Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Patent
1997-06-30
2000-08-01
Cunningham, Thomas M.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
4241931, 435 724, 435 693, 530300, 530395, 530403, 536 235, A61K 3900, C07K 14725
Patent
active
06096314&
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates generally to peptide sequences, and methods of their use, which sequences modulate the activity of anti-idiotypic T cells. The activity of the anti-idiotypic T cells of interest is related to the ability of these T cells to recognize anti-p277 T cells. The peptides of the present invention thus comprise important tools in the effort to diagnose, prevent, alleviate or treat disease related to insulin-dependent diabetes mellitus (IDDM).
BACKGROUND OF THE INVENTION
Type I diabetes, or IDDM, is an autoimmune disease caused by T cells that attack and destroy the insulin-producing cells located in the islets of the pancreas (23). The autoimmune process culminating in IDDM begins and progresses without symptoms. The disease surfaces clinically only when the cumulative loss of .beta.-cells exceeds the capacity of the residual .beta.-cells to supply insulin. Indeed, the collapse of glucose homeostasis and clinical IDDM is thought to occur only after 80-90% of the .beta.-cells have been inactivated by the immune system. Thus, patients who can be identified as suffering from IDDM are bound to be in an advanced stage of autoimmune destruction of their .beta.-cells. Moreover, diagnosis of incipient, pre-clinical diabetes by the detection of immunological markers of .beta.-cell autoimmunity can be made only after the onset of the autoimmune process. Therefore, the therapeutic quest is to find a safe, specific and effective way to turn off an autoimmune process that is already well underway.
The present inventors have examined this question before by studying the spontaneous diabetes developing in mice of the NOD strain, which is considered to be a faithful model of human IDDM (23-25). NOD mice develop insulitis around one month of age, which begins as a mild peri-islet infiltrate and progresses to severe intra-islet inflammation. Hyperglycemia, which attests to insulin insufficiency, begins in the females in our colony at about three months of age. By six months of age, almost all the female NOD mice have developed severe diabetes and most die in the absence of insulin treatment. Male NOD mice have a lower incidence of disease, for reasons that are not clear. The diabetes of NOD mice has been shown to be caused by autoimmune T cells (26).
T cell reactivity and auto-antibodies to various antigens have been detected in human IDDM patients as well as in NOD mice (27), and it is not clear whether immunity to any single one of the possible target antigens is the primary cause of the disease. Beyond the question of causation is the question of therapy.
It has been demonstrated that the initiation of the autoimmune process in NOD mice can be prevented by subjecting the mice, before the onset of diabetes, to various manipulations such as restricted diet, viral infections, or non-specific stimulation of the immune system (24). NOD diabetes is also preventable by induction of immunological tolerance in pre-diabetic mice to the antigen glutamic acid decarboxylase (GAD) (28, 29).
Anti-idiotypic T cells are T cells that recognize peptides derived from the antigen receptors of other T cells (6). It is thought that anti-idiotypic T cells are involved in regulating the activities of the T cells whose T cell receptor (TCR) peptides they recognize. Autoimmune T cells might be subject to regulation by anti-idiotypic T cells: anti-idiotypic T cells have been detected following intentional T cell vaccination of rodents in the model of experimental autoimmune encephalomyelitis (EAE) (6) or of humans (7) suffering from multiple sclerosis (MS) with autoimmune T cells.
European patent application 261,648 discloses the use of activated T cells specific for an autoimmune disease for the treatment of such disease. The T cells are preferably first pressure treated, subjected to a chemical cross-linking agent and/or subjected to a cytoskeletal disrupting agent in order to improve their immunogenicity. The entire treated cell or fraction thereof may be used as a vaccine against the autoimmune d
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Cohen Irun R.
Elias Dana
Cunningham Thomas M.
Yeda Research and Development Co. Ltd.
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