Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Conjugate or complex
Reexamination Certificate
1997-02-04
2002-12-10
Navarro, Mark (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Conjugate or complex
C424S265100, C424S269100, C514S002600
Reexamination Certificate
active
06491922
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to methods and novel compounds for treating autoimmune and vascular disease. In particular, the invention relates to the use of lipophosphoglycan and novel lipophosphoglycan analogs to treat these diseases.
BACKGROUND OF THE INVENTION
Pro-inflammatory cytokines, such as interleukin-1 (IL-1), tumor necrosis factor (TNF-&agr;), and interleukin-6 (IL-6) are important mediators of sepsis, rheumatoid arthritis and reactive arthritis. They are also associated with other conditions such as atherosclerosis, progression of disease in persons infected with the human immunodeficiency virus, and autoimmune disorders. There were 250,000 reported cases of sepsis in the United States in 1987. Rheumatoid arthritis in the adult population is estimated at 1%, with an additional 1% of the population estimated to have reactive arthritis or juvenile rheumatoid arthritis. Therefore, pro-inflammatory cytokines play a direct role in the pathogenesis of conditions in nearly 3 million persons. Current therapeutic methods are not very effective in reducing the morbidity and/or mortality associated with these diseases.
Depressed cellular immunity and IL-1&bgr; production are associated with leishmaniasis caused by
Leishmania donovani. Leishmania donovani
is an obligate intracellular parasite of the mammalian macrophage. It is worldwide in distribution and annually causes disease in 20 million persons. The life cycle of Leishmania parasites consists of two stages. The flagellated promastigote form propagates in the alimentary tract of its insect vector (the sandfly) and develops into the infectious metacyclic promastigote stage. During the sandfly's blood meal, the metacyclic promastigotes are inoculated into the mammalian host. The promastigotes evade local host defense, disseminate, and enter macrophages throughout the reticuloendothelial system. Within macrophages they transform into the amastigote form which remains for the life of the new host. S. J. Turco and A. Descoteaux, “The Lipophosphoglycan of Leishmania parasites,”
Annu. Rev. Microbiol
., 46:65-94 (1992); J. L. Ho, R. Badaro, D. Hatzigeorgiou, S. G. Reed, and W. D. Johnson, Jr., “Cytokines in the Treatment of Leishmaniasis: From Studies of Immunopathology to Patient Therapy,”
Biother
. 7:223-35 (1994).
The two poles of immune responses in patients infected with
L. donovani
are: 1) a delayed type hypersensitivity (“DTH”) and CMI to Leishmania antigens which is associated with containment of infection, and 2) B cell activation with absence of DTH, and T-cell reactivity that is associated with visceral leishmaniasis (“VL”). J. L. Ho, R. Badaro, D. Hatzigeorgiou, S. G. Reed, and W. D. Johnson, Jr., “Cytokines in the Treatment of Leishmaniasis: From Studies of Immunopathology to Patient Therapy,” Biother. 7:223-35 (1994). Patients with acute VL have both a functional T-cell defect with decreased production of IL-2 and IFN-&ggr; in response to Leishmania antigens or mitogens, and a presumed monocytic defeat with decreased in vitro production of IL-1&bgr; and TNF-&agr; in response to Leishmania systate, LPS, or Listeria. E. M. Carvalho, R. Badaro, S. Reed, W. D. Johnson, Jr., and T. Jones, “Absence of IFN-&ggr; and IL-2 Production During Active Visceral Leishmaniasis,”
J. Clin. Invest
, 76:2066-9 (1985). These defects are attributed either to Leishmania products, or to a predominance of the T helper-2 (“Th2”) type of lymphocytes. S. J. Turco and A. Descoteaux, “The Lipophosphoglycan of Leishmania Parasites,”
Annu. Rev. Microbiol
., 46:65-94 (1992); P. Scott, “IFN-&ggr; Modulates the Early Development of Th1 and Th2 Responses in a Murine Model of Cutaneous Leishmaniasis,”
J. Immunmol
., 147:3149-3155 (1991); K. Varkla, R. Chatelain, L. M. C. C. Leal, and L. Coffman, “Reconstitution of C.B-17 SCID Mice with BALB/c T cells Initiates a T Helper Type-1 Response and Renders Them Capable of Healing Leishmania Major Infection,”
Eur. J. Immunol
. 23:262-268 (1992); C. L. Karp, S. H. El-Sagi, T. A. Wynn, M. M. H. Satti, H. M. Kordojani, F. A. Hashim, M. Hag-Ali, F. A. Neva, T. B. Nutman, and D. L. Sacks, “In vivo Cytokine Profiles in Patients with Kala-azar: Marked Elevation of Both Interleukin 10 and Interferon-gamma,”
J. Clin. Invest
. 91:1644-8 (1993); H. G. Ghalib, M. R. Piuvezam, Y. A. W. Skeiky, M. Siddig, F. A. Hashim, A. M. El-Hassan, D. M. Russo, and S. G. Reed, “Interleukin 10 Production Correlates with Pathology in Human
Leishmania donovani
Infections,”
J. Clin. Invest
. 92:324-9 (1993); L. Morris, A. B. Troutt, E. Handman, and A. Kelso, “Changes in the Precursor Frequencies of IL-4 and IFN-&ggr; Secreting CD4+ Cells Correlate with Resolution of Lesions Inmurin Cutaneous Leishmaniasis,”
J. Immunol
. 149:2715-2721 (1992); M. D. Sadick, F. P. Heinzel, B. J. Hodaday, R. T. Pu, R. S. Dawkins, and R. M. Locksley, “Cure of Murine Leishmaniasis with Anti-interleukin 4 Monoclonal Antibody; Evidence for a T cell-Dependent, Interferon-&ggr;-independent Mechanism,”
J. Exp. Med
. 171:115-127 (1990); L. M. Leal, D. W. Moss, R. Kuhn, W. Muller, and F. Y. Liew, “Interleukin-4 Transgenic Mice of Resistant Background are Susceptible to Leishmania Major Infection,”
Eur. J. Immunol
. 23:566-5690 (1993).
