Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,...
Reexamination Certificate
2000-10-19
2003-12-09
Chan, Christina (Department: 1644)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
C424S143100, C424S144100, C424S184100, C530S387100
Reexamination Certificate
active
06660266
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to the therapeutic modulation of inflammatory response modulation, and in particular to the suppression of macrophage proinflammatory responses to infectious and/or inflammatory stimuli.
BACKGROUND OF THE INVENTION
Macrophages are prodigious secretory cells which can produce a number of molecules which can either potentiate or dampen immune responses (Nathan,
J. Clin. Invest
. 79:319-322, 1987). In response to infectious or inflammatory stimuli, macrophages can produce several proinflammatory molecules, including TNF&agr;, IL-1, IL-6 and IL-12 (Nathan,
J. Clin. Invest
. 79:319-322, 1987; Trinchieri et al.,
J. Leukocyte Biol
. 59:505-511, 1996). These proinflammatory molecules are important for host defense, because experimentally infected animals deficient in these cytokines are invariably more susceptible to acute bacterial infections than are normal animals (Dalrymple et al.,
Infect. Immun
. 63:2262-2268, 1995; Kincy-Cain et al.,
Infect. Immun
. 64:1437-1440, 1996).
IL-12 is a 70 kDa heterodimer consisting of two covalently linked polypeptide chains, one of 35 kDa (p35) and the other of 40 kDa (p40). IL-12 plays an important role in the development of T
H
1-type immune responses (Trinchieri et al.,
J. Leukocyte Biol
. 59:505-511, 1996). This cytokine is a potent inducer of IFN&ggr; from T and NK cells, and it has been shown to play a crucial role in the development of immunity to intracellular pathogens (Heinzel et al.,
J. Exp. Med
. 177:1505-1512, 1993; Tripp et al.,
Proc. Nat. Acad. Sci. USA
90:3725-3729, 1993).
IL-12 is a potent inducer of cell-mediated immune responses, and animals lacking IL-12 are invariably more susceptible to infections with intracellular pathogens (Mattner et al.,
Eur. J. Immunol
. 26:1553-1559, 1996). It has been recently demonstrated that some microbes can influence IL-12 production by macrophages. Leishmania major, measles virus, and HIV have all been shown to downregulate the production of IL-12 by macrophages or monocytes infected with them (Carrera et al.,
J. Exp. Med
. 183:515-526, 1996; Karp et al.,
Science
273:228-231, 1996; Chehimi et al.,
J. Exp. Med
. 179:1361-1366, 1994). This downmodulation of IL-12 has the potential of providing these pathogens with a means of suppressing the development of cell-mediated immunity.
The production of proinflammatory cytokines such as IL-12, however, must be tightly regulated, since their production is also correlated with many of the pathologies associated with acute sepsis or with autoimmune diseases. The overproduction of IL-12 during an immune response, however, has the potential to be detrimental to the host. IL-12 produced during endotoxemia (Wysocka et al.,
Eur. J. Immunol
. 25:672-676, 1995), and during a number of autoimmune disorders, including insulin-dependent diabetes mellitus (Trembleau et al.,
J. Exp. Med
. 181:817-821, 1995), experimental allergic encephalomyelitis (Leonard et al.,
J. Exp. Med
. 181:381-386, 1995), or collagen-induced arthritis (Germann et al.,
Proc. Natl. Acad Sci. USA
92:4823-4827, 1995), can lead to exacerbated disease.
In many instances, macrophages can participate in the regulation of proinflammatory cytokines by the production of anti-inflammatory molecules. The secretion of prostaglandins, TGF&bgr;, and IL-10 by macrophages has been associated with anti-inflammatory responses (Tsunawaki et al.,
Nature
334:260-262, 1988; Bogdan et al.,
J. Exp. Med
. 174:1549-1555, 1991; Kunkel et al.,
J. Biol. Chem
. 263:5380-5384, 1988). These anti-inflammatory molecules have the potential to ameliorate the potentially deleterious effects of an overly aggressive immune response. Thus, the balance between the secretion of pro- and anti-inflammatory molecules by macrophages is a critical component of the acute phase response and has the potential to affect the adaptive immune response that subsequently develops.
