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Hybrid thymus, methods of making and methods of use for inducing xenograft tolerance, restoring immunocompetence and thymus function

An inducible, thymic technology, applied in biochemical equipment and methods, artificially induced pluripotent cells, new species of animal cells, etc., can solve problems such as inability to efficiently identify foreign antigens

Pending Publication Date: 2021-08-31
THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] However, remaining limitations include suboptimal receptor immune function that cannot efficiently recognize foreign antigens; suboptimal survival, homeostasis, and inefficient removal of autoreactive T cells; and the limitation of positive selection of regulatory T cells to prevent autoimmunity. lack

Method used

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  • Hybrid thymus, methods of making and methods of use for inducing xenograft tolerance, restoring immunocompetence and thymus function
  • Hybrid thymus, methods of making and methods of use for inducing xenograft tolerance, restoring immunocompetence and thymus function
  • Hybrid thymus, methods of making and methods of use for inducing xenograft tolerance, restoring immunocompetence and thymus function

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0171] Example 1 - Generation of human / pig hybrid thymus for immune tolerance to porcine antigens and optimal immune function

[0172] Robust immune responses to xenografts are difficult to control with conventional immunosuppression without undue toxicity. Thymus transplantation is a promising approach to induce T cell tolerance to xenografts. Humanized mice generated with human hematopoietic stem cell (HSC) and porcine (SW) thymus grafts were previously shown to be tolerant to both species. However, this method still has some challenges. First, T cells selected on the SW MHC of the porcine thymus may not optimally recognize antigens presented by human MHC (HLA) in the periphery. Second, since SW thymic epithelial cells (TECs) do not display human tissue-restricted antigens (TRAs), there may be impaired negative selection and lack of Tregs against human TRAs. These problems were overcome by generating the human / pig hybrid thymus described herein.

[0173] method

[017...

Embodiment 2

[0180] Example 2 - Development of a method for producing hybrid thymus

[0181] Injection method

[0182]Cells were resuspended in Matrigel to prevent them from leaking out of the porcine thymus after injection. As a proof of principle, in this experiment, human PBMCs were used instead of human thymic epithelial cells. First, 10 million human PBMCs were stained with CFSE (2.5 μM) as a tracking dye. CFSE-stained PBMCs (8 million cells) were resuspended in 140 μl Matrigel on ice at a cell concentration of 50,000 cells / μl. Three different methods were used to inject cells into thawed porcine fetal thymus fragments:

[0183] Method A: Inject using a Hamilton syringe while placing the pellet in a well of a V-bottom 96-well plate (5-8 μl);

[0184] Method B: Injection (20 μl) using PE50 tubing;

[0185] • Method C: Injection was performed using a Hamilton syringe while holding the tablet with tweezers outside the well until the Matrigel solidified (4-6 μl).

[0186] All inje...

Embodiment 5

[0224] Example 5 - Generation of hybrid thymuses with embryonic stem cell-derived TECs (ES-TECs) and long-term persistence of human TECs in hybrid thymuses

[0225] method

[0226] Human fetal or pediatric thymic stromal cells (hu-TEC) or hPSC-TEC progenitor cells (1-2x10 5 TECs) were injected into fetal swine thymus tissue (SW THY), which were then transplanted under the renal capsule of thymectomized immunodeficient NSG (Nod / Scid / Ilr2g- / -) mice that had been intravenously Inject 2x10 5 Individual fetal liver-derived CD34+ cells. As a control, fetal pig thymus tissue that was not injected with human TEC was implanted.

[0227] Approximately 20 weeks after transplantation, the transplanted thymus was removed, sectioned, and stained for detection of human TECs using two-photon confocal microscopy.

[0228] Cells were then released from the interstitium and cell numbers determined by flow cytometry.

[0229] result

[0230] Such as Figure 10 As shown, there is long-t...

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Abstract

The present disclosure relates to making a hybrid pig-human thymic tissue and using the hybrid thymic tissue to induce tolerance in xenotransplantation. The hybrid thymic tissue can also be used for restoring or inducing immunocompetence in a recipient as well as restoring or promoting the thymus-dependent ability for T cell progenitors to develop into mature functional T cells in a recipient.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Patent Application Serial No. 62 / 734,019 filed September 20, 2018, which is hereby incorporated by reference in its entirety. [0003] Statement of Government Interest [0004] This invention was made with government support under AI084903, AI045897, and AI106697 awarded by the National Institutes of Health. The government has certain rights in this invention. technical field [0005] The present disclosure relates to the preparation of pig-human hybrid thymus and the use of the hybrid thymus to induce tolerance in xenografts. Background technique [0006] Currently, a critical shortage of allogeneic donors limits the number of organ transplants that can be performed. This supply-demand gap can be corrected by using organs from other species (xenografts). Given the ethical concerns and impracticalities associated with the use of nonhuman primates, pigs are considered the most ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N5/0789C12N5/078
CPCC12N5/065C12N5/0697C12N2517/02A61K48/00A61K39/4611A61P37/06A61K2121/00A61K2300/00A61L27/3604A61L27/3695A61L27/3813C12N2506/02C12N2506/45
Inventor M·赛克斯M·科斯拉维-马哈洛伊N·丹兹尔
Owner THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK
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