Methods of preventing rejection of transplanted tissue by administering anti-CD40L antibody and dendritic cells loaded with Hsp60sp peptide
Inventors
Assignees
Columbia University in the City of New York • National Institutes of Health NIH
Publication Number
US-8911739-B2
Publication Date
2014-12-16
Expiration Date
2030-02-09
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Abstract
A method is provided for preventing rejection by an immune system of a recipient subject of a tissue transplanted from a donor subject into the recipient subject without the need for long-term administration of non-specific immunosuppressive drugs.
Core Innovation
The invention provides a method for preventing rejection by the immune system of a recipient subject to tissue transplanted from a donor subject, without requiring long-term administration of non-specific immunosuppressive drugs. The method involves administering irradiated peripheral blood mononuclear cells (PBMCs) from the donor, which cannot proliferate in vivo, in combination with a monoclonal antibody that specifically binds to CD40 ligand, prior to transplantation to inhibit activation of allo-reactive T cells in the recipient.
Subsequent to transplantation, the method further comprises administering an agent that enhances the down-regulation of donor tissue-activated HLA-E+ T cells by HLA-E-restricted CD8+ T cells, thereby enhancing regulation of the immune response against the transplanted tissue and preventing rejection. The agent may be dendritic cells loaded with Hsp60sp peptide, HLA-E/IgG fusion proteins, HLA-E/Hsp60sp tetramers, or dendritic cell-derived HLA-E-bearing exosomes loaded with type B self-peptides.
The problem addressed relates to transplant rejection wherein conventional treatments rely on long-term use of non-specific immunosuppressive drugs that carry risks such as failure and heightened infection risk. Existing understanding indicates that high-avidity allo-reactive T cells mediate acute rejection and are resistant to down-regulation, whereas intermediate-avidity T cells mediate chronic rejection and are subject to down-regulation by regulatory CD8+ T cells recognizing the Qa-1/HLA-E-peptide complexes. The invention utilizes this immunological mechanism to establish transplantation tolerance without the drawbacks of continuous immunosuppression.
Claims Coverage
The patent includes one independent claim describing a two-step method for preventing tissue transplant rejection involving donor PBMC administration with anti-CD40L antibody and subsequent administration of dendritic cells loaded with Hsp60sp peptide.
Administration of irradiated donor PBMCs and anti-CD40L antibody to inhibit allo-reactive T cell activation
The method comprises administering to the recipient subject, prior to transplantation, a plurality of peripheral blood mononuclear cells (PBMCs) from the donor that are irradiated to prevent proliferation in vivo along with an anti-CD40 ligand antibody to inhibit activation of allo-reactive T cells.
Post-transplant administration of dendritic cells loaded with Hsp60sp peptide to enhance down-regulation of HLA-E+ T cells
Following transplantation, the method includes administering dendritic cells loaded with Hsp60sp peptide (amino acid sequences SEQ ID NO:2 or NO:3) to enhance down-regulation of donor tissue-activated HLA-E+ T cells by HLA-E-restricted CD8+ T cells, thereby preventing rejection.
The inventive features focus on a two-stage immunomodulatory method that first inhibits allo-reactive T cell activation before transplantation and then enhances regulatory T cell-mediated down-regulation of activated donor-specific T cells after transplantation, collectively preventing tissue rejection without reliance on long-term immunosuppressive drugs.
Stated Advantages
Prevents tissue rejection without the need for long-term administration of non-specific immunosuppressive drugs.
Induces permanent allograft tolerance by modifying the allo-reactive T cell repertoire to eliminate high avidity T cells and promote regulation.
Reduces risk of thromboembolic side effects by limiting use of anti-CD40L antibody to a short-term regimen combined with antithrombotic therapy.
Allows specific down-regulation of intermediate avidity allo-reactive T cells while preserving immunity to infections and tumors.
Documented Applications
Prevention of rejection of transplanted tissues including lung, heart, kidney, liver, retinal, corneal, skin, pancreatic, intestinal, genital, ovary, bone, tendon, or vascular tissue.
Use in transplantation of intact organs.
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