JPWO2019165197A5

JPWO2019165197A5 -

Info

Publication number: JPWO2019165197A5
Application number: JP2020543913A
Authority: JP
Publication date: 2022-01-31
Anticipated expiration: 2039-02-22

Claims

A method for promoting donor-specific tolerance for allogeneic solid organ transplantation obtained from a deceased donor in a recipient requiring a solid organ transplant, said method.
(A) The recipient's thymus removal step and
(B) The recipient is treated with an induced immunosuppressive regimen containing one or more immunosuppressive agents to deplete the recipient's T cells and / or the recipient's T cells are transplanted. Steps to suppress the rejection of solid organs,
(C) Steps to provide both suitable solid human organs and thymus from deceased donors,
(D) The step of transplanting the solid human organ to the recipient,
(E) A step of treating the recipient with a maintenance immunosuppressive regimen,
(F) In the step of providing a product derived from allogeneic cultured postnatal thymus tissue, the allogeneic cultured postnatal thymus tissue-derived product is obtained from an appropriate thymus tissue of the solid organ donor, and the donor thymus tissue is obtained after allogeneic culture. The conditioning regimen is subjected to a conditioning regimen for a period of up to 21 days to produce thymic tissue-derived products, and the conditioning regimen for the donor thymic tissue is subjected to sterile treatment of the donor thymic tissue in a thymic organ medium to partially treat the donor thymic tissue. T cell-depleted donor thymus tissue pieces were produced, and the partially T-cell depleted donor thymus tissue pieces produced cytokeratin (CK) (antibodies AE1 / AE3) scattered throughout the tissue. Use) positive regions, the presence of at least one thymus, CK14 staining scattered throughout the tissue, and the presence of intact nuclei, with steps.
(G) The step of transplanting the allogeneic cultured postnatal thymic tissue-derived product to the recipient 12 to 21 days after the conditioning regimen, wherein the dose of the thymic tissue piece is about 1,000 to 20,000 mm ² . A method comprising a thymic tissue surface area / 1 m ² recipient body surface area, wherein the transplanted allogeneic postnatal thymic tissue-derived product induces thymic lymphocyte neoplasia and tolerance in the recipient. ..

On the day of collection, more than 50% of the area of the donor thymus is positive for keratin with a lace-like staining pattern, the presence of Hassal bodies, CK14 staining with a lace-like pattern, and 90% of the nucleus. The method of claim 1, indicating that the super is intact.

The method of claim 1, wherein the induced immunosuppressive regimen comprises an immunosuppressive agent selected from the group of glucocorticoids, antithymocyte globulin (rabbit), antithymocyte globulin (horse), and alemtuzimab. ..

The method of claim 1, wherein the second immunosuppressive regimen comprises administration of a glucocorticoid.

The method of claim 4 , wherein the glucocorticoid comprises sodium methylprednisolone succinate.

The second immunosuppressive regimen comprises further administration of glucocorticoids and tacrolimus or cyclosporine, as well as further administration of mycophenolate mofetil, an equivalent of mycophenolate mofetil, or azatroprine. The method described in.

The method according to claim 1 , wherein the solid organ transplant is a heart transplant.

The method of claim 7 , wherein the heart transplant is a pediatric heart transplant.

The method of claim 1 , wherein the heart transplant is an adult heart transplant.

The method of claim 1, further comprising assessing the recipient for an HLA class I or HLA class II panel reactive antibody ("PRA") score prior to transplanting the solid organ.

The method of claim 1, wherein a portion of the allogeneic postnatal thymic tissue-derived product is surgically transplanted into the recipient's quadriceps muscle.

The method of claim 1, wherein the conditioning regimen has a period of about 12 to about 21 days.

12. The method of claim 12 , wherein the conditioning period is approximately 21 days.

The method of claim 3 , wherein the induced immunosuppressive regimen comprises a rabbit-derived antithymocyte globulin.

The method of claim 1, wherein the second immunosuppressive regimen comprises one or more immunosuppressive agents selected from the group consisting of a calcineurin inhibitor and an inosinic monophosphate dehydrogenase inhibitor, or azathioprine.

15. The method of claim 15 , wherein the immunosuppressant is a calcineurin inhibitor.

15. The method of claim 15 , wherein the immunosuppressant is an inosinic acid dehydrogenase inhibitor.

17. The method of claim 17 , wherein the inosinic acid dehydrogenase inhibitor is mycophenolate mofetil.

The method of claim 1, wherein the second immunosuppressive regimen further comprises a glucocorticoid selected from the group consisting of methylprednisolone, prednisone, and prednisolone.

15. The method of claim 15 , wherein the calcineurin inhibitor is tacrolimus.

15. The method of claim 15 , wherein the calcineurin inhibitor is cyclosporin A.

The method of claim 1, wherein administration of one or more immunosuppressive agents in the second immunosuppressive agent regimen is withdrawn after the naive T cells reach 10% of all T cells.

The method of claim 1, wherein the transplanted allogeneic postnatal thymic tissue-derived product is biopsied 2-12 months post-transplant to evaluate evidence of thymic lymphocyte neoplasia by immunochemistry.

To obtain suitable thymic tissue from a donor, the donor thymic tissue is subjected to a conditioning regimen for a period of up to 21 days, and the conditioning regimen for the donor thymic tissue is further provided in the thymic organ medium with the donor. The thymic tissue was treated sterile to produce a donor thymic tissue fragment partially depleted of T cells, wherein the donor thymic tissue fragment was scattered throughout the tissue 5-9 days after collection. A positive region for AE1 / AE3, the presence of at least one Hassal body, CK14 staining scattered throughout the tissue, and the presence of intact nuclei to obtain and the partially depleted donor thymus. Allogeneic cultured postnatal thymic tissue-derived product for transplantation into subjects undergoing solid organ transplantation prepared by recovering tissue pieces as allogeneic cultured postnatal thymic tissue-derived product.

On the day of collection, the thymus is positive for keratin with a lace-like staining pattern in more than 50% of the area, the presence of Hassal bodies, the CK14 staining with a lace-like pattern, and more than 90% of the nucleus. 24. The allogeneic cultured postnatal thymic tissue-derived product, indicating that is intact.