Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Patent
1997-08-01
1999-11-02
Caputa, Anthony C.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
4242341, 4241841, 4241851, 4242481, 530300, 530350, 530412, 530413, 530326, 530417, 514 2, A61K 3904, A61K 3803, C07K 1435
Patent
active
059765437
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to agents that may be used for the treatment of autoimmune diseases, and more particularly to a protein having a molecular weight of about 12-kDa isolated and purified from the purified protein derivative (PPD), the major fraction of Mycobacterium tuberculosis (Mt) that protects mice against the induction of experimental autoimmune encephalomyelitis (EAE), and to salts, functional derivatives, analogs and active fractions thereof.
ABBREVIATIONS
In the specification, the following abbreviations will be used: Ag, antigen; EAE, experimental autoimmune encephalomyelitis; PPD, purified protein derivative; MBP, myelin basic protein; Mt, Mycobacterium tuberculosis; PLP, proteolipid protein; RPLC, reverse phase high-pressure liquid chromatography; CFA, complete Freund's adjuvant; IFA, incomplete Freund's adjuvant; SDS-PAGE, sodium dodecyl sulphate polyacrylamide gel electrophoresis; hsp, heat shock protein.
BACKGROUND OF THE INVENTION
Increasing evidence suggests that infectious agents can affect the development of autoimmune diseases. Viruses have been most often implicated in the etiology of autoimmune diseases, although bacteria may also be involved: streptococcal infection may lead to rheumatic fever and myocarditis, Mycoplasma arthriditis or its toxins can cause arthritis in mice or rats, and arthritis has also been associated with reactivity to mycobacterial antigens, both in humans and rats. However, several reports indicate that viruses and bacteria may also enhance the natural propensity of mice to become resistant to an autoimmune disease. Thus, non-obese diabetic mice infected with lymphocytic choriomeningitis virus become resistant to the development of insulin-dependent diabetes mellitus, and mice infected with lactic dehydrogenase virus are refractory to the development of experimental autoimmune encephalomyelitis (EAE). Similarly, bacteria may also be involved in conferring resistance to autoimmune diseases, as demonstrated in a previous study by the present inventor (Lehman and Ben-Nun, 1992).
EAE is an autoimmune disease of the central nervous system (CNS) that is caused by CD4.sup.+ T lymphocytes specific for myelin antigens, such as MBP or PLP (Ben-Nun and Lando, 1983). In SJL/J mice, the disease can be induced by injecting the animals with CNS homogenate, MBP or PLP, or with peptides derived therefrom (Raine, 1984). However, disease induction is dependent on the presence of immunoadjuvant in the inoculum. Mt is routinely used as the immunopotentiating agent in the induction of experimental autoimmune diseases. However, its mode of action in enhancing the development of the disease remains unclear. Although controversial data were obtained, there is an indication that Mt can also protect Lewis rats against the induction of an autoimmune disease (Lisak and Kies, 1968; MacPhee and Mason, 1990; Hempel et al., 1985). The inventor recently analyzed the effect of Mt and other bacteria on EAE in SJL/J mice, and observed that mice pre-exposed to Mt acquired long-lasting resistance to EAE, even when the bacteria were administered as an aqueous preparation, rather than as an emulsion in IFA. This study clearly demonstrated that Mt can not only promote the development of EAE, but can also protect against the disease, depending on the time of exposure to the bacteria (Lehman and Ben-Nun, 1992). Because effective protection was obtained with non-pathogenic bacterial preparations (heat-killed bacteria), it was speculated that immunity against a particular component(s) of Mt may be sufficient to confer resistance against induction of an autoimmune disease. Accordingly, it was recently demonstrated by the inventor that PPD is the major fraction of Mt which confers on mice resistance to induction of EAE (Ben-Nun et al., 1993). The protection observed following immunization with PPD was not a simple consequence of a non-specific effect on the immune balance, as other immunogens, both bacterial and non-bacterial, had only marginal or no protective effect.
REFERENCES:
patent: 4879213 (1989-11-01), Fox et al.
A. Ben-Nun et al., "A 12-KDA Protein of Mycobacterium Tuberculosis Protects Mice Against Experimental Autoimmune Encephalomyelitis." J. Immul., vol. 154, No. 6, pp. 2939-2948 (Mar. 15, 1995).
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A. Ben-Nun et al., "Protection Against Autoimmune Disease by Bacterial Agents II. PPD and Pertussis Toxin as Proteins Active in Protecting Mice Against Expiremental Autoimmune Encephalomyelitis." Eur. J. Immunol., vol. 23, No. 3, pp. 689-696 (1993).
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Dan Lehmann et al., "Bacterial Agents Protect Against Autoimmune Disease. I. Mice Pre-exposed to Bordetella Pertussis or Mycobacterium Tuberculosis are Highly Refractory to Induction of Experimental Autoimmune Encephalomyelitis", Journal of Autoimmunity, vol. 5, pp. 675-690, 1992.
Robert P. Lisak et al., "Mycobacterial Suppression of Delayed Hypersensitivity in Experimental Allergic Encephalomyelitis", Proc. Soc. Exp. Biol. Med., vol. 128, pp. 214-218, 1968.
Iain A.M. MacPhee et al., "Studies on the Refractoriness to Reinduction of Experimental Allergic Encephalomyelitis in Lewis Rats That Have Recovered From One Episode of the Disease", Journal of Neuroimmunology, vol. 27, pp. 9-19, 1990.
Caputa Anthony C.
Masood Khalid
Yeda Research and Development Co. Ltd.
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