Abstract
678 Hematopoietic stem cell (HSC) chimerism induces donor-specific tolerance for solid organ and cellular transplants. HSC chimerism can be achieved through bone marrow transplantation (BMT). However, the application of this therapy is limited by the morbidity and mortality associated with lethal conditioning. The development of partial conditioning strategies will allow the widespread application of BMT for the induction of tolerance. The goal of this study was to identify a partial conditioning strategy to achieve chimerism induction in nonobese diabetic (NOD) mice with monoclonal antibodies (mAb). The NOD mouse demonstrates a relative resistance to engraftment compared to disease resistant-strains. While 600 cGy TBI is sufficient conditioning to achieve HSC chimerism in normal mice, ≥ 750 cGy TBI is required to condition NOD recipients. Methods: NOD mice were conditioned with anti-CD8, anti-CD4, anti-THY1.2, anti-DX5 (NK) mAb, or saline in vivo. All mAb were titrated for maximal effect prior to use with BMT. CD8, CD4, THY1.2 mAb were depleting antibodies. Since NOD mice do not express NK1.1, a pan natural killer (NK) marker, DX5 was employed. DX5 is a coating antibody. Antibodies were administered as a single intraperitoneal injection on Day −2. Animals were irradiated with 700 cGy TBI and reconstituted with 30 × 106 unmodified B10.BR bone marrow cells on Day 0. The level of chimerism was evaluated by flow cytometry at 28 days. Bone marrow controls were irradiated at 750 cGy. Results: Depletion of host CD8+ cells results in engraftment at a lower dose of TBI than the other mAb. Eliminating host NK cells, Thy 1.2+ cells, or CD4+ T cells does not enhance engraftment. These results suggest that a specific CD8+ T cell population contributes to the resistance to engraftment observed in NOD mice. Partial conditioning strategies such as these will allow BMT to be used for the induction of tolerance to islet and pancreas transplants in patients with diabetes. (Table)Table
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