

confidence: 90%

In utero Allotransplantation of Fetal Hepatocytes in Primates

et al. 2003

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“…In the absence of immunosuppression, only microchimerism has been achieved in human fetal recipients or nonhuman primate models of IUHCT. [1][2][3][4][5][6] These levels are too low for the correction of most diseases and have not been demonstrated to predict tolerance. The reasons for this failure are unclear and reflect a limited understanding of the engraftment barriers involved in clinical IUHCT.…”

Section: Introductionmentioning

confidence: 99%

Early chimerism threshold predicts sustained engraftment and NK-cell tolerance in prenatal allogeneic chimeras

Durkin

Jones

Rajesh

et al. 2008

Blood

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The failure of engraftment in human cases of in utero hematopoietic cell transplantation (IUHCT) in which no immunodeficiency exists suggests the presence of an unrecognized fetal immune barrier. A similar barrier in murine IUHCT appears to be dependent on the chimerism level and is poorly explained by a lack of T-cell tolerance induction. Therefore, we studied the effect of the chimerism level on engraftment and host natural killer (NK)-cell education in a murine model of IUHCT. The dose of transplanted cells was found to exhibit a strong correlation with both the engraftment rate and chimerism level. More specifically, a threshold level of initial chimerism (> 1.8%) was identified that predicted durable engraftment for allogeneic IUHCT, whereas low initial chimerism (< 1.8%) predicted a loss of engraftment. NK cells taken from chimeras above the "chimerism threshold" dis-

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“…One possible approach to overcome the immunological complications associated with organ transplantation might be to transplant cells in utero before the development of immune competence (3). Cells introduced prior to the development of immunologic 'self ' will be incorporated into the developing fetus and should not elicit an immunologic response after the maturation of the immune system.…”

Section: Introductionmentioning

confidence: 99%

In utero as a potential location for cell transplantation

Suckow

Rosen

2007

Journal of Organ Dysfunction

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A variety of diseases, including some which affect the hemostatic and blood coagulation systems, result from dysfunction of specific cell types. Attempts to ameliorate such diseases by implantation of healthy donor cells typically fail due to immune rejection of the donor cells. One method to possibly overcome this limitation is to administer donor cells prior to immune competence, thus inducing immune tolerance to the donated cells. To accomplish this, donor cells must be administered in utero, relatively early in the developmental process. We describe herein studies in which engraftments of fetal hepatocytes and a hepatoblast line were successfully accomplished by in utero administration of cells in mice. This approach reversed the clinical outcome of Factor X (FX) deficiency, increasing the survival time of FX null mice. Further, engraftment of donor cells was observed in the liver, as well as the spleen, brain, interstitium of the gonad, and lung. These results demonstrate the potential for application of in utero administration of fetal or blast cells for correction of disease related to specific cell or tissue dysfunction. The potential for ectopic engraftment suggests that this approach requires further refinement.

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In utero allotransplantation of retrovirally transduced fetal hepatocytes in primates: Feasibility and short-term follow-up

Cited by 4 publications

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In utero Allotransplantation of Fetal Hepatocytes in Primates

In utero Allotransplantation of Fetal Hepatocytes in Primates

Early chimerism threshold predicts sustained engraftment and NK-cell tolerance in prenatal allogeneic chimeras

In utero as a potential location for cell transplantation

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