Drug – bio-affecting and body treating compositions – Lymphokine – Interleukin
Reexamination Certificate
1998-10-09
2003-12-09
Eyler, Yvonne (Department: 1646)
Drug, bio-affecting and body treating compositions
Lymphokine
Interleukin
C424S198100, 51, C530S351000
Reexamination Certificate
active
06660258
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to methods of stimulation of host defense mechanisms in a mammal by administration of Th1 or Th2 specific cytokines via the oromucosa, as well as to compositions for oromucosal delivery of Th1 or Th2 specific cytokines. In particular, the invention is applicable to methods of treatment of autoimmune, allergic, inflammatory, intracellular bacterial, neoplastic, neurological, parasitic, and viral diseases.
BACKGROUND OF THE INVENTION
Interleukins (ILs) are a diverse class of secreted peptides and proteins whose principal function is the mediation of local interactions among cells. Most information regarding ILs comes from work with leukocytes, especially lymphocytes.
It is now generally accepted that CD4 T cells can be divided into two functionally distinct subsets, T helper 1 (Th1) and T helper 2 (Th2) cells, characterized by the pattern of cytokines which they produce. Thus, mouse Th1 cells produce interferon &ggr; (IFN-&ggr;), tumor necrosis factor &bgr; (TNF &bgr;), and interleukin 2 (IL-2), whereas mouse Th2 cells produce IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13. Human Th1 and Th2 cells have similar patterns of cytokine secretion, although the synthesis of IL-2, IL-6, IL-10, and IL-13 is not as tightly restricted to a single subset as in the mouse. Several other cytokines are secreted by both Th1 and Th2 cells, including IL-3, TNF &agr;, granulocyte-macrophage colony-stimulating factor (GM-CSF), Met-enkephalin, and certain chemokines-(CK). Other novel cytokines, such as IL-18 (Yoshimoto et al. 1997, Proc. Natl. Acad. Sci. USA, 94, 3948-3953), originally designated interferon gamma inducing factor (IGIF), which potentiates Th1 responses continue to be described, and it is highly probable that other novel cytokines which influence either a Th1 or Th2 response, will be discovered in the future.
Th1 and Th2 patterns of cytokine secretion correspond to activated effector phenotypes generated during an immune response. They do not exist among naive T cells. Thus, when first stimulated by antigen on antigen-presenting cells (APC), naive CD4+ T cells initially produce only IL-2, and then differentiate into phenotypes that secrete other cytokines. A third class of CD4+ T. cells, designated Th0 cells, has been identified, which consists of partially differentiated effector cells which express both the Th1 and Th2 patterns of cytokine expression and may represent a transient stage along the differentiation pathway into Th1 and Th2 cells. A fourth class of CD4+ T cells termed Th3 cells, producing high levels of transforming growth factor P (TGFP), has also been recognized.
Th1 and Th2 cells not only produce different sets of cytokines, resulting in distinct functional properties, but also preferentially express certain activation markers. Thus, human Th1 cells preferentially express lymphocyte activation gene 3 (LAG-3), a member of the immunoglobulin superfamily, while human Th2 cells preferentially express CD 30, a member of the TNF receptor family. LAG-3 expression is enhanced by IFN &ggr; and inhibited by IL-4, while CD 30 expression is dependent upon the presence of IL-4. Th1 cells also express E-selectin, p-selectin ligands and the &bgr;chain of the IL-12 receptor, which are not expressed by Th2 cells.
CD8+ T cell cytotoxic (Tc) cell subsets can also be distinguished on the basis of the cytokines they produce. Thus, Tc1 cells secrete IL-12 and IFN &ggr; and cells with a Tc2 profile secrete IL-4 and IL-5 and are found in certain pathological conditions, such as lepromatous leprosy and HIV infected individuals with high IgE levels.
The functions of Th1 and Th2 cells correlate well with their distinctive cytokines. Thus Th1 cells are involved in cell mediated immune responses (macrophage activation, antibody-dependent cell cytotoxicity and delayed type hypersensitivity) and resistance to virus infection, and several Th1 cytokines activate cytotoxic and inflammatory reactions. Th2 cytokines potentiate antibody production, particularly IgE responses, and also enhance mucosal immunity through production of growth and differentiation factors for mast cells and eosinophils. Accordingly, Th2 cells are associated with antibody production, allergic reactions, and susceptibility to virus infection.
