Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Reexamination Certificate
1999-11-30
2002-08-06
Stucker, Jeffrey (Department: 1647)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
C435S069100, C435S069500, C435S440000, C435S445000, C530S351000, C530S387300, C536S023500, C536S023520, C536S023720, C536S023100, C514S002600, C514S008100, C514S012200
Reexamination Certificate
active
06428985
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention generally relates to the fields of cytokines and immunology. More specifically, it concerns the surprising delineation of the immunosuppressive and immunostimulatory properties of the molecule, IL-10. The invention thus provides mammalian and human IL-10 biological compositions that have only immunosuppressive properties, and are not comprised by immunostimulatory effects. The new IL-10 constructs may thus be used in various in vitro and in vivo methods, particularly in immunosuppressive therapies, and combinations thereof, for various inflammatory diseases and disorders, and in transplantation.
2. Description of Related Art
IL-10 was originally described as cytokine synthesis inhibitory factor (Fiorentino et al., 1989) because of its ability to turn off cytokine production by T cells. IL-10 is now known to have both immunostimulatory and immunosuppressive effects, which may vary depending on the cell types involved and other events in immune regulation.
Early in vitro studies showed that IL-10 can directly inhibit TH1 and TH2 IL-2 production (de Waal et al., 1993) and IL-5 production (Schandene et al., 1994) at the level of the T cell. T cell stimulation in vitro in the presence of IL-10 can lead both to long term anergy (Groux et al., 1996) and the production of a negative regulatory T cell subset (Groux et al., 1997). In vivo, IL-10 inhibits T cell mediated delayed type hypersensitivity and contact hypersensitivity (Powrie et al., 1993; Enk et al., 1994; Ferguson et al., 1994; Li et al., 1994; Berg et al., 1995; Flores-Villanueva et al., 1996).
Further investigations demonstrated that the immunosuppressive effects of. IL-10 are more often at the level of the APC and not directly at the level of the T cell (Fiorentino et al., 1991a). Thus, IL-10 inhibits monocyte and macrophage synthesis of IL-l&agr;, IL-&bgr;, IL-6, IL-8, IL-12, TNF&agr;, GM-CSF, and reactive oxygen and nitrogen intermediates (de Waal et al., 1991a; Bogdan et al., 1991; Fiorentino et al., 1991b; D'Andrea et al., 1993). IL-10 inhibits dendritic cell stimulation of TH1 IFN&ggr; production (Macatonia et al., 1993); APC B7 expression (Ding et al., 1993; Willems et al., 1994; Villanueva et al., 1994); and antigen presentation to TH1 but not TH2 cells (Enk et al., 1993), while inducing IL-1 receptor antagonist production in neutrophils (Cassatella et al., 1994).
IL-10 also suppresses epidermal Langerhans cell APC functions (Chang et al., 1994; Beissert et al., 1995), chemokine expression by monocytes (Berkman et al, 1995), and the bactericidal response of macrophages to IFN&ggr; (Murray et al., 1997). IL-10 treated dendritic cells induce peptide antigen and alloantigen specific tolerance (Steinbrink et al., 1997). Additional studies demonstrated that IL-10 inhibits the immune function of other cell types, too. Thus, IL-10 inhibits NK cell production of IFN&ggr; (Tripp et al., 1993), ICAM-1 expression on activated vascular endothelial cells (Eissner et al., 1996), and T independent responses of B cells (Pecanha et al., 1993).
Therefore, investigations have shown that the predominant effect of IL-10, is to suppress multiple immune responses through individual actions on T cells, B cells, APCs, and other cell types. The prominent effects on IL-12 and IFN&ggr; production and responsiveness suggest that IL-10 channels immunity away from TH1 and toward TH2 responses, although both types of responses can be inhibited under some circumstances (de Waal et al., 1993; Schandene et al., 1994; Fiorentino et al., 1991a; Macatonia et al., 1993; Enk et al., 1993; Steinbrink et a., 1997). It is not clear why IL-10 has opposing effects on TH2 subsets, inhibiting or promoting subset activity.
