Combined organ and hematopoietic cells for transplantation tolerance of HLA mismatched grafts

Patent metadata

Field	Value
Publication number	US-9504717-B2
Application number	US-201414175832-A
Country	US
Kind code	B2
Filing date	Feb 7, 2014
Priority date	Feb 26, 2013
Publication date	Nov 29, 2016
Grant date	Nov 29, 2016

Abstract

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.

First claim

What is claimed is:

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.

Assignees

• Univ Leland Stanford Junior

Inventors

• Strober Samuel
• Lowsky Robert

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P1/04

  for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants · CPC title

• A61P1/18

  for pancreatic disorders, e.g. pancreatic enzymes · CPC title