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  Immunomodulatory methods using oligosaccharidesUSPTO Application #: 20060040893Title: Immunomodulatory methods using oligosaccharides Abstract: Methods for modulating immune responses are provided. The methods involve contacting an immune cell with an agent that modulates interaction of a compound comprising a Lewis antigen with the immune cell such that production by the immune cell of at least one cytokine that regulates development of a T helper type 1 or T helper type 2 response is modulated. In one embodiment, the agent is a stimulatory form of a compound comprising a Lewis antigen, such as a Lewisy, Lewisx or Lewisa oligosaccharide, or a derivative thereof. In another embodiment, the agent is an inhibitory form of a compound comprising a Lewis antigen, such as a Lewisy, Lewisx or Lewisa oligosaccharide, or a derivative thereof. In various embodiments, the immune cell is a human immune cell, a macrophage or a T cell. Pharmaceutical compositions for modulating immune responses are also provided. (end of abstract) Agent: Lahive & Cockfield, LLP. - Boston, MA, US Inventors: Donald A. Harn, Palanivel Velupillai USPTO Applicaton #: 20060040893 - Class: 514054000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), O-glycoside, Polysaccharide The Patent Description & Claims data below is from USPTO Patent Application 20060040893. Brief Patent Description - Full Patent Description - Patent Application Claims
RELATED APPLICATION [0001] This application is a continuation of U.S. application Ser. No. 08/597518 filed Jan. 31, 1996 (now U.S. Pat. No. 6841543, issued Jan., 11, 2005), the entire contents of which are hereby incorporated by reference. BACKGROUND OF THE INVENTION [0003] The T lymphocyte compartment of the immune system can be divided into a variety of cell subsets. For example, CD4+ T cells represent the T helper cell subset, whereas CD8+ T cells represent the cytotoxic T cell subset. Additionally, CD4+ T helper cells mature into distinct subpopulations that produce different panels of cytokines: the T helper type 1 (Th1) subset produces interleukin-2 (IL-2), interferon-.gamma. (IFN-.gamma.) and tumor necrosis factor-.uparw. (TNF-.beta.), whereas the T helper type 2 (Th2) subset produces interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-6 (IL-6) and interleukin-10 (IL-10). The Th1 and Th2 subsets also have differing functional activities. Th1 cells are involved in inducing delayed type hypersensitivity responses, whereas Th2 cells are involved in providing efficient "help" to B lymphocytes and stimulate production of IgG1 and IgE antibodies. For a review of Th1 and Th2 subsets, see Seder, R. A. and Paul, W. E. (1994) Ann. Rev. Immunol. 12:635-673. [0004] Cytokines are thought to play a dominant role in controlling the differentiation of .tau. helper precursors (Thp) to either the Th1 or Th2 lineage. Th1-associated cytokines, such as IFN-.gamma., can enhance the development of Th1 cells and inhibit the development of Th2 cells, whereas Th2-associated cytokines, such as IL-4 and IL-10, can enhance the development of Th2 cells and inhibit the development of Th1 cells. Thus, cytokines can reciprocally regulate the development and/or progression of either a Th1 or a Th2 response. [0005] The course of certain disease states is influenced by whether a predominant Th1 response or Th2 response is mounted. For example, in experimental leishmania infections in mice, animals that are resistant to infection mount predominantly a Th1 response, whereas animals that are susceptible to progressive infection mount predominantly a Th2 response (Heinzel, F. P., et al. (1989) J. Exp. Med 169:59-72; Locksley, R. M. and Scott, P. (1992) Immunoparasitology Today 1:A58-A61). In murine schistosomiasis, a Th1 to Th2 switch is observed coincident with the release of eggs into the tissues by female parasites and is associated with a worsening of the disease condition (Pearce, E. J., et al. (1991) J. Exp. Med. 173:159-166; Grzych, J-M., et al. (1991)J. Immunol. 141:1322-1327; Kullberg, M. C., et al. (1992) J. Immunol. 148:3264-3270). Many human diseases, including chronic infections (such as with human immunodeficiency virus (HIV) or tuberculosis) and certain metastatic carcinomas, also are characterized by a Th1 to Th2 switch, with elevated expression of IL-10 (see e.g., Shearer, G. M. and Clerici, M. (1992) Prog. Chem. Immunol. 54:21-43; Clerici, M and Shearer, G. M. (1993) Immunology Today 14:107-111; Yamamura, M., et al. (1993) J. Clin. Invest. 91:1005-1010; Pisa, P., et al. (1992) Proc. Natl. Acad. Sci. USA 89:7708-7712; Fauci, A. S. (1988) Science 239:617-623). Furthermore, certain autoimmune diseases have been shown to be associated with a predominant Th1response. For example, patients with rheumatoid arthritis have predominantly Th1 cells in synovial tissue (Simon, A. K., et al. (1994) Proc. Natl. Acad. Sci. USA 91:8562-8566) and experimental autoimmune encephalomyelitis (EAE) can be induced by autoreactive Th1 cells (Kuchroo, V. K., et al. (1993) J. Immunol. 