Specific tolerance in transplantation

Details Specific tolerance in transplantation Specific tolerance in transplantation

1997-08-13

2001-10-23

Priebe, Scott D. (Department: 1632)

Chemistry: molecular biology and microbiology

Animal cell, per se ; composition thereof; process of...

C435S366000, C435S372000, C424S093200, C424S093210

Reexamination Certificate

active

06306651

ABSTRACT:

BACKGROUND OF THE INVENTION
The invention relates to conferring tolerance to foreign tissue.
Tolerance to self major histocompatibility (MHC) antigens occurs during T cell maturation in the thymus (McDuffie et al., 1988,
J. Immunol.
141:1840). It has been known since the landmark experiments of Billingham, Brent and Medawar (Billingham et al., 1953,
Nat.
172:603) that exposure of the immune system to allogeneic MHC antigens during ontogeny can cause the immune system to lose reactivity to those antigens, thus leaving the animal specifically tolerant into adult life. Ever since that time, 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). This approach has also recently been extended to the miniature swine large animal model, in which it was demonstrated that bone marrow transplants across MHC barriers led to the induction of long-term, specific transplantation tolerance to kidney grafts from donors MHC matched to the bone marrow donors (Guzzetta et al., 1991,
Transplan.
51:862).
The use of MHC mismatched BMT as a means of inducing tolerance to organ allografts is usually accompanied by several major disadvantages: the preparative regimen required for allogeneic BMT 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); and 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 (e.g., leukemia), 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 nevertheless effective.
There have been previous reports of the use of cell lines transfected with allogeneic class I and class II genes to selectively modify the immune response to subsequent tissue grafts bearing the foreign gene (Madsen et al., 1989,
Transplant. Proc.
21:477). Graft prolongation by this technique was not permanent, and the mechanism is unclear. Several laboratories have demonstrated the utility of retroviral mediated gene transfer for the introduction of new genetic material into totipotent hematopoietic stem cells of mice. In general, these protocols involve the transduction of bone marrow by recombinant retroviral vectors ex vivo, with the subsequent reintroduction of the treated cells into myeloablated recipients (for review, see Dick et al., 1986,
Trends in Genetics
2:165).
SUMMARY OF THE INVENTION
In general, the invention features a method of inducing tolerance in a recipient mammal, e.g., a human, of a first species to a tissue obtained from a mammal, e.g., a swine, e.g., a miniature swine, of a second species, which tissue expresses an MHC antigen, including inserting DNA encoding an MHC antigen of the second species into a bone marrow hematopoietic stem cell from the recipient mammal, and allowing the MHC antigen encoding DNA to be expressed in the recipient.
Preferred embodiments include those in which: the cell is removed from the recipient mammal prior to the DNA insertion and returned to the recipient mammal after the DNA insertion; the DNA is obtained from the individual mammal from which the tissue is obtained; the DNA is obtained from an individual mammal which is syngeneic with the individual mammal from which the tissue is obtained; the DNA is obtained from an individual mammal which is MHC matched, and preferably identical, with the individual mammal from which the tissue is obtained; the DNA includes an MHC class I gene; the DNA includes an MHC class II gene; the DNA is inserted into the cell by transduction, e.g., by a retrovirus, e.g., by a Moloney-based retrovirus; and the DNA is expressed in bone marrow cells and/or peripheral blood cells of the recipient 14, preferably 30, more preferably 60, and most preferably 120 days, after the DNA is introduced into the recipient.
In another aspect, the invention features a method of inducing tolerance in a recipient mammal, e.g., a human, to a tissue obtained from a donor mammal of the same species, which tissue expresses an MHC antigen, including: inserting DNA encoding an MHC antigen of the donor into a bone marrow hematopoietic stem cell of the recipient mammal; and allowing the MHC antigen encoding DNA to be expressed in the recipient.
Preferred embodiments include those in which: the cell is removed from the recipient prior to the DNA insertion and returned to the recipient after the DNA insertion; the DNA includes a MHC class I gene; the DNA includes a MHC class II gene; the DNA is inserted into the cell by transduction, e.g., by a retrovirus, e.g., by a Moloney-based retrovirus; and the DNA is expressed in bone marrow cells and/or peripheral blood cells of the recipient 14, preferably 30, more preferably 60, and most preferably 120 days, after the DNA is introduced into the recipient.
Tolerance, as used herein, refers to the inhibition of a graft recipient's ability to mount an immune response which would otherwise occur, e.g., in response to the introduction of a nonselr MHC antigen into the recipient. Tolerance can involve humoral, cellular, or both humoral and cellular responses.
Bone marrow hematopoietic stem cell, as used herein, refers to a bone marrow cell which is capable of developing into mature myeloid and/or lymphoid cells.
MHC antigen, as used herein, refers to a protein product of one or more MHC genes; the term includes fragments or analogs of products of MHC genes which can evoke an immune response in a recipient organism. Examples of MHC antigens include the products (and fragments or analogs thereof) of the human MHC genes, i.e., the HLA genes. MHC antigens in swine, e.g., miniature swine, include the products (and fragments and analogs thereof) of the SLA genes, e.g., of the DRB gene.
Miniature swine, as used herein, refers to partially inbred miniature swine.
Graft, as used herein, refers to a body part, organ, tissue, or cells.
The invention allows the reconstitution of a graft recipient's bone marrow with transgenic autologous bone marrow cells expressing allogeneic or xenogeneic MHC genes. Expression of the transgenic MHC genes confers tolerance to grafts which exhibit the products of these or closely related MHC genes. Thus, methods of the invention provide for the induction of specific transplantation tolerance by somatic transfer of MHC genes.
Methods of the invention avoid the undesirable side effects of broad spectrum immune suppressants which are often used in transplantation. Drugs such as Prednisone, Imuran, CyA, and most recently FK506, have all had important impact on the field of transplantation. However, all of these drugs cause nonspecific suppression of the immune system which must be titrated sufficiently to avoid rejection while not completely eliminating immune function. Patients must stay on chronic immunosuppressive therapy for the remainder of their lives, facing the major complications of too much or too little immunosuppression, infection and rejection, respectively.
Tolerance to transplantation antigens can be achieved through induction of lymphohematopoietic chimerism by bone marrow transplantation (BMT). However, successful BMT across MHC barriers

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