US 12,064,452 B2
Cultured thymus tissue transplantation promotes donor-specific tolerance to allogeneic solid organ transplants
Mary Louise Markert, Durham, NC (US)
Assigned to Duke University, Durham, NC (US)
Filed by Duke University, Durham, NC (US)
Filed on Sep. 27, 2021, as Appl. No. 17/486,045.
Application 17/486,045 is a division of application No. 16/283,007, filed on Feb. 22, 2019, granted, now 11,819,520.
Application 16/283,007 is a continuation of application No. PCT/US2019/019137, filed on Feb. 22, 2019.
Claims priority of provisional application 62/634,377, filed on Feb. 23, 2018.
Prior Publication US 2022/0079989 A1, Mar. 17, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 38/13 (2006.01); A01N 1/02 (2006.01); A61K 9/00 (2006.01); A61K 31/343 (2006.01); A61K 31/436 (2006.01); A61K 31/573 (2006.01); A61K 35/26 (2015.01); A61K 35/34 (2015.01); A61K 38/17 (2006.01); A61K 39/00 (2006.01); A61K 39/395 (2006.01); A61L 27/38 (2006.01); A61P 37/06 (2006.01); C07K 16/28 (2006.01); G01N 33/50 (2006.01); A61K 35/12 (2015.01)
CPC A61K 35/26 (2013.01) [A01N 1/0284 (2013.01); A61K 9/0019 (2013.01); A61K 31/343 (2013.01); A61K 31/436 (2013.01); A61K 31/573 (2013.01); A61K 35/34 (2013.01); A61K 38/13 (2013.01); A61K 38/1722 (2013.01); A61K 39/0008 (2013.01); A61K 39/3955 (2013.01); A61L 27/3804 (2013.01); A61L 27/3895 (2013.01); A61P 37/06 (2018.01); C07K 16/2893 (2013.01); G01N 33/5047 (2013.01); A61K 2035/122 (2013.01); A61L 2430/20 (2013.01); A61L 2430/40 (2013.01); C07K 2317/24 (2013.01); G01N 2800/245 (2013.01)] 12 Claims
 
1. A method for promoting donor-specific tolerance to an allogeneic solid organ transplant obtained from a human donor, in a human recipient in need of a solid organ transplant, the method comprising the steps of:
(a) removal of the thymus of the recipient;
(b) treating the recipient with an induction immunosuppressive regimen comprising one or more immunosuppressive agent to deplete the recipient's T cells and/or to suppress the recipient's T cells from rejecting the transplanted solid organ;
(c) providing a suitable solid organ from a human donor;
(d) transplanting the solid organ into the recipient;
(e) treating the recipient with a maintenance immunosuppressive regimen;
(f) providing a cryopreserved allogeneic cultured postnatal thymus tissue-derived product maintained in a cryopreserved allogeneic cultured postnatal thymus tissue-derived product bank; wherein the cryopreserved allogeneic cultured postnatal thymus tissue-derived product is processed from thymus tissue from a thymus donor expressing HLA alleles matched to HLA alleles in the recipient that are not present in the solid organ transplant;
wherein the donor thymus tissue has been processed into donor thymus tissue slices, wherein the donor thymus tissue slices have been assessed by pathology and show >50% of areas positive for keratin in a lacy staining pattern, show Hassall bodies, show cytokeratin 14 (CK14) staining in a lacy pattern, and show >90% intact nuclei of thymic epithelial cells and other stromal cells, wherein the donor thymus tissue has been subjected to a conditioning regimen for a period up to 12 days; wherein the conditioning regimen for the donor thymus tissue comprises aseptically processing the donor thymus tissue in a thymus organ medium to produce partially T-cell depleted thymus tissue slices, wherein the partially T-cell depleted thymus tissue slices are assessed by pathology and, between day 5 and 9 of the conditioning regimen, show staining positive for keratin, show CK14 staining scattered throughout, show at least one Hassall body, and show intact nuclei of thymic epithelial cells and other stromal cells;
(g) thawing the cryopreserved allogeneic cultured postnatal thymus tissue-derived product; and
(h) implanting the thawed cryopreserved allogeneic cultured postnatal thymus tissue-derived product into the recipient, wherein the dosage of the cryopreserved allogeneic cultured postnatal thymus tissue-derived product is about 1,000-20,000 mm2 of thymus tissue surface area/recipient body surface area in m2, and further wherein the implanted allogeneic cultured postnatal thymus tissue-derived product induces thymopoiesis and tolerance in the recipient.