151:4371-4381). [0006] Velupillai and Harn (Proc. Natl. Acad. Sci. USA (1994) 91:18-22) have shown that schistosome egg antigen (SEA), which expresses the Lewis.sup.x antigen, and conjugates of the Lewis.sup.x antigen, can stimulate IL-10 production by B cells from Schistosoma mansoni infected mice, but not B cells from uninfected mice, suggesting that during the course of S. mansoni infection, the observed Th1to Th2 shift may results from IL-10 production by B cells induced by SEA. This work, however, did not demonstrate whether human immune cells (e.g., human immune cells in the absence of S. mansoni infection) were responsive to Lewis antigen-containing compounds, nor whether cell types other than B cells, such as macrophages or T cells, could produce IL-10 in response to stimulation with compounds comprising a Lewis antigen in the absence of S. mansoni infection. Moreover, this work did not demonstrate whether production other cytokines that regulate development of Th1 and Th2 responses, such as IL-4, could be stimulated SUMMARY OF THE INVENTION [0007] Given the role of either Th1 or Th2 cells in the development or progression of many disease states, methods for influencing whether a Th1 or Th2 response is mounted are desirable for a variety of clinical situations. This invention provide methods for modulating immune responses by modulating the interaction of immune cells with a compound comprising a Lewis antigen such that production by the immune cells of at least one cytokine that regulates development of a Th1 or Th2 response is modulated. The invention is based, at least in part, on the discovery that stimulation of human immune cells, T cells or macrophages with Lewis antigen-containing conjugates results in the production of cytokines that regulate the development of Th1 or a Th2 response. Moreover, it has now been discovered that human immune cells are sensitive to stimulation by Lewis.sup.y antigen-containing conjugates, that cells from human allergy patients and cancer patients show responsiveness to Lewis antigens, that IL-4 production can be stimulated by Lewis antigen-containing conjugates and that conjugates wherein the sugars represent approximately 20-24% of the conjugate by weight, or greater, are preferred for stimulation. The immunomodulatory methods of the invention allow for an immune response to be directed to either a Th1 or a Th2 response. The ability to influence the development of either a Th1 or a Th2 response using the immunomodulatory methods of the invention is applicable to the treatment of a wide variety of disorders, including cancer, infectious diseases (e.g., HIV and tuberculosis), allergies and autoimmune diseases. [0008] In one embodiment, the invention provides an immunomodulatory method comprising contacting a human immune cell with an agent that modulates interaction of a compound comprising a Lewis antigen with the human immune cell such that production by the human immune cell of at least one cytokine that regulates development of a Th1 or Th2 response is modulated. The human immune cell can be, for example, a T cell, a macrophage or a B cell. In another embodiment, the invention provides an immunomodulatory method comprising contacting a macrophage with an agent that modulates interaction of a compound comprising a Lewis antigen with the macrophage such that production by the macrophage of at least one cytokine that regulates development of a Th1 or Th2 response is modulated. In yet another embodiment, the invention provides an immunomodulatory method comprising contacting a T cell with an agent that modulates interaction of a compound comprising a Lewis antigen with the T cell such that production by the T cell of at least one cytokine that regulates development of a Th1 or Th2 response is modulated. [0009] In one embodiment of the immunomodulatory methods of the invention, production by immune cells of at least one cytokine (preferably IL-10 or IL-4) that regulates development of a Th1 or Th2 response is stimulated. In this embodiment, the agent with which the immune cells are contacted preferably is a stimulatory form of a compound comprising a Lewis antigen, such as a compound comprising cross-linked (i.e., multivalent) Lewis.sup.y oligosaccharides, Lewis.sup.x oligosaccharides, Lewis.sup.a oligosaccharides or derivatives thereof (e.g., sulfated, sialylated or sulfo-sialylated forms of these oligosaccharides). The stimulatory compound can be, for example, a conjugate of the Lewis antigen and a carrier molecule (e.g., human serum albumin or polyacrylamide). For stimulating responses by human immune cells, the agent preferably comprises a Lewis.sup.y oligosaccharide or a derivative thereof. [0010] In