Summary:To investigate whether we could create a radiation-free conditioning regimen to induce permanent mixed and multilineage chimerism and donor-specific tolerance, we treated recipient mice with anti-T-cell antibodies, varying and fractionated doses of Treosulfan and fully MHC disparate bone marrow cells. Treosulfan is mainly used in the treatment of ovarian cancer. It is a structural analog of busulfan, but it does not induce severe hepatotoxicity or veno-occlusive disease at or above the maximum tolerated dose, lacks significant nonhematological toxicity and has limited organ toxicity. We report here the successful induction of permanent mixed multilineage chimerism and donor-specific tolerance as was proven by skin transplantation and IFN-c ELISPOT. In conclusion, because of its lower nonhematological toxicity, compared with other myeloablative regimens (eg irradiation or busulfan administration), Treosulfan could be a better candidate for conditioning to induce donor-specific allograft tolerance.

Summary:Treosulfan is a water-soluble structural analog of busulfan, acting as a prodrug of alkylating epoxide species. It does not induce severe hepatotoxicity or veno-occlusive disease at or above the maximum tolerated dose, lacks significant nonhematological toxicity and has a limited organ toxicity. It is mainly indicated for the treatment of patients with ovarian cancer. In the present study, we report that permanent donor-specific tolerance and stable mixed multilineage chimerism can successfully be achieved across haploidentical MHC barriers when Treosulfan is administered in combination with anti-T-cell mAb and T-celldepleted donor bone marrow cells. Furthermore, we show that less T-cell suppression is required when Treosulfan is included in the conditioning regimen. In conclusion, Treosulfan is a well-tolerated myeloablative agent with a low toxicity, and is a promising candidate drug for conditioning prior to bone marrow transplantation.

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