One unique characteristic of Leishmania infection is that the macrophage is unable to kill the parasite. In macrophages infected with Leishmania or treated with lipophosphoglycan (LPG) of promastigotes of
L. donovani
, impaired macrophage functions including production of IL-1&bgr; have been reported. S. J. Turco and A. Descoteaux, “The Lipophosphoglycan of Leishmania Parasites,”
Annu. Rev. Microbiol
. 46:65-94 (1992); T. B. McNeely and S. Turco, “Requirements of Lipophosphoglycan for Intracellular Survival of
Leishmania donovani
Within Human Monocytes,”
J. Immunol
. 144:2745-50 (1992); S. Frankenburg, V. Leibovici, N. Mansbach, S. J. Turco, and G. Rosen, “Effect of Glycolipids of Leishmania Parasites on Human Monocyte Activity,”
J. Immunol
. 145:4284-89 (1990); S. Frankenburg, A. Gross, and V. Leibovici, “
Leishmania major
and
Leishmania donovani
: Effect of LPG-containing and LPG-deficient Strains on Monocyte Chemotaxis and Chemiluminescence,”
Exp. Parsitol
. 75:442-8 (1992); A. Descoteaux and G. Matlashewski, “C-fos and Tumor Necrosis Factor Gene Expression in
Leishmania donovani
-infected Macrophages,”
Molecular Cell Biol
. 9:5223-7 (1989); N. E. Reiner, W. Ng, C. B. Wilson, R. McMaster, and S. K. Burchett, “Modulation of in vitro Monocyte Cytokine Response to
Leishmania donovani
. Interferon-&ggr; Prevents Parasite-induced Inhibition of Interleukin-1 Production and Primes Monocytes to Respond to Leishmania by Producing Both Tumor Necrosis Factor-&agr; and Interleukin-1
,” J. Clin. Invest
. 85:1914-240 (1990). Similarly, diminished macrophage activation and/or IL-1 production have been reported to Th-2 derived cytokines such as, IL-4, IL-6, and IL-10. Essner, R. K. Rhoades, W. H. Mcbride, D. L. Morton, and J. S. Economou, “IL-4 Down-regulates IL-1 and TNF Gene Expression in Human Monocytes,”
J. Immunol
. 142:3857-61 (1989); J. L. Ho, S. H. He, M. J. C. Rios, and E. A. Wick, “Interkeukin-4 Inhibits Human Macrophage Activation by Tumor Necrosis Factor, Granulocyte-macrophage Colony Stimulating Factor and Interleukin-3 for Anti-leishmania Activity and Oxidative Burst Capacity,”
J. Infect. Dis
. 165.344-51 (1992); D. H., Hatzigeorgiou, S. H. He, J. Sobel, A. Hafner, K. Grabstein, and J. L. Ho, “Interleukin-6 Down-modulates Cytokine-enhanced Antileishmanial Killing,”
J. Immunol
. 151:3682-92 (1993); C. Bogdan, J. Paik, Y. Vodovotz, and C. Nathan, “Contrasting Mechanisms for Suppression of Macrophage Cytokine Release by Transforming Growth Factor-&ggr; and Interleukin-10
,” J. Biol. Chem
. 267:23301-8 (1992). IL-1&bgr; produced by macrophages and other antigen-presenting cells mediates T-cell activation and proliferation and triggers T-cell production of IL-2. M. Luqman, L. Greenbaum, D. Lu, and K. Bottomly, “Differential Effect of Interleukin 1 on Naive and Memory CD4+ T Cells
Cornell Research Foundation Inc.
Navarro Mark
Nixon & Peabody LLP
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