Chemistry: analytical and immunological testing – For preexisting immune complex or auto-immune disease
Patent
1998-04-27
2000-08-29
Chan, Christina Y.
Chemistry: analytical and immunological testing
For preexisting immune complex or auto-immune disease
436542, 530350, 530827, 530868, 530326, G01N 33564, G01N 33536, C07K 708, C07K 1400
Patent
active
061107468
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to novel peptides being epitopes of the human 60 KDa heat shock protein (hsp 60) and to pharmaceutical compositions comprising them for the diagnosis and treatment of 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 .beta.-cells located in the islets of the pancreas (Castano and Eisenbarth, 1990). 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 (Castano and Eisenbarth, 1990). NOD mice develop insulitis around 4 weeks 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 14-17 weeks of age. By 35-40 weeks 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 (Bendelac et al., 1987).
T cell reactivity and autoantibodies to various antigens have been detected in human IDDM patients as well as in NOD mice (Elias, 1994), 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 (Bowman et al., 1994). NOD diabetes is also preventable by induction of immunological tolerance in pre-diabetic mice to the antigen glutamic acid decarboxylase (Kaufman et al., 1993; Tisch et al., 1993).
Insulin dependent diabetes mellitus (IDDM) developing spontaneously in NOD female mice has been associated with immune reactivity to a variety of self-antigens (Bach, 1994). Notable among these antigens is the p277 peptide from the sequence of the mammalian 60 kDa heat shock protein (hsp60) molecule. This corresponds to residues 437-460 in the human hsp60 molecule (Elias et al 1991, Israel Patent Application No. 94241, PCT patent publication W090/10449). The human p277 peptide has the following sequence: -Pro-Ala-Asn-Glu-Asp (a.a. 437-460 of SEQ ID NO:1).
Pre-diabetic NOD mice manifest spontaneous, diabetogenic T cell responses to hsp60 and to the human (2) or mouse variants of the p277 peptide (3). The mouse and human peptides differ by 1 amino acid and are immunologicaly cross-reactive (3). Some non-diabetes prone strains of mice, such as C57BL/6, develop transient hyperglycemia and insulitis when immunized to p277 covalently conjugated to a foreign immunogenic carrier molecule (4). And mice of the C57BL/KsJ strain develop spontaneous T-cell responses to hsp60 and to p277 after treatment with a ver
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Abulafia Rivka
Bockova Jana
Cohen Irun R.
Elias Dana
Chan Christina Y.
VanderVegt F. Pierre
Yeda Research and Development Co. Ltd.
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