Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1999-02-04
2003-02-04
Park, Hankyel T. (Department: 3738)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
Reexamination Certificate
active
06514513
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to tissue and organ transplantation.
The field of organ transplantation has enjoyed substantial progress during the last two decades, resulting in marked improvements in short-term graft survival. Organ transplant recipients, however, still face substantial risks of long-term morbidity and mortality. Though modern immunosuppressive regimens have led to a dramatic reduction of the incidence of acute rejection episodes, they have yet to achieve a similar effect for chronic rejection, which is still the leading cause of graft loss during long-term follow-up. In addition, the requirement for life-long immunosuppressive drug therapy carries a significant risk of severe side effects, including tumors, infections and metabolic disorders. The reliable induction of donor-specific tolerance would solve both problems by obviating the need for chronic non-specific immunosuppression and by abrogating detrimental immunological reactions against the allograft.
SUMMARY OF THE INVENTION
The invention provides methods of inducing tolerance to foreign antigens. The methods feature preparative regimens which may minimize or eliminate the need for thymic irradiation, T cell inhibiting antibodies, and in some cases hematopoietic space-creating irradiation, e.g. preparative whole body irradiation.
Accordingly, the invention features a method of promoting acceptance, by a recipient mammal, of a graft from a donor mammal of a second species. The method includes:
administering to the recipient, an inhibitor, e.g., a blocker, of a costimulatory pathway, (e.g., one or both of, an inhibitor, e.g., a blocker, of the CD40 ligand-CD40 interaction and an inhibitor, e.g., a blocker, of the CD28-B7 interaction);
introducing, e.g., by intravenous injection, into the recipient mammal, hematopoietic stem cells, e.g., a bone marrow preparation; and
preferably, implanting the graft in the recipient. The hematopoietic cells are believed to prepare the recipient for the graft that follows, by inducing tolerance at both the B-cell and T-cell levels.
In preferred embodiments the CD40 ligand-CD40 interaction is inhibited by administering an antibody or soluble ligand or receptor for the CD40 ligand or CD40, e.g., by administering an anti-CD40L antibody, e.g., 5c8 or an antibody with similar efficacy or an antibody whose epitope overlaps that of 5c8, (see U.S. Pat. No. 5,474,711, hereby incorporated by reference). Preferably the inhibitor binds the CD40 ligand.
In preferred embodiments the CD28-B7 interaction is inhibited by administering a soluble ligand or receptor or antibody for the CD28 or B7, e.g., a soluble CTLA4, e.g., a CTLA4 fusion protein, e.g., a CTLA4 immunoglobulin fusion, e.g, CTLA4/Ig. Preferably, the inhibitor binds B7. In preferred embodiments anti-B7-1 and/or anti-B7-2 antibodies are administered.
In preferred embodiments CTLA4-Ig and an anti-CD40L antibody are administered.
In preferred embodiments, a blocker of the CD40/CD40L interaction, e.g., an anti-CD40L antibody is administered prior to administration of a blocker of the CD28/B7 interaction, e.g., CTLA4/Ig. The CD40/CD40L blocker can be administered on the day donor tissue is introduced and the CD28/B7 blocker administered 2, 3,4 5 or more days later.
The recipient mammal can be, by way of example, a human. The donor mammal can be, by way of example, a swine, e.g., a miniature swine. The graft is preferably from a discordant species. The graft preferably expresses a major histocompatibility complex (MHC) antigen, preferably a class II antigen. In particularly preferred embodiments the recipient is a primate, e.g., a human, and the donor is a swine, e.g., a miniature swine.
In preferred embodiments the method can be practiced without the administration of hematopoietic space-creating irradiation, e.g., whole body irradiation.
In certain embodiments the method is practiced without T cell depletion or inactivation, e.g., without the administration of thymic irradiation, or anti-T cell antibodies.
In certain embodiments the method is practiced with T cell depletion or inactivation, e.g., by the administration of thymic irradiation, or anti-T cell antibodies.
In certain embodiments the method is practiced with partial T cell depletion or inactivation, e.g., by the administration of thymic irradiation, or anti-T cell antibodies, in such amount to result in partial depletion of recipient T cells.
In preferred embodiments the method includes administering a sufficiently large number of donor hematopoietic cells to the recipient such that, donor stem cells engraft, give rise to mixed chimerism without space-creating treatment. Thus, in preferred embodiments inhibitors of both pathways and a quantity of hematopoietic stem cells sufficient to give rise to mixed chimerism, without the need for hematopoietic space-creating irradiation, is administered to the recipient. In preferred embodiments the number of donor hematopoietic stem cells is at least 200%, is at least equal to, or is at least 75, 50, or 25% as great as, the number of bone marrow hematopoietic stem cells found in an adult of the recipient species. In the case where an inbred population of the donor species exists, e.g., where the donor species is miniature swine, the number of available donor cells is not limited to the number of cells which can be obtained from a single animal. Thus, in such cases, the donor cells administered to the recipient can come from more than one, e.g., from two, three, four, or more animals. As is discussed below the donor stem cells can be provided in two or more separate administrations.
In preferred embodiments, mixed chimerism is induced in the recipient and the state of mixed chimerism is formed in the absence of the induction of hematopoietic space, e.g., in the absence of hematopoietic space created by space creating irradiation, e.g., whole body irradiation.
The number of donor cells administered to the recipient can be increased by either increasing the number of stem cells provided in a particular administration or by providing repeated administration of donor stem cells.
Repeated stem cell administration can promote engraftment, mixed chimerism, and preferably long-term deletional tolerance in graft recipients. Thus, the invention also includes methods in which multiple hematopoietic stem cell administrations are provided to a recipient. Multiple administration can substantially reduce or eliminate the need for hematopoietic space-creating irradiation. Administration can be given prior to, at the time of, or after graft implantation. In preferred embodiments multiple administrations of stem cells are provided prior to the implantation of a graft. Two, three, four, five, or more administrations can be provided. The period between administrations of hematopoietic stem cells can be varied. In preferred embodiments a subsequent administration of hematopoietic stem cell is provided: at least two days, one week, one month, or six months after the previous administration of stem cells; when the recipient begins to show signs of host lymphocyte response to donor antigen; when the level of chimerism decreases; when the level of chimerism falls below a predetermined value; when the level of chimerism reaches or falls below a level where staining with a monoclonal antibody specific for a donor PBMC antigen is equal to or falls below staining with an isotype control which does not bind to PBMC's, e.g. when the donor specific monoclonal stains less than 1-2% of the cells; or generally, as is needed to maintain a level of mixed chimerism sufficient to maintain tolerance to donor antigen.
One or more post graft-implantation-administrations of donor stem cells can also be provided to minimize or eliminate the need for irradiation. Post graft administration of hematopoietic stem cells can be provided: at least two days, one week, one month, or six months after the previous administration of stem cells; at least two days, one week, one month, six months, or at any time in the life span of the recipient after the implant
Hale and Dorr LLP
Park Hankyel T.
The General Hospital Corporation
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