Combined organ and hematopoietic cells for transplantation tolerance of HLA mismatched grafts
View Patent ↗Methods and compositions are provided for combined transplantation of a solid organ and hematopoietic cells to an HLA mismatched recipient, where tolerance to the graft is established through development of a persistent mixed chimerism. An individual with persistent mixed chimerism, usually for a period of at least six months, is able to withdraw from the use of immunosuppressive drugs after a period of time sufficient to establish tolerance.
1. A method for transplantation of a HLA mismatched solid human organ, said method comprising:
implanting said HLA mismatched solid human organ in a recipient human body, wherein said HLA mismatched solid human organ is from a donor;
treating said recipient with non-myeloablative conditioning;
infusing said recipient with an engineered hematopoietic cell composition, said engineered hematopoietic cell composition comprising at least 1×10 7 CD34 + cells/kilogram recipient weight and at least 1×10 7 CD3 + T cells/kilogram recipient weight; and
maintaining said recipient on an immunosuppressive regimen for a period of time sufficient to develop mixed chimerism for at least 6 months.
2. The method of claim 1 , wherein said HLA mismatched solid human organ is selected from a group consisting of a kidney, a heart, an intestine, a liver, a lung, and a pancreas.
3. The method of claim 1 , wherein said engineered hematopoietic cell composition comprises about 5×10 7 CD3 + T cells/kilogram recipient weight.
4. The method of claim 1 , wherein said non-myeloablative conditioning comprises lymphoid tissue irradiation in combination with T cell depleting antibodies or drugs.
5. The method of claim 1 , wherein said immunosuppressive regimen comprises a calcineurin inhibitor or a purine metabolism inhibitor, or said calcineurin inhibitor and said purine metabolism inhibitor, and wherein said recipient is maintained on said immunosuppressive regimen for a period of at least six months.
6. The method of claim 1 , further comprising the step of:
monitoring said recipient for a stable mixed chimerism, wherein said stable mixed chimerism is defined as one of the following: (i) having at least 1% and less than 95% circulating donor hematopoietic cells, (ii) having at least 1% and less than 95% circulating immune cells or, (iii) having at least 1% and less than 95% of combined circulating hematopoietic cells and immune cells.
7. The method of claim 1 , wherein said immunosuppressive regimen is withdrawn from said recipient found to have said mixed chimerism for at least six months.
8. The method of claim 1 , wherein said donor is living or deceased.
9. The method of claim 1 , wherein said CD34 + cells are isolated and purified from said donor.
10. The method of claim 1 , wherein said CD34 + cells are purified to a purity of greater than 70%.
11. The method of claim 1 , wherein a ratio of said CD3 + T cells to said CD34 + cells is at least 1.
12. The method of claim 1 , wherein said HLA-mismatched solid human organ comprises at least one of HLA-A, HLA-B and HLA-DR that are different between said donor and said recipient.