In utero hematopoietic cell transplantation: induction of donor specific immune tolerance and postnatal transplants.

William H Peranteau

doi:10.3389/fphar.2014.00251

Abstract

In utero hematopoietic cell transplantation (IUHCT) is a non-myeloablative non-immunosuppressive transplant approach that allows for donor cell engraftment across immunologic barriers. Successful engraftment is associated with donor-specific tolerance. IUHCT has the potential to treat a large number of congenital hematologic, immunologic, and genetic diseases either by achieving high enough engraftment levels following a single IUHCT or by inducing donor specific tolerance to allow for non-toxic same-donor postnatal transplants. This review evaluates donor specific tolerance induction achieved by IUHCT. Specifically it addresses the need to achieve threshold levels of donor cell engraftment following IUHCT to consistently obtain immunologic tolerance. The mechanisms of tolerance induction including partial deletion of donor reactive host T cells by direct and indirect antigen presentation and the role of regulatory T cells in maintaining tolerance are reviewed. Finally, this review highlights the promising clinical potential of in utero tolerance induction to provide a platform on which postnatal cellular and organ transplants can be performed without myeloablative or immunosuppressive conditioning.

Highlights

The fetal environment offers the unique opportunity to take advantage of the developing immune system to induce immunologic tolerance to foreign antigen
In utero hematopoietic cell transplantation (IUHCT) has been shown to be a non-myeloablative nonimmunosuppressive transplant approach that allows for engraftment across immunologic barriers and is associated with the induction of donor specific tolerance (Flake and Zanjani, 1999; Kim et al, 1999; Peranteau et al, 2002)
We focus on the progress that has been made in understanding and achieving immunologic tolerance following IUHCT and how this tolerance can be used as a platform for non-myeloablative non-immunosuppressive postnatal transplants to either achieve clinically acceptable levels of engraftment or allow for solid organ transplants

Summary

INTRODUCTION

The fetal environment offers the unique opportunity to take advantage of the developing immune system to induce immunologic tolerance to foreign antigen. Chimeric mice in which engraftment was successfully enhanced demonstrated reduced donor cell reactivity of recipient cells by MLR following IUHCT and prior to the postnatal transplant These studies highlight the potential to increase allogeneic donor cell engraftment to clinically relevant levels by a combination of tolerance induction by IUHCT and engraftment enhancement by a postnatal BMT using the same prenatal donor. They demonstrate the need for some conditioning regimen to provide a competitive advantage to the donor cell population to achieve the desired engraftment levels independent of preexisting immunologic tolerance. The 33% success rate of enhancing engraftment in dogs with initial chimerism levels

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Findings

CONCLUSION