another embodiment of the immunomodulatory methods of the invention, production by immune cells of at least one cytokine (preferably IL-10 or IL-4) that regulates development of a Th1 or Th2 response is inhibited. In this embodiment, the agent with which the immune cells are contacted preferably is an inhibitory form of a compound comprising a Lewis antigen, such as a soluble, monovalent (i.e., non-crosslinked) form of a Lewis.sup.y oligosaccharide, a Lewis.sup.x oligosaccharide, a Lewis.sup.a oligosaccharide or a derivative thereof (e.g., sulfated, sialylated or sulfo-sialylated forms of these oligosaccharides). For inhibiting responses by human immune cells, the agent preferably comprises a Lewis.sup.y oligosaccharide or a derivative thereof. [0011] The stimulatory or inhibitory compounds of the invention can be contacted with immune cells in vitro to produce one or more cytokines that regulate the development of a Th1 or Th2 response. After in vitro stimulation, the immune cells can be administered to a subject to influence whether a Th1 or a Th2 response predominates in the subject. Alternatively, a stimulatory or inhibitory compound of the invention can be administered to a subject such that production of at least one cytokine that regulates development of a Th1 or Th2 response is either stimulated or inhibited, respectively, in the subject, thereby influencing whether a Th1 or a Th2 response predominates in the subject. Accordingly, another aspect of the invention pertains to pharmaceutical compositions suitable for pharmaceutical administration. The pharmaceutical compositions of the invention typically comprise a stimulatory or inhibitory agent of the invention (e.g., a compound comprising a Lewis antigen) and a pharmaceutically acceptable carrier. In one embodiment, the composition is formulated to modulate responses by human immune cells. In this embodiment, the active agent preferably comprises a Lewis.sup.y oligosaccharide. In another embodiment, the composition is formulated to modulate responses by macrophages. In yet another embodiment, the composition is formulated to modulate responses by T cells. BRIEF DESCRIPTION OF THE DRAWINGS [0012] FIG. 1A is a bar graph depicting the proliferation of splenocytes from S. mansoni infected mice when stimulated with either media alone, Con A, LPS. anti-IgM, SEA or LNFP III conjugated to HSA. [0013] FIG. 1B is a graph depicting the proliferation of splenocytes from S. mansoni infected mice when stimulated with increasing amounts of either Lewis.sup.a antigen, Lewis.sup.x antigen, sialyl-Lewis.sup.x antigen or sialyl-Lewis.sup.a antigen, each conjugated to polyacrylamide. [0014] FIG. 1C is a bar graph depicting the proliferation of splenocytes from uninfected mice when stimulated with either media alone, Con A, LPS. anti-IgM, SEA or LNFP III conjugated to HSA. [0015] FIG. 1D is a graph depicting the proliferation of splenocytes from uninfected mice when stimulated with increasing amounts of either Lewis.sup.a antigen, Lewis.sup.x antigen, sialyl-Lewis.sup.x antigen or sialyl-Lewis.sup.a antigen, each conjugated to polyacrylamide. [0016] FIG. 2A is a bar graph depicting the production of IL-10by splenocytes from S. mansoni infected mice when stimulated with either media alone, Con A, LPS. anti-IgM, SEA or LNFP III conjugated to HSA. [0017] FIG. 2B is a graph depicting the production of IL-10 by splenocytes from S. mansoni infected mice when stimulated with increasing amounts of either Lewis.sup.a antigen, Lewis.sup.x antigen, sialyl-Lewis.sup.x antigen or sialyl-Lewis.sup.a antigen, each conjugated to polyacrylamide. [0018] FIG. 2C is a bar graph depicting the production of IL-10 by splenocytes from uninfected mice when stimulated with either media alone, Con A, LPS. anti-IgM, SEA or LNFP III conjugated to HSA. [0019] FIG. 2D is a graph depicting the production of IL-10 by splenocytes from uninfected mice when stimulated with increasing amounts of either Lewis.sup.a antigen, Lewis.sup.x antigen, sialyl-Lewis.sup.x antigen or sialyl-Lewis.sup.a antigen, each conjugated to polyacrylamide. [0020] FIG. 3A is a bar graph depicting the production of IL-4 by splenocytes from S. mansoni infected mice when stimulated with either media alone, Con A, LPS. anti-IgM, SEA or LNFP III conjugated to HSA. [0021] FIG. 3B is a graph depicting the production of IL-4 by splenocytes from S. mansoni infected mice when stimulated with increasing amounts of either Lewis.sup.a antigen, Lewis.sup.x antigen, sialyl-Lewis.sup.x antigen or sialyl-Lewis.sup.a antigen, each conjugated to polyacrylamide. Continue reading... Full patent description for Immunomodulatory methods using oligosaccharides Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Immunomodulatory methods using oligosaccharides patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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