Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus
Reexamination Certificate
1998-05-29
2001-12-04
Clark, Deborah J. R. (Department: 1633)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Genetically modified micro-organism, cell, or virus
C424S093100, C514S002600, C435S069100, C435S325000, C435S335000
Reexamination Certificate
active
06325999
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to suppression of T-lymphocyte-mediated immune responses, including those directed against autologous tissue in autoimmune conditions and/or transplanted tissues, e.g., rejection of autologous tissue in autoimmune conditions or of allogeneic or xenogeneic tissue transplanted into patients in need of such tissues, e.g., transplants of porcine islet cells into patients who have or are at risk of developing diabetes mellitus.
Type I or juvenile onset diabetes is a major health problem in the United States. Diabetes and its complications double the risk of fatal heart disease and increase the risk of blindness and stroke at least four fold. Diabetes mellitus is characterized by insulin deficiency which prevents normal regulation of blood glucose levels, and which leads to hyperglycemia and ketoacidosis. The primary cause of kidney failure leading to kidney transplantation is diabetes.
Insulin, a peptide hormone, promotes glucose utilization, protein synthesis, formation and storage of neutral lipids, and the growth of some cell types. Insulin is produced by the &bgr; cells within the islets of Langerhans of the pancreas. Early-onset diabetes (10-20% of cases) is caused by an auto-immune reaction that causes complete destruction of &bgr; cells. Adult-onset diabetes has a number of causes, but in most cases the &bgr; islet cells are defective in secretion of insulin.
Insulin injection therapy, usually with porcine or bovine insulin, prevents severe hyperglycemia and ketoacidosis, but fails to completely normalize blood glucose levels. While injection therapy has been quite successful, it fails to prevent the premature vascular deterioration that is now the leading cause of morbidity among diabetics. Diabetes-related vascular deterioration, which includes both microvascular degeneration and acceleration of atherosclerosis, can eventually cause renal failure, retinal deterioration, angina pectoris, myocardial infarction, peripheral neuropathy, and arteriosclerosis.
Large scale production of human insulin has become possible with the cloning of the human insulin gene, which has begun to replace bovine and porcine insulin as the treatment of choice. Use of human insulin has eliminated some of the problems associated with other forms of insulin, including antibody-mediated insulin resistance and allergic reactions resulting from the slightly different structures of non-human insulins. Despite these advantages, treatment with human insulin does not prevent vascular deterioration.
Insulin delivery pumps have been developed which administer varying doses of insulin based on activity, diet, time of day, and other pre-programmed factors. While such devices improve blood sugar control, they also do not prevent vascular deterioration.
While the maintenance of blood sugar control with exogenous insulin has proved of significant value in reducing diabetes-related complications, the most effective form of therapy is thought to be providing patients with an endogenous source of insulin. Surgical transplantation of part or all of the pancreas is difficult, however, because the pancreas is a fragile and complicated organ, the only practical source is a deceased donor. Further, only a small portion of the pancreas, the &bgr; cells of the islet of Langerhans, produce insulin; the remainder of the pancreas presents a potent target for transplant rejection. Transplantation of just the islets of Langerhans is a desirable goal, as they continue to secrete appropriate amounts of insulin in response to nutritional signals even when isolated from the rest of the pancreas.
Islet cell transplantation has been successfully performed in animals made diabetic by prior treatment with a drug which destroys &bgr; cells. Successful transplantation in these animals has been shown to restore normal blood glucose regulation and reduce further vascular deterioration. In these animal models, it is possible to use islet cells from donors which are syngeneic (fully tissue compatible, also referred to as histocompatible) to the diabetic recipient. In humans, fully tissue compatible donors are rare (1 in 200,000) and so from a practical standpoint, islets from mismatched humans (allografts) or non-humans (xenografts) will need to be employed.
A major problem associated with transplantation of any tissue is immune-mediated graft rejection in which the recipient's T-lymphocytes recognize donor histocompatibility antigens as foreign. Thus, even though human and xenogeneic insulin can be used to partially control diabetes, the use of allografts and/or xenografts as a true therapy for diabetes depends on preventing transplant rejection. Current regimes for transplanting many tissues and organs require life-long administration of immunosuppressive drugs. these drugs have serious side-effects and can cause increased susceptibility to infection, renal failure, hypertension, and tumor development.
In addition to transplant rejection based on recognition of allogeneic and xenogeneic tissue differences, it has been observed first in diabetic rodents and later in humans that transplanted islet cells could be destroyed in diabetic hosts even when host and donor were genetically identical. Naji et al. (1981) Science 213:1390 showed that spontaneously diabetic animals maintained a skin and bone marrow allograft while an islet allograft of the same genetic makeup as the skin and bone marrow allograft was destroyed. It appears that the disease process that destroyed the native islet &bgr; cells can recur and destroy transplanted islet cells. This phenomenon, termed disease recurrence, is the process in which a target tissue is destroyed independent of histocompatibility differences between donor and host that are involved in allograft responses. This disease differs from conventional transplantation responses in several ways. Perhaps the most important difference is that the dose of immunosuppression which can be effectively used to prevent acute rejection of most allografts (e.g., kidney, liver, etc.) is not nearly as effective in preventing disease recurrence in diabetes. This lack of effectiveness is equally true for xenografts. Increasing the dose of immunosuppression leads to toxicity. Thus, it is clear that approaches must be developed which protect transplanted cells against both transplant rejection and disease recurrence.
A second problem has been the paucity of islet tissue suitable for transplantation. While sources of donor insulin from non-primate species is clinically effective in reversing hyperglycemia, xenogeneic donor tissue is subject to violent rejection. Further, the ready accessibility of non-human donors as a source of islet tissue has been to date of no practical value.
Several immunologically privileged sites in mammals allow prolonged survival of transplanted allografts (Naji & Barker (1976) J. Surg. Res. 20:261-267). The remarkable survival of islet allo- and xenografts transplanted into abdominal testes has been reported (Selawry & Fojaco (1985) Diabetes 34:1019-1024; Bellgrau & Selawry (1990) Transplantation 50:654-657; Selawry et al. (1987) Diabetes 36:1061-1067). Selawry et al. (1991) Transplantation 52:846-850 have shown that an unknown factor or factors released by testicular Sertoli cells appears to be responsible for the protection of the intratesticular islet allo- and xenografts against rejection. This unknown factor (s) has been reported to inhibit the production of IL-2 in vitro (Selawry et al. (1991) supra)
Selawry & Cameron (1993) Cell Transplantation 2:123-129 studied the use of Sertoli cells to establish an immunologically privileged site in vivo in the renal subcapsular space. Diabetic PVG rats received rat islet cells grafts with and without Sertoli cells (Sertoli enriched fraction, or SEF) and with and without cyclosporine (CsA). The results showed that 70%-100% of the recipient rats receiving islet cells alone, islet cells and CsA alone, or islet cells and SEF alone, remained hyperglycemic. In contrast, prolonged normoglycemia in excess of 1
Bellgrau Donald
Duke Richard C.
Clark Deborah J. R.
Kaushal Sumesh
Ross P.C. Sheridan
University Technology Corporation
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