Tolerance induction by hematopoietic cell transplantation: Combined use of stem cells and progenitor cells

Abstract

Donor-specific hematopoietic cell transplantation (HCT) in the form of bone marrow transplantation has been long recognized experimentally as a means of inducing tolerance for subsequently transplanted organs. Clinical translation has been limited, however, due to HCT-associated complications. Unrelated myeloid progenitors (MP) can be administered simultaneously with hematopoietic stem cells (HSC). This reduces susceptibility to bacterial and fungal infections in neutropenic mice in laboratory studies. It is not known, however, if the addition of third-party MP interferes with tolerance induction. BALB/c (H-2d) mice were irradiated and reconstituted with 4,000 AKR (H-2k) HSC or with 4,000 AKR HSC combined with 10(5) FVB (H-2q) MP. After 2 months, the mice received skin grafts from these three strains or from an unrelated strain, C57BL/6 (H-2b). Composition and origin of hematopoietic cells was analyzed using flow cytometry. Mice in both groups accepted all the host-type- and HSC-donor-matched grafts, and rejected unrelated grafts. Surprisingly, recipients of both HSC and MP also accepted MP-matched skin grafts (14 of 14), even with very low levels of MP-derived cells in circulation. The analysis revealed that, although most hematopoietic cells were derived from HSC donors, regulatory T cells were derived from both donors as well as the recipient. The addition of third-party MP cells does not interfere with HCT-induced tolerance induction and, surprisingly, induces MP-specific tolerance.