Interleukin-10 (IL-10) is an 18 kDa cytokine produced by the T
H
2 subset of CD4+ helper cells. It is also produced by some activated B cells, by some T
H
1 cells (in humans), by activated macrophages, and by some non-lymphocytic cell types (e.g., keratinocytes). In contrast to IL-12, IL-10 has been associated with an inhibition of T
H
1-type immune responses. IL-10 has been shown to inhibit the production of T
H
1 cytokines and the proliferation of T
H
1 cells to antigen (Malefyt et al.,
J. Exp. Med
. 174:915-924, 1991; Fiorentino et al.,
J. Immunol
. 146:3444-3451, 1991). IL-10 inhibits IL-12 production by macrophages (D'Andrea et al.,
J. Exp. Med
. 178:1041-1048, 1993), and the administration of exogenous IL-10 can diminish the toxicity of LPS (Howard et al.,
J. Exp. Med
. 177:1205-1208, 1993; Berg et al.,
J. Clin. Invest
. 96:2339-2347, 1995). IL-10 has been considered for the treatment of autoimmune diseases such as arthritis (Hart et al.,
Immunology
84:536-542, 1995) and colitis (Davidson et al.,
J. Exp. Med
. 184:241-251, 1996).
The Fc&ggr; receptor (Fc&ggr;R) is a receptor for the Fc region of IgG. B and T lymphocytes, natural killer cells, polymorphonuclear leukocytes, mononuclear phagocytes, and platelets contain Fc&ggr; receptor. The three types of Fc&ggr; receptors include Fc&ggr;RI (CD64), Fc&ggr;RII (CD32) and Fc&ggr;RIII (CD16). CD16, the Fc&ggr;RIII, is the prototypical proinflammatory Fc receptor. Ligating Fc&ggr;RIII has been associated with the production of proinflammatory cytokines (Cassatella et al.,
J. Exp. Med
. 169:549-567, 1989), and mice lacking Fc&ggr;RIII undergo diminished Arthus reactions (Hazenbos et al.,
Immunity
5:181-188, 1996). CD32, the Fc&ggr;RII, is a negative regulator of immune complex-triggered immune responses, and mice lacking Fc&ggr;RII have augmented anaphylactic responses to IgG (Takai et al.,
Nature
379:346-349, 1996). Fc&ggr;RI represents a high-affinity receptor found on mononuclear phagocytes. In humans, its binds IgG1 and IgG3. Fc&ggr;RII and Fc&ggr;RIII are low-affinity IgG receptors.
A mechanism whereby receptor ligation can downmodulate IL-12 production by macrophages has been described (Sutterwala et al.,
J. Exp. Med
. 185:1977-1985 (1997). However, this previously described mechanism of IL-12 downregulation did not exhibit specificity with regard to the macrophage phagocytic receptors that could induce this downmodulation.
Lipopolysaccharide endotoxin (LPS) is a complex macromolecule from the cell walls of certain bacteria, some of which cause diseases like typhoid fever, dysentery, and urinary tract infections and from other bacteria which are common inhabitants of animal and human intestinal tracts but ordinarily do not cause disease. All of these bacteria have in common the same type of cell wall and are classified as Gram-negative. LPS induces the production and release of immunologically active cytokines and other mediators of the proinflammatory response.
There are many pathophysiological effects of LPS, one of which is endotoxemia or septic shock which results from large amounts of endotoxin in the blood. The majority of the cases of septic shock are a consequence of Gram-negative bacteremia (bacteria in the blood). However, the septic shock syndrome can be induced by other organisms including Gram-positive bacteria and fungi. A key factor in the development of toxic shock is the release of LPS from Gram-negative bacteria and the subsequent effects of the endotoxin on various cells in the body which become highly activated. As a result, the host is overwhelmed with many cell substances that lead to circulatory failure, shock and death.
There is a need for a therapeutic modality which is capable of reversing the proinflammatory responses of macrophages to stimuli such as bacteria and bacterial products, and stimuli associated with autoimmune disease. There is needed a therapeutic modality which is capable of inhibiting host proinflammatory immune responses while at the same time inducing host anti-inflammatory responses. In particular what is needed is a modality for dampening the acute response to inflammatory stimuli, su
Mosser David M.
Sutterwala Fayyaz
Belyavski Michail A.
Chan Christina
Drinker Biddle & Reath LLP
Temple University - of The Commonwealth System of Higher Educati
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