Th1 and Th2 cytokines are mutually inhibitory for the differentiation and effector functions of the reciprocal phenotype. Thus, IL-12 and IFN &ggr; selectively inhibit the proliferation of Th2 cells and IL-4 and IL-10 inhibit Th1 development. In many cases the use of cytokines or anticytokines can reverse host resistance or susceptibility to infection. See the Th1-Th2 Paradigm, Sergio Romagani, Immunology Today, June 1997, 18:6 (263-266).
Interleukin-2 (IL-2) is a biological response modifier which activates cytolytic T-cells and natural killer cells (see Kuziel, W. A. and Gree, W. C. (1991), Interleukin-2, in The Cytokine Handbook, A. Thompson (Ed.), San Diego, Calif., Academic Press, pages 83-102). Therefore, IL-2 has been examined for its therapeutic potential against malignancies, immunodeficiencies and chronic infections.
Basically, IL-2 regulates the proliferation and differentiation of T-lymphocytes and other lymphoid cells, by binding to a high affinity cell surface receptor composed of three polypeptide chains: alpha, beta and gamma (Waldmann, T. A., 1993, Immunol. Today, 14:264). Data presented by Vasily Gelfanov et al. (Proceedings of the Keystone Symposium on Mucosal Immunity, 1997, S1124:12) show that intestinal intra-epithelial lymphocytes, which are known to differ in a number of important respects from T-cells of the central immune system, respond preferentially to a recently identified T-cell growth factor, interleukin 15 (IL-15), rather than to the classical T-cell growth factor, IL-2.
IL-15 interacts with a heterotrimeric cell surface receptor that consists of the beta and gamma subunits of the IL-2 receptor as well as a specific high-affinity IL-15 binding subunit designated IL-15R alpha. Since both the beta and gamma subunits of the IL-2 receptor are required for signalling by either IL-2 or IL-15, it is not surprising that these two cytokines have been reported to share a number of common biologic activities (Kennedy, M. K. and Park L. S., 1996, J. Clin. Immunol., 16:134-143).
In common with interferon alpha, IL-12 is one of the principal regulators of natural killer (NK) cell activity, which plays an important role in host defense against neoplastic cells (Kobayashi, M., 1989, J. Exptl. Med., 170:827). IL-12, which is produced principally by macrophages, also induces the release of interferon gamma by activated T-cells and NK cells, and synergizes with IL-2 to generate lymphokine-activated killer (LAK) cells (Aragane et al., 1994, J. Immunol., 153:5366-5372). IL-12 together with IL-2 and interferon gamma plays a pivotal role in the development of T helper type 1 (Th1) effector cells. A Th1 response is often associated with resistance to infection and has been shown to play a decisive role in the antiviral action of interferon alpha 2 in patients infected with human papillomavirus (Arany, I. and Tyring, K., 1996, J. Interferon and Cytokine Res., 16:453-460).
The antitumor activity of systemically administered IL-2 is thought to be mediated principally by LAK cells (Natuk et al., 1989, J. Virol., 63:4969-4971). The antiviral activity of systemically administered IL-2 is thought to be mediated principally by macrophage mediated antibody-dependent cellular cytotoxicity (ADCC), which involves the induction of interferon gamma in helper T-cells (Kohe et al., J. Inf. Dis., 159:239-247), and through LAK cells (Natuk et al., 1989, J. Virol.; 63:4969-4971).
Interleukins are generally administered parenierally. However, parenteral administration of IL-2 is associated with a number of severe side-effects, such as hematological toxicity and renal dysfunction (see Haworth, C., and Feldmann; M., 1991, Applications of cytokines in human immunotherapy in The Cytokine Handbook, A. Thompson (Ed.), San Diego, Calif.: Academic Pre
Andres J.
Browdy and Neimark , P.L.L.C.
Eyler Yvonne
Pharma Pacific Pty Ltd
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