John Tisdale

John Tisdale received his M.D. degree from the Medical University of South Carolina in Charleston in 1990. He completed an internal medicine and chief residency at Vanderbilt University Medical Center in Nashville and then trained in hematology in the Hematology Branch, National Heart, Lung and Blood Institute (NHLBI), where he served as a postdoctoral fellow. He joined the Molecular and Clinical Hematology Branch of NHLBI in 1998 and is currently a senior investigator in that lab.  His group focuses on bone marrow stem cell-based approaches to treat sickle cell disease.  The work focuses on the development of methods for transplantation of either normal donor-derived or genetically modified patient-derived bone marrow stem cells.

Abstract: Non-myeloablative allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with severe sickle cell disease (SCD)

Allo-HSCT remains the only curative approach for patients with SCD, yet a high risk of procedural toxicities and graft-versus-host disease (GvHD) limit this at approach to highly selected children. We developed a low-dose radiation approach utilizing sirolimus based upon its unique ability to promote T cell tolerance through mTOR inhibition in a mouse transplantation model.  We then applied this approach to adults with severe SCD.  Entry criteria include irreversible SCD-related complications (stroke, nephropathy, or tricuspid regurgitant jet velocity >2.5 m/s), or reversible complications not ameliorated by a 6-month course of hydroxyurea (frequent vaso-occlusive crises or acute chest syndrome). Conditioning consists of 1mg/kg of alemtuzumab divided over 5 days, a single total body irradiation dose of 300cGy, and oral sirolimus targeting trough levels between 10-15 ng/ml. Donor chimerism is measured by microsatellite PCR of CD3 and CD14/15 positive white cells.  25 patients have been transplanted, and their ages range from 17 to 64 years. All are alive at 4 months to 7 years post allo-HSCT.  Conditioning was well-tolerated and all received unmanipulated G-CSF mobilized peripheral blood progenitors obtained from 8/8 HLA-matched siblings. CD34+ cell doses ranged from 5.5 to 31 x 10e6/kg (median 14.4), and CD3+ cell doses, 1.6-5.4 x 10e8/kg (median 3.4).  Two patients received preemptive treatment with ganciclovir or foscarnet for presumed CMV reactivation (blood PCR >300 genome/mL) before day 30.  Treatment in both patients was discontinued 1 week later with negative blood PCR and prophylaxis with acyclovir was resumed.  Three patients engrafted temporarily and rejected their grafts between the 2nd and 3rd months post transplant and had recurrent SCD.   22 patients engrafted with donor cells.  Hemoglobin electrophoresis revealed replacement by donor type hemoglobin in 21 patients by 1 year, with amelioration of the SCD phenotype allowing for therapeutic phlebotomy.  One patient experienced delayed erythroid recovery due to anti-donor red cell antibodies.  In 17 patients who are 1 year or more post allo-HSCT, 5 had CD3 chimerism >50% which allowed complete withdrawal of immunosuppression; they have maintained stable mixed chimerism. There were 2 patients with zoster at 2 and 3 years post allo-HSCT.  Finally, no engrafted patient to date has developed any evidence of acute or chronic GVHD.  Our results demonstrate that this relatively simple conditioning regimen is well-tolerated across a broad age range of adults, and is effective in achieving stable mixed chimerism without the development of GVHD, suggesting this combination of hematopoietic suppression, lymphocyte reduction and mTOR inhibition is sufficient to induce functional tolerance.

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