Additional correlative studies have focused on the role of IL-10 in various disease states or models. IL-10 can effectively treat the cytokine syndrome and toxicity caused by anti-CD3
MAb or endotoxin by inhibiting the production of proinflammatory cytokines (Wissing et al., 1997; Howard et al., 1993; Pajkrt et al., 1997). Autoimmune models of rheumatoid arthritis (Katsikis et al., 1994), thyroiditis (Mignon-Godefroy et al., 1995), and collagen-induced arthritis (Kasama et al., 1995) and a model of herpetic stromal keratitis (Daheshia et al., 1997); all suggest negative regulatory roles for IL-10 in limiting inflammation and immunopathology.
IL-10 can inhibit tumor immunity (Qin et al., 1997); and there are numerous examples of a relation among IL-10 expression, allograft survival, and decreased alloreactivity (Gorczynski and Wojcik, 1994; Bacchetta et al., 1994; Mottram et al., 1995; Mutsuda et al., 1994; Péguet-Navarro et al., 1994; Danzer et al., 1994; Burke et al., 1995; Sayegh et al., 1995; Gorczynski et al., 1995). IL-10 deficient knockout mice have highly polarized TH1 responses and develop a severe colitis related to chronic stimulation by enteric antigens (Rennick et al., 1997). In humans, Crohn's colitis may even be susceptible to treatment with systemically administered IL-10 (van Deventer et al., 1997). Likewise, psoriasis may be due to unregulated cutaneous TH1 responses and IL-10 administration may be effective treatment for humans (Asadulla et al., 1998).
Further reinforcement for the notion that IL-10 is an immunosuppressive cytokine came from the discovery of vIL-10 (Moore et al., 1990), which was shown to have identical immunosuppressive properties to cIL-10, inhibiting IFN&ggr; production (Hsu-et al., 1990), MHC class II expression (de Waal et al., 1991b), T cell proliferation (Del Prete et al., 1993), and B cell IgE production (Punnonen et al., 1993). There is speculation that vIL-10 is important for EBV pathogenesis through suppression of the specific anti-viral immune response. A recent case report provides circumstantial evidence for this view (Nast et al., 1997).
Despite the acceptance of IL-10 as an immunosuppressive molecule, a number of findings suggest that IL-10 has actions which are more complex than originally proposed. IL-10 can inhibit T independent B cell responses, but not T dependent responses (Pecanha et al., 1993).
In fact, IL-10 can act as a B cell growth factor (Fei et al., 1990), a property shared by cIL-10 and vIL-10, and even support the autocrine growth of B cell lymphomas (Beatty et al., 1997). IL-10 can act as a proliferative co-factor for immature and mature thymocytes stimulated by IL-2 plus IL-4,(MacNeil et al., 1990). Interestingly, while cIL-10 can co-stimulate thymocyte proliferation and B cell MHC class II expression, vIL-10 cannot (Fei et al., 1990; MacNeil et al., 1990), suggesting differences in the structure and function of the two molecules.
IL-10 genes transfected into ovarian or mammary tumors promote anti-tumor immunity and rejection, instead of suppressing the immune response (Richter et al., 1993; Allione et al., 1994). Most significantly, transduction of tumors with a retroviral vector encoding mIL-10 results in enhanced tumor immunity and rejection, while vIL-10 tumor cell transduction results in immune suppression and tumor growth (Suzuki et al., 1995). Studies using a cardiac allograft model also showed that vIL-10 prolongs graft survival while mIL-10 impairs graft survival (Qin et al., 1996a). These results demonstrate that cIL-10 is not necessarily exclusively immunosuppressive in its actions, and that vIL-10 is immunosuppressive under conditions in which cIL-10 is immunostimulatory.
There are a large number of studies in which there has been a general failure to correlate the presence or absence of IL-10 with allograft survival or rejection (Baan et al., 1994; Shirwan et al., 1994; Cunningham et al., 1994; Le Moine et al., 1994; Sun et al., 1994; Allen et al., 1993; Garlisi et al., 1993; Bishop et al., 1993; Merville et al., 1993; Delvaux et al., 1994; Merville et al., 1995; Krenger et al., 1994). One interpretation of these results is that the presence or absence of other cytokines such as IL-4, IFN&ggr;, or IL-12 could affect the final immune outcome. Another view, however, is that IL-10
Bromberg Jonathan S.
Ding YaoZhong
Qin LiHui
Fulbright & Jaworksi LLP
Seharaseyon Jegatheesan
Stucker Jeffrey
The Regents of the University of Michigan
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