Methods of cell therapies
Described herein are methods of cell therapies. Also described herein are methods of generating donor derived T cells in an organ transplant recipient, by administering bone marrow stem cells to the organ transplant recipient about 1 to about 30 days after the organ transplant recipient receives one or more organ transplants.
1. A method of establishing a mixed chimerism, establishing a T-cell macrochimerism of at least about 4%, preventing a host-versus-graft response, and/or preventing a rejection of a donor organ in a subject that has received an organ transplant, wherein said donor organ comprises an intestine and wherein said organ transplant comprises an intestinal transplant (“ITx”), the method comprising:
a) generating a lymphohematopoietic graft-versus-host response (“LGVHR”) in the subject; and
b) upon generation of said LGVHR, administering to said subject a population of CD34+ cells, wherein said population of CD34+ cells is selected for such that said population of CD34+ cells comprises no more than about 1×10 4 CD3+ cells per kilogram of said subject.
2. The method of claim 1 , wherein said population of CD34+ cells comprises at least about 1×10 6 CD34+ cells per kilogram of said subject, at least about 2×10 6 CD34+ cells per kilogram of said subject, or at least about 3×10 6 CD34+ cells per kilogram of said subject.
3. The method of claim 1 , wherein said organ transplant further comprises a liver transplant, or a stomach transplant, and any combination thereof.
4. The method of claim 1 , wherein said organ transplant further comprises a multivisceral transplant comprising transplantation of two or more of stomach, pancreas, liver, and kidney.
5. The method of claim 1 , wherein said organ comprises a population of hematopoietic stem cells or hematopoietic progenitor stem cells.
6. The method of claim 1 , wherein said population of CD34+ cells is derived from a cadaver.
7. The method of claim 1 , wherein said population of CD34+ cells comprises CD34+ cells that are HLA-matched to said organ.
8. The method of claim 1 , wherein said population of CD34+ cells and said organ are obtained from the same person or said population of CD34+ cells and said organ are not obtained from the same person.
9. The method of claim 1 , wherein the method further comprises administering rabbit anti-thymocyte globulin to said subject on the day of said organ transplant, 1 day after said organ transplant, 2 days after said organ transplant, and/or 3 days after said organ transplant, optionally, at a dose of from about 1.5 mg to about 9 mg per kilogram of said subject, thereby reducing circulating CD4+ T cell concentrations below 50/μl.
10. The method of claim 1 , wherein the method further comprises administering one or more corticosteroids to said subject on the day of said organ transplant, 1 day after said organ transplant, 2 days after said organ transplant, 3 days after said organ transplant, 4 days after said organ transplant, 5 days after said organ transplant, and/or 6 days after said organ transplant, optionally, wherein said one or more corticosteroids are administered for about 6 months to about 12 months after said organ transplant.
11. The method of claim 10 , wherein said administration of said one or more corticosteroids in a subsequent administration is tapered relative to a previous administration, including the first administration.
12. The method of claim 1 , wherein the method further comprises administering tacrolimus to said subject for at least one day after said organ transplant and/or daily for days following said organ transplant.
13. The method of claim 12 , wherein said tacrolimus is administered from about 3 ng/ml to about 15 ng/ml and, optionally, maintained at trough levels of 10-15 ng/ml for the first month, 8-12 ng/ml for the second through sixth month, 5-10 ng/ml for the remainder of the first year, and/or 3-7 ng/ml at one or more time points after the first year.
14. The method of claim 13 , wherein said administration of tacrolimus in a subsequent administration is tapered relative to a previous administration, including the first administration.
15. The method of claim 14 , wherein said administration of tacrolimus is tapered by 25% one year after said organ transplant, is tapered by 50% about 380 to about 395 days after said organ transplant, and/or is tapered to discontinuation beginning about 1 year after said organ transplant.
16. The method of claim 1 , wherein administering to said subject the population of CD34+ cells does not result in a Grade II or greater graft-versus-host disease within a month, within a year, or within three years after said organ transplant.
17. The method of claim 1 , wherein the method further comprises administering one or more mTOR inhibitors to said subject.
18. The method of claim 17 , wherein said administration of one or more mTOR inhibitors in a subsequent administration is tapered relative to a previous administration, including the first administration.
19. The method of claim 1 , wherein said administering to said subject the population of CD34+ cells occurs at least 10 days after said organ transplant.
20. The method of claim 1 , wherein said administering to said subject the population of CD34+ cells occurs 11 days after said organ transplant.