Flt3-L Augments the Engraftment of Donor-Derived Bone Marrow Cells When Combined With Sublethal Irradiation and Costimulatory (CD28/B7 and CD40/CD40L) Blockade

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Abstract:

T-cell costimulatory blockade as a constituent for recipient conditioning prior to bone marrow transplantation has led to the development of less toxic protocols for the establishment of donor cell chimerism. We therefore hypothesized that the addition of the hematopoietic growth factor, Flt3-ligand (Flt3-L), to the perioperative inhibition of the CD28/B7 and CD40/CD40 ligand costimulatory pathways would enhance the engraftment of allogeneic bone marrow. Recipient BALB/c ByJ (H-2d, Mlsc, Vβ6+/Vβ8+ TCR) received a single sublethal dose of total body irradiation (300 rad) 6 h prior to transplantation IV with unfractionated donor CBA/J (H-2k, Mlsd, Vβ6-/Vβ8+ TCR) bone marrow cells. CTLA4-Ig and/or MR1 were administered at 500 μg IP on days 0, 2, 4, and 6 posttransplantation. Flt3-L was administered at 10 μg IP on days 0–6. Donor cell chimerism was determined on days 30–90 by flow cytometric analysis. Donor-specific tolerance was assessed by skin grafting. In vitro TCR cross-linking assays and flow cytometry were utilized to explore the deletion of donor-reactive T cells. Recipients receiving CTLA4-Ig and MR1 engrafted allogeneic bone marrow cells in the peripheral blood (3/6; 50%) with chimerism being detected at 2–31%. Addition of Flt3-L to this preconditioning regimen enhanced the incidence of engraftment of donor bone marrow cells (10/13; 3–70%). Long-term survival of donor but not third-party-specific skin grafts demonstrated that donor- specific tolerance had been achieved in the chimeric recipients. Deletion of the donor-reactive T cells within the chimeric recipients was also observed. The addition of hematopoietic growth factors and cytokines to the nonmyeloablative regimen of sublethal irradiation and T-cell costimulatory blockade provides a novel strategy for the establishment of donor cell chimerism and for the induction of stable and robust donor-specific tolerance. The deletion of donor-reactive T cells using this protocol suggests the reliability and feasibility of this protocol for clinical transplantation.

Keywords: Chimerism;; Costimulation; Key words: Flt3-ligand

Document Type: Research Article

DOI: http://dx.doi.org/10.0000/096020198389870

Affiliations: 1: *Section of Cellular Transplantation, Thomas E. Starzl Transplantation Institute, and the Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh PA 15261 2: †Section of Cellular Transplantation, Thomas E. Starzl Transplantation Institute, and the Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh PA 15261

Publication date: January 1, 2002

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  • Cell Transplantation publishes original, peer-reviewed research and review articles on the subject of cell transplantation and its application to human diseases. To ensure high-quality contributions from all areas of transplantation, separate section editors and editorial boards have been established. Articles deal with a wide range of topics including physiological, medical, preclinical, tissue engineering, and device-oriented aspects of transplantation of nervous system, endocrine, growth factor-secreting, bone marrow, epithelial, endothelial, and genetically engineered cells, among others. Basic clinical studies and immunological research papers are also featured. To provide complete coverage of this revolutionary field, Cell Transplantation will report on relevant technological advances, and ethical and regulatory considerations of cell transplants. Cell Transplantation is now an Open Access journal starting with volume 18 in 2009, and therefore there will be an inexpensive publication charge, which is dependent on the number of pages, in addition to the charge for color figures. This will allow work to be disseminated to a wider audience and also entitle the corresponding author to a free PDF, as well as prepublication of an unedited version of the manuscript.
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