Methods of controlling T lymphocyte mediated immune responses

Details Methods of controlling T lymphocyte mediated immune responses Methods of controlling T lymphocyte mediated immune responses

1995-06-07

2001-03-27

Cunningham, Thomas M. (Department: 1644)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving antigen-antibody binding, specific binding protein...

C435S006120, C530S300000, C530S350000, C530S327000

Reexamination Certificate

active

06207389

ABSTRACT:

This invention relates to methods for controlling T lymphocyte mediated immune responses. It also relates to methods and compositions for the prevention or amelioration of diabetes.
BACKGROUND OF THE INVENTION
T lymphocyte mediated immune responses are important in the development of most autoimmune diseases, including Type 1 insulin dependent diabetes mellitus (IDDM), and in transplant and tumour rejection in mammals (Slattery R M, Kjer-Nielsen L, Allison J, Charlton B, Mandel T E, Miller J F., “Prevention of diabetes in non-obese diabetic I-A
K
transgenic mice”, Nature, (1990), vol. 345, pp. 724-6; Lund T, O'Reilly L, Hutchings P, et al., “Prevention of insulin-dependent diabetes mellitus in non-obese diabetic mice by transgenes encoding modified I-A beta-chain or normal I-E alpha-chain”, Nature, (1990), vol. 345, pp. 727-9; Hutchings P R, Simpson E, O'Reilly L A, Lund T, Waldmann H, Cooke A., “The involvement of Ly2+T cells in beta cell destruction”, J. Autoimmun. (1990), vol. 1, pp. 101-9).
Genetic components have been identified in several T cell mediated autoimmune diseases which heighten the risk of disease development. There is, however, strong evidence that non-genetic (environmentally acquired) agents or events also participate and trigger or sustain the autoimmune response. This has been shown, for example, in IDDM (Thorsby E, Rønningen K S, “Particular HLA-DQ molecules play a dominant role in determining susceptibility or resistance to Type 1 (insulin dependent) diabetes mellitus”, Diabetologia, (1993), vol. 36, pp. 371-377).
There is at present no universally accepted model of autoimmunity, but mimicry models have received much attention. In these models, autoimmunity is perceived as an immunological cross-reaction between an auto- or self-antigen and a bona fide external antigen (Gray C, Matzinger P., “T cell memory is shortlived in the absence of antigen”, J. Exp. Med. (1991), vol. 174, pp. 969-972; Beverly PCL, “Is T cell memory maintained by cross-reactive stimulation?”, Immunol. Today, (1990), vol. 11, pp. 203-205). T cell sensitisation to self-antigens has been demonstrated in several diseases, including multiple sclerosis where sensitisation to myelin basic protein occurs, IDDM, ulcerative colitis, and arthritis. In IDDM, both mimicry antigen and disease-related self-antigen have been identified.
A conventional view of autoimmune diseases would suggest that administration of the autoantigen or self-antigen against which T cells are sensitised, or of analogues or fragments of the autoantigens, should cause T cell proliferation and exacerbation of the disease.
Lake et al. (Intl. Immunol. (1993), vol. 5, pp. 461-466) and Sloan-Lancaster et al. (Nature (1993), vol. 363, pp. 156-159) have reported on in vitro studies of anergy induction in activated T lymphocytes when the cells were exposed to analogues or high concentrations of an exogenous antigen or peptide to which the cells had previously been sensitised by experimental immunisation.
The present inventors are the first to demonstrate anergy induction in diabetes by a bona fide self-antigen. Using IDDM as a model, they have shown that under conditions in which the endogenous mimicry antigen has a fully stimulatory effect on activated T lymphocytes, the related autoantigen renders these cells anergic. Surprisingly, the anergenic effect was shown to be dominant, so that T lymphocyte can be rendered anergic by the self-antigen even in the presence of the fully stimulatory mimicry antigen.
The inventors have shown that development of IDDM can be prevented by treatment early in life with the self-antigen or fragments thereof. They have also demonstrated suppressed or delayed development of IDDM by immunisation with the mimicry antigen or fragments thereof.
SUMMARY OF THE INVENTION
