Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-03
2004-09-28
Cook, Rebecca (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S825000, C514S903000
Reexamination Certificate
active
06797722
ABSTRACT:
The present invention relates to a method for the treatment of autoimmune diseases, which are effectively treated by administering the compound 3-(2-ethylphenyl)-5-(3-methoxyphenyl)-1H-1,2,4-triazole.
BACKGROUND OF THE INVENTION
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that is thought to be mediated by an autoimmune attack directed against CNS myelin antigens. Based on animal models, as well as on data gathered from analyses of leukocytes and tissues from patients with MS, antigen specificity is considered to reside within T cells expressing the &agr;&bgr; T cell receptor (TCR), with encephalitogenic activity dependent on the expression of a cytokine profile characteristic of a Th1-type phenotype: interferon-gamma (IFN&ggr;), lymphotoxin (LT) and tumor necrosis factor-alpha (TNF&agr;). T cells that express a Th2-type cytokine profile (IL-4, IL-5 and IL-13) or regulatory cytokines such as transforming growth factor-beta (TGF&bgr;) and IL-10, are thought to interfere with this process by blocking the acquisition of the Th1-phenotype and/or by blocking the downstream targets of effector cytokines, such as the activation of macrophages.
The critical nature of the cytokine profile of the antigen-reactive &agr;&bgr; T cells to disease expression raises the question as to the nature of the antigen recognition process that results in the acquisition of these specific cytokine profiles. Although it has been known for some time that the presence of adjuvants and the route of antigen presentation are important determinants of encephalitogenic activity in animals, how these processes shape the nature of the acquired immune response, as well as the contribution of other non-antigen-specific leukocyte populations, have only recently started to come into sharper focus with an expanding recognition of the different cell populations that function at the interface between the innate and acquired immune response.
The innate immune response functions as a first line of defense against a wide range of infectious and toxic agents. Historically, this response has been attributed to cells with phagocytic activity, such as macrophages and polymorphonuclear cells, and/or potent cytotoxic activity, such as natural killer cells (NK cells), mast cells and eosinophils. The activity of these different cell populations is aided and abetted by a number of different soluble molecules collectively known as acute phase proteins, such as the interferons, specific components of the complement cascade and cytokines, that serve to enhance phagocytic and cytotoxic activity, as well as lead to the accumulation of these cells at sites of tissue injury. If these first lines of defense are breached, then activation of the adaptive immune response ensues, leading to the formation of a specific immune response that may display anyone of a number of different characteristics. The generation of this acquired immune response is an exclusive property of lymphocytes.
More recently, however, it has become recognized that minor subpopulations of lymphocytes may also function as part of the innate immune response. Although it is likely that the complete functional role of these specialized subsets of lymphocytes remains poorly understood, current interest in them has focused on their role in defining the cytokine milieu at sites of tissue injury, influencing the nature of the adaptive immune response that is generated. Thus, many of these studies have focused on the role of IFN&ggr; and IL-12 in defining a Th1-type cytokine profile and IL-4 a Th2-type cytokine profile. Subpopulations of all of the three major groups of lymphocytes, &agr;&bgr; T cells, &ggr;&dgr; T cells and B cells, likely fall into this category. These lymphocyte populations are characterized by the use of a highly conserved antigen receptor complexes, expression of additional pattern-recognition receptors, such as members of the Toll-like receptor family or receptors normally detected on NK cells, and the rapid release of high levels of cytokines and chemokines following interaction with specific ligands.
&ggr;&dgr; T cells: T cells expressing the &ggr;&dgr; T cell receptor (TCR) constitute a minor population of the total circulating T cell population. In common with &agr;&bgr; T cells, &ggr;&dgr; T cells express a rearranged TCR, but the mechanisms involved in the acquisition of TCR diversity, as well as the nature of the antigens recognized, are clearly different (Chien Y. H. et al.
Annu. Rev. Immuniol.
1996;14:511-32). Analysis of CDR3 length distributions, as well as crystallographic studies, have suggested greater structural similarity of the &ggr;&dgr; TCR to immunoglobulin heavy chain genes, lending further support to the conclusion that the molecular nature of antigen recognition by &ggr;&dgr; T cells is fundamentally different from that utilized by &agr;&bgr; T cells. &ggr;&dgr; T cells also differ from &agr;&bgr; T cells in that most &ggr;&dgr; T cells coexpress receptors found on natural killer cells (NK—R) (Battistini L. et al.;
J. Immunol.
1997;159:3723-30). Expression of these receptors on T cells has been shown to modulate several T cell functions including cytotoxicity, cytokine release and transendothelial cell migration (Reyburn H. et al.,
Immunol. Rev.
1997;155:119-25) These data indicate that the regulation of &ggr;&dgr; T cell function is likely to be different from that found in most &agr;&bgr; T cells, involving activation (or inhibition) by signaling through both the TCR and NK—R. It has been suggested that NK—R functions as costimulatory molecules that are exquisitely responsive to changes in cell surface expression of MHC modulated by infection or to the activation state of the cells (Reyburn H. et al.,
ibid.
).
In healthy adults the majority of &ggr;&dgr; T cells express a TCR that utilizes the V&ggr;9V&dgr;2 gene segments The expansion of this specific population of &ggr;&dgr; T cells is thought to be due to a response to non-protein bacterial antigens such as pyrenil-pyrophosphate derivatives and other components of bacterial cell walls, without classical MHC-restriction (Salerno A et al.,
Crit. Rev. Immunol.
1998;18:327-57)). The response to these types of antigens has been found to be critically dependent upon the use of germline encoded lysine residues in the J&ggr;1.2 segment (Miyagawa F. et al.,
J. Immunol.
2001;167:6773-6779). Thus, although the response to phosphate antigens may be polyclonal in nature, conserved elements are used by the responding cells. Conserved sequences of &ggr;&dgr; T cell receptor have been noted in cells and/or tissues isolated from patients with MS, suggesting a response to a common antigen.
&ggr;&dgr; T cells share many features in common with the &agr;&bgr;TCR+NK-T cells, including the expression of NK receptors, constitutive expression of the IL-2r&bgr;, usage of highly conserved TCR sequences and restriction, at least for some subsets, by CD1 molecules (Spada F. M. et al,
J. Exp. ed.
2000;191:937-48). This would suggest that some &ggr;&dgr; T cells may provide a similar link between the innate and acquired immune response (Poccia F. et al.,
Immunol. Today
1998;19:253-6). Consistent with such a notion is that activation of V&dgr;2+ T cells with phosphate antigens has been shown to lead to the rapid release of large amounts of both cytokines and chemokines (Poccia F. et al.,
J. Immunol.
1997;159:6009-17; Cipriani B. et al,
Blood
2000;95:39-47). Interestingly, there are accumulating data that suggest that V region usage may implicate specific subsets of &ggr;&dgr; T cells in mediating Th1 or Th2-type responses—with V&dgr;2+ cells showing a Th1-type bias and V&dgr;1+ cells a Th2-type bias. So for example, it has been shown that &ggr;&dgr; T cells in MS lesions express a predominantly V&dgr;2 phenotype (Battistini L. et al.,
Mol. Med.
1995;1:554-62) and that V&dgr;2 cells in the peripheral blood of patients with MS show evidence of activation. In the CSF, however, V&dgr;1 cells are the predominant &ggr
Battistini Luca
Borsellino Giovanna
Carminati Paolo
De Santis Rita
Cook Rebecca
Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.
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