Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1999-02-04
2001-08-28
Park, Hankyel T. (Department: 1648)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S343200, C530S388750, C424S422000
Reexamination Certificate
active
06280957
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 allo-antigens. The methods feature preparative regimens which minimize or eliminate the need for one or both of thymic irradiation and T cell inhibiting antibodies.
Accordingly, the invention features a method of promoting acceptance, by a recipient mammal, e.g., a primate, e.g., a human, of a graft from a donor mammal of the same species. The method includes:
administering to the recipient, an inhibitor, e.g., a blocker, of the CD40 ligand-CD40 interaction (optionally, an inhibitor or blocker of the CD28-B7 interaction can also be administered);
introducing, e.g., by intravenous injection, into the recipient mammal, hematopoletic stem cells, e.g., a bone marrow preparation; and
preferably, implanting the graft in the recipient. The hematopoletic 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 which has an epitope which overlaps the epitope of 5c8 (see U.S. Pat. No. 5,474,711, hereby incorporated by reference). Preferably the inhibitor binds the CD40 ligand.
In embodiments wherein the CD28-B7 interaction is inhibited, it can be 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., a 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 the donor and recipient both are humans.
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 graft preferably expresses a major histocompatibility complex (MHC) antigen, preferably a class II antigen.
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.
One or more post graft-implantation-administration of donor stem cells can also be provided. 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 implantation of the graft; when the recipient begins to show signs of rejection, e.g., as evidenced by a decline in function of the grafted organ, by a change in the host donor specific antibody response, or by a change in the 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 tolerance or otherwise prolong the acceptance of a graft.
Although methods in which blockers of both pathways are administered may usually eliminate the need for other preparative steps, some embodiments include inactivating T cells, preferably graft reactive T cells of the recipient mammal. This can be accomplished, e.g., by introducing into the recipient mammal an antibody capable of binding to T cells of the recipient mammal. The administration of antibodies, or other treatment to inactivate T cells, can be given prior to introducing the hematopoictic stem cells into the recipient mammal or prior to implanting the graft in the recipient.
Monoclonal preparations can be used in the methods of the invention.
Other preferred embodiments include: the step of introducing into the recipient mammal, donor species-specific stromal tissue, preferably hematopoietic stromal tissue, e.g., fetal liver or thymus. In preferred embodiments: the stromal tissue is introduced simultaneously with, or prior to, the hematopoietic stem cells; the hematopoietic stem cells are introduced simultaneously with, or prior to, the antibody.
Although methods in which blockers of both pathways are administered may usually eliminate the need for other preparative steps, some embodiments include the inactivation of thymocytes or T cells, which can be performed prior to hematopoietic stem cell or graft transplantation. In preferred embodiments the method includes diminishing or inhibiting thymocyte or T cell activity, preferably the activity of thymic or lymph node T cells by administering to the recipient a short course of an immunosuppressive agent, e.g., a chemical or drug, e.g., cyclosporine, sufficient to inactivate thymocytes or T cells, preferably thymic or lymph node T cells. The duration of the short course of immunosuppressive agent is: approximately equal to or less than 30, 40, 60, 120, or 365 days; approximately equal to or less than 8-12 days, preferably about 10 days; approximately equal to or less than two, three, four, five, or ten times the 8-12 or 10 day period. The short course can begin: before or at about the time the treatment to induce tolerance is begun, e.g., at about the time stem cells are introduced into the recipient; on the day the treatment to induce tolerance is begun, e.g., on the day stem cells are introduced into the recipient; within 1, 2, 4, 6, 8, 10, or 30 days before or after the treatment to induce tolerance is begun, e.g., within 1, 2, 4, 6, 8, 10, or 30 days before or after stem cells are introduced into the recipient. The short course of an immunosuppressive can be administered in conjunction with an anti-T cell antibody The short course of an immunosuppressive should be sufficient in concentration and duration to inactivate T cells, e.g., thymic or lymph node T cells, which would not be inactivated by antibody-based inactivation of T cells, e.g., inactivation by intravenous administration of ATG antibody, or similar, preparations.
Other preferred embodiments include those in which: the same ma
Sayegh Mohamed
Sykes Megan
Hale and Dorr LLP
Park Hankyel T.
The General Hospital Corporation
LandOfFree
Costimulatory blockade and mixed chimerism in... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Costimulatory blockade and mixed chimerism in..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Costimulatory blockade and mixed chimerism in... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2500007