Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus
Reexamination Certificate
1995-05-26
2001-10-02
Campell, Bruce R. (Department: 1632)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Genetically modified micro-organism, cell, or virus
C424S093100, C424S093700, C424S130100, C424S577000, C424S579000
Reexamination Certificate
active
06296846
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to organ transplantation.
Organ procurement currently poses one of the major problems in organ transplantation, as the number of patients requiring transplants far exceeds the number of organs available. Xenotransplantation may provide a solution to this problem. Phylogenetically, non-human primates are the most closely related species to humans and might therefore represent the first choice as donors. In 1969, Reemtsma et al., achieved the first successful kidney human xenograft from a chimpanzee (Reetsma, K. et al., 1964,
Ann. Surg.
160:384). However, the potential utilization of primate donors is limited by insufficient numbers, legal and ethical considerations, and the potential for transmitting dangerous viral diseases. Swine represent one of the few large animal species in which breeding characteristics make genetic experiments possible, making it possible to develop MHC homozygous lines of miniature swine. Miniature swine can be maintained at maximum adult weights of 200 to 300 lbs and are anatomically and physiologically close to humans. Therefore the organs of miniature swine might be appropriate for use as xenografts for human beings of all ages.
Tolerance to self major histocompatibility (MHC) antigens occurs during T cell maturation in the thymus (McDuffie et al., 1988,
J. Immunol.
141:1840). Exposure of the immune system to MHC antigens during ontogeny can cause the immune system to lose reactivity to those antigens, thus leaving the animal specifically tolerant into adult life (Billingham et al., 1953,
Nature
172:603). Transplantation immunologists have sought means of inducing tolerance in adult animals by production of lymphohematopoietic chimeras. The induction of tolerance across MHC barriers in adult mice by whole body irradiation (WBI) and bone marrow transplantation (BMT) has been studied extensively in murine models (Rayfield et al., 1983, Transplan. 36:183; Mayumi et al., 1989,
J. Exp. Med.
169:213; Sykes et al., 1988,
Immunol. Today
9:23).
The use of MHC mismatched BMT as a means of inducing tolerance to organ grafts can be accompanied by several major disadvantages: the preparative regimen involves lethal irradiation, with its inherent risks and toxicities; clinical applicability is limited by the fact that most potential recipients do not have an appropriate MHC-matched donor, and BMT across MHC barriers causes severe graft-vs-host-disease (GVHD). Removing the T lymphocytes in allogeneic bone marrow inocula (Rodt et al., 1971,
Eur. J. Immunol.
4:25) to prevent GVHD is associated with increased rates of engraftment failure (Martin et al., 1988,
Bone Marrow Transplant
3:445; O'Reilly et al., 1985,
Transplant. Proc.
17:455; Soderling et al., 1985,
J. Immunol.
135:941). While these drawbacks are generally considered acceptable for the treatment of otherwise lethal malignant diseases, they would severely limit the application of this methodology as a preparative regimen for organ transplantation, in which non-specific immunosuppressive agents, while not without major complications, are effective.
Use of a relatively non-toxic, non-myeloablative preparative regimen for bone marrow engraftment and specific transplantation tolerance has been applied to the concordant rat to mouse species combination (Sharabi, Y. et al., 1990,
J. Exp. Med.
172:195-202). The treatment involved administration of monoclonal antibodies to eliminate mature T cell subsets (CD4 and CD8) as well as NK cells (NK1.1). These monoclonal antibodies permitted engraftment of xenogeneic bone marrow after only a sub-lethal (300 rads) dose of WBI and a local dose of 700 rads thymic irradiation. The resulting lymphoid reconstitution was superior to that of previously mixed xenogeneic chimeras prepared by lethal irradiation and reconstitution with mixtures of T cell-depleted syngeneic and xenogeneic bone marrow (Sharabi, Y., et al., 1990,
J. Exp. Med.
172:195-202; Ildstad, et al., 1984,
Nature
307:168-170) as recipients did not suffer toxic effects from the preparative regimen. In addition, attempts have been made to lengthen the survival of skin allografts in primates and man by intravenously administering a polyclonal preparation of horse anti-human antithymocyte globulin (ATG). The ATG was injected simultaneously with and on days immediately following grafting (Cosimi, A. B., et al., 1970.
Surgery.
68:54-61).
In discordant species combinations, the humoral (antibody mediated) component of the immune system poses a major barrier. When primarily vascularized organs are grafted between discordant species, natural antibodies that recognize determinants expressed on the surfaces of vascular endothelial cells cause rejection of the organ within minutes of vascular anastomosis, due to activation of the complement and coagulation cascades (Hammer, C., et al., 1973,
Eur. Sug. Res.
5:162; Hardy, M. A. et al, 1984, in S. Slavin, ed. Elsevier, B. V., p. 515). In attempts to prolong cardiac xenografts from pig donors, pre-existing natural antibodies have been absorbed from the blood of recipient primates by hemoperfusion of a donor-specific kidney (Cooper, D. K. C., et al. 1988,
J. Heart Transplan.
7:238-246; Fischel, R. J., et al., 1990,
Transplant. Proc.
22:1077).
SUMMARY OF THE INVENTION
In general, the invention features a method of inducing tolerance in a recipient mammal, e.g., a primate, e.g., a human, of a first species to a graft obtained from a mammal of a second species, e.g., a discordant species. The method includes: prior to or simultaneous with transplantation of the graft, introducing into the recipient mammal hematopoietic stem cells, e.g., bone marrow cells, or fetal liver or spleen cells, of the second species; (preferably, the hematopoietic stem cells home to a site in the recipient mammal); and prior to introducing the hematopoietic stem cells into the recipient mammal, introducing into the recipient mammal an antibody capable of binding to natural killer (NK) cells of the recipient mammal, to prevent NK mediated rejection of the hematopoietic cells. As will be explained in more detail below, the hematopoietic cells prepare the recipient for the graft that follows, by inducing tolerance at both the B-cell and T-cell levels. Preferably, hematopoietic cells are fetal liver or spleen, or bone marrow cells, including immature cells (i.e., undifferentiated hematopoietic stem cells; these desired cells can be separated out of the bone marrow prior to administration), or a complex bone marrow sample including such cells can be used.
One source of anti-NK antibody is anti-human thymocyte polyclonal anti-serum. As is discussed below preferably, a second, anti-mature T cell antibody can be administered as well, which lyses T cells as well as NK cells. Lysing T cells is advantageous for both bone marrow and xenograft survival. Anti-T cell antibodies are present, along with anti-NK antibodies, in anti-thymocyte anti-serum. Repeated doses of anti-NK or anti-T cell antibody may be preferable. Monoclonal preparations can be used in the methods of the invention.
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; and the step of prior to hematopoietic stem cell transplantation, introducing into the recipient mammal an antibody capable of binding to mature T cells of the recipient mammal.
Preferred embodiments include those in which: the same mammal of the second species is the donor of both the graft and the hematopoietic cells; the donor mammal is a swine, e.g., a miniature swine; the introduction is by intravenous injection; and the antibody is an anti-human thymocyte polyclonal anti-serum, obtained, e.g., from a horse or pig.
Preferred embodiments include: the step of prior to hematopoietic stem cell transplantation, irradiating the recipient mammal with low dose, e.g., between about 100 and 400 rads, whole body irradiation; and the step of prior to hematopoietic stem cell t
Cosimi A. Benedict
Sachs David H.
Sykes Megan
Beckerleg Anne Marie S.
Campell Bruce R.
Fish & Richardson P.C.
The General Hospital
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