In accordance with one embodiment of the present invention, there is provided a method for preventing the development of a T cell mediated autoimmune disease in a mammal having a population of T cells sensitised to an antigen related to said autoimmune disease comprising administering to the mammal an effective amount of a protein or peptide selected from the group consisting of
(a) the antigen;
(b) an effective fragment of the antigen; and
(c) an effective analogue of the antigen to prevent the expansion of the population of sensitised T cells.
In accordance with another embodiment of the present invention, there is provided a composition for preventing the development of a T cell mediated autoimmune disease in a mammal having a population of T cells sensitised to an antigen related to said autoimmune disease, said composition comprising an effective amount of a protein or peptide selected from the group consisting of
(a) the antigen;
(b) an effective fragment of the antigen; and
(c) an effective analogue of the antigen and a pharmaceutically acceptable carrier.
In accordance with a further embodiment of the present invention, there is provided a method for preventing the development of diabetes in a susceptible mammal comprising administering to the mammal an effective amount of a protein or peptide selected from the group consisting of
(a) p69 protein;
(b) peptide AFIKATGKKEDE (SEQ ID NO 23); and
(c) an analogue or fragment of (a) or (b).
In accordance with a further embodiment of the present invention, there is provided a composition for preventing the development of diabetes in a susceptible mammal comprising an effective amount of a protein or peptide selected from the group consisting of
(a) p69 protein;
(b) peptide AFIKATGKKEDE; and
(c) an analogue or fragment of (a) or (b) and a pharmaceutically acceptable carrier.
In accordance with a further embodiment of the present invention, there is provided a method for preventing or delaying the development of a T cell mediated autoimmune disease in a mammal having a population of T cells sensitised to an antigen related to said autoimmune disease comprising administering to the mammal an immunogenic composition comprising an effective amount of a protein or peptide selected from the group consisting of
(a) the antigen;
(b) an effective fragment of the antigen; and
(c) an effective analogue of (a) or (b) and a suitable adjuvant.
In accordance with a further embodiment of the present invention, there is provided a composition for preventing or delaying the development of a T cell mediated autoimmune disease in a mammal having a population of T cells sensitised to an antigen related to said autoimmune disease, said composition comprising an effective amount of a protein or peptide selected from the group consisting of
(a) the antigen;
(b) an effective fragment of the antigen; and
(c) an effective analogue of the antigen and a suitable adjuvant.
In accordance with a further embodiment of the present invention, there is provided a method for preventing or delaying the development of diabetes in a susceptible mammal comprising administering to the mammal an immunogenic composition comprising an effective amount of a protein or peptide selected from the group consisting of
(a) the antigen;
(b) an effective fragment of the antigen; and
(c) an effective analogue of (a) or (b) and a suitable adjuvant.
In accordance with a further embodiment of the present invention, there is provided an immunogenic composition for preventing or delaying the development of diabetes in a susceptible mammal comprising an effective amount of a protein or peptide selected from the group consisting of
(a) the antigen;
(b) an effective fragment of the antigen; and
(c) an effective analogue of the antigen and a suitable adjuvant.
In accordance with a further embodiment of the present invention, there is provided an isolated nucleic acid molecule having a nucleotide sequence selected from the group consisting of
(a) the sequence set out in
FIG. 1
a
(SEQ ID NO:1);
(b) the sequence set out in
FIGS. 2
a
and
2
b
(SEQ ID NO:3);
(c) the sequence set out in
FIG. 17
a
(SEQ ID NO:29);
(d) the sequence set out in
FIG. 17
b
(SEQ ID NO:30);
(e) the sequence set out in
FIG. 17
c
(SEQ ID NO:31);
(f)

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