Improving engraftment and immune reconstitution in umbilical cord blood transplantation

Abstract

Umbilical cord blood (UCB) is an important source of hematopoietic stem cells (HSC) for allogeneic transplantation when HLA-matched sibling and unrelated donors (MUD) are unavailable. Although the overall survival results for UCB transplantation are comparable to the results with MUD, UCB transplants are associated with slow engraftment, delayed immune reconstitution, and increased opportunistic infections. While this may be a consequence of the lower cell dose in UCB grafts, it also reflects the relative immaturity of cord blood. Furthermore, limited cell numbers and the non-availability of donor lymphocyte infusions currently prevent the use of post-transplant cellular immunotherapy to boost donor-derived immunity to treat infections, mixed chimerism, and disease relapse. To further develop UCB transplantation, many strategies to enhance engraftment and immune reconstitution are currently under investigation. This review summarizes our current understanding of engraftment and immune recovery following UCB transplantation and why this differs from allogeneic transplants using other sources of HSC. It also provides a comprehensive overview of promising techniques being used to improve myeloid and lymphoid recovery, including expansion, homing, and delivery of UCB HSC; combined use of UCB with third-party donors; isolation and expansion of natural killer cells, pathogen-specific T cells, and regulatory T cells; methods to protect and/or improve thymopoiesis. As many of these strategies are now in clinical trials, it is anticipated that UCB transplantation will continue to advance, further expanding our understanding of UCB biology and HSC transplantation.

Keywords: engraftment; hematopoietic stem cells; immune reconstitution; transplantation; umbilical cord blood.

Figure 1

Kinetics of immune reconstitution and transplant-related complications in children following UCB transplantation. The post-transplantation period can be divided in three phases. The pre-engraftment period (Phase I, days 0–30) is characterized by general immunosuppression (i.e., depletion of lymphocytes in the recipient by ATG), neutropenia, low platelet counts, and high susceptibility to fungal infections. Host residual APCs progressively disappear during Phase I. Massive proliferation leads NK cells to reach normal levels within 1 month post-transplantation. They may represent 80% of the recipient’s PBLs during the post-engraftment period (Phase II, days 31–100). During Phase II, patients experience high susceptibility to bacterial infections, viral infections (i.e., CMV), and acute GvHD. Some UCB T cells are believed to persist in the recipient and proliferate through HE. This period culminates with the de novo generation of T cells through thymopoiesis and the end of the 100-day high-risk window. The late phase (Phase III) is characterized by a higher incidence of VZV infection/reactivation and a progressive reconstitution of B cell and T-cell subsets, which can reach normal levels at 6–9 months post-transplant [figure and legend originally published by Merindol and colleagues (226); used with the permission of H. Soudeyns and the Journal of Leukocyte Biology (Copyright FASEB Office of Publications, Bethesda, MD, USA)].