Compositions and methods for tolerization in immune...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai

Reexamination Certificate

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C514S002600, C514S053000, C514S061000, C424S181100, C424S184100, C424S185100, C424S193100, C424S194100, C424S195110, C424S204100, C424S278100, C424S279100, C424S280100, C424S282100

Reexamination Certificate

active

06245752

ABSTRACT:

FIELD OF THE INVENTION
The present invention is related to novel compositions and methods for tolerization of specific B lymphocytes in humans. More particularly, the present invention is related to compositions comprising a suppressive amount of a repeated, antigenic carbohydrate determinant linked to a carrier molecule; and methods for using the compositions to tolerize shed antigen-specific B lymphocytes involved in immune complex-mediated disease progression.
BACKGROUND OF THE INVENTION
1. Pathology of the Immune Response in Lymphatic Tissues
Peripheral lymphatic tissues (“lymphoid tissues”) provide the environment for generation of a specific immune response to certain antigens when the lymphoid tissues are extra-regional to or draining a principal source of the antigen. In particular, cellular proliferation in lymphoid tissues has been noted in certain pathological conditions including solid, non-lymphoid tumors, and Leishmaniasis. 1.1 Solid, non-lymphoid tumors
The response of an individual to tumor cells involves the reactions and counteractions mediated by both cellular and humoral arms of the immune system. Tumor cell growth may represent a disturbance in the equilibrium of the immune system that is pre-existing, and/or induced by the tumor cells themselves. However, most investigations to date have focused on the role of T cells in tumor immunity. The role of B cells in a tumor-bearing individual still remains unclear. Previous studies have shown that lymph nodes and other lymphoid tissues extra-regional to a primary solid non-lymphoid tumor in cancer patients, and in vivo experimental animal models of tumor development, can undergo a prominent cellular expansion in the germinal centers of the tissue (see, e.g., Eremin et al., 1980,
Br. J. Cancer
41:62; Bertschmann et al., 1984,
Br. J. Cancer
49:477-484). Such lymphoid tissues contain immune cells that include B lymphocytes (B cells). However, the reason(s) for this observed B cell proliferative response remains unclear, and has been hypothesized be due to either activation and stimulation directly by tumor cells, and/or indirectly by stimulation of T-helper cells which then activate and stimulate B cells.
Such B cells appear to be able to elicit anti-tumor immunity. In that regard, there are numerous reports that cancer patients have circulating antitumor antibodies (see, e.g., Carey et al., 1976,
Proc. Natl. Acad. Sci. USA
73:3278-3282; Abe et al., 1989,
Cancer Res.
80:271-276; Christensen et al., 1989,
Int. J. Cancer
37:683-688). Thus, it appears that a humoral immune response towards tumor-associated antigens can be mounted in cancer patients. However, the roles of B cells, tumor associated antigens, and lymphoid tissues containing B cells, in the host response to tumor remain poorly defined.
1.2 Leishmaniasis
Protozoans of the genus Leishmania comprise a number of species causing disease (Leishmaniasis) in humans and animals; and hence, is considered a major health problem worldwide. The symptoms and sequelae of the disease depend on several factors relating to the infecting species and host resistance. For example, leishmanial infections range in severity from self-healing, localized cutaneous lesions, to a disseminating, highly destructive mucosal disease. Disseminated disease is ultimately lethal, and is characterized by hepatosplenomegaly, fever, wasting, and pan-cytopenia. Currently, it is believed that CD4+ T cells are responsible for both the protective immune response as well as the disease promoting immune response observed in individuals infected with a Leishmania species (see, e.g., Bogdan et al., 1990,
Eur. J. Immunol.
20:2533-2540). The outcome of the infection is determined, at least in part, by the balance of Th1 cells and Th2 cells, wherein a Th1response is host protective, and a Th2 response can lead to disease exacerbation (Liew et al., 1990,
J. Exp. Med.
172:1359-65). The mechanism by which Th2 cells exacerbate disease is thought to be Th2 cell secretion of IL-4 which neutralizes the macrophage-activating function of interferon-gamma produced by Th1 cells (Liew et al., 1990, supra). Thus, most investigations to date have focused on the role of T cells in immunity to Leishamania species. The role of B cells in an infected individual still remains unclear. However, it is known that the humoral immune response during an infection is characterized by high levels of parasite-specific and non-parasite directed antibodies, with the latter being a result of polyclonal B-cell activation (Evans et al., 1988,
Infect. Immun.
56:3139-44).
Previous studies have shown that lymph nodes and other lymphoid tissues draining the site of a Leishmania infection are believed to be the principal site for the development of the parasite-specific cellular immune response (Laskay et al., 1997,
J. Immunol.
158:1246-53). In a study of draining lymph nodes from 8 patients infected with Leishmania major, all such lymph nodes showed mild to marked cellular proliferation with active germinal centers. While only 1 lymph node was seen to contain the parasite (in the amastigote form), all lymph nodes contained a wide distribution of leishmanial antigen, most commonly seen associated with dendritic cells in the interfollicular zone, germinal center, paracortex, and marginal sinus (Al-Gindan et al., 1989,
Int. J. Dermatol.
28:248-254). These leish-manial containing-lymphoid tissues also contain immune cells that include B lymphocytes (B cells) and plasma cells. However, the roles of B cells, leishmanial antigens, and lymphoid tissues, in the host response to leishmanial infection remain poorly defined.
2. Immunologic Tolerance
Immunologic tolerance is an actively induced unresponsiveness to a specific antigen as the result of antigen-induced functional inactivation or death of lympho-cytes specific for that antigen. Antigens that induce such tolerance are termed “tolerogens”, so as to be distinguished from immunogens which are antigens that generate immune responses. Much more is known about the induction of tolerance of CD4+ T cells than in other lymphocytes such as B cells. One mechanism of B cell tolerance and failure to produce antibodies involves interaction of antigens with specific B cells, the first step in B cell activation, in the absence of stimulation by helper T cells or other antigen presenting cells (the second step in B cell activation). Other mechanisms of B cell tolerance have been proposed. B cells can become anergic due to a block in surface immunoglobulin-mediated signaling (“antigen-competition”), in absence of T cell help. Additionally, in absence of co-stimulation by an antigen presenting cell, strong crosslinking of B cell surface immunoglobulins by antigen can induce apoptotic death of normal, mature B cells, but may not induce apoptosis in B cells that produce autoimmune antibodies (see, e.g., Tsubata et al., 1994,
Curr. Biol.
4:8-17).
Various compounds employed in the development of compositions for inducing humoral anergy to self-antigens (e.g. as encountered in autoimmune diseases such as systemic lupus erythematosus or myasthenia gravis) or allergens are known in the art (see, e.g., U.S. Pat. Nos. 5,126,131, 5,276,013, 5,268,454, the disclosures of which are herein incorporated by reference). Briefly, substantially non-immunogenic compounds comprising either polymers or non-polymers have been used as a platform or carrier molecule to which is conjugated a B-cell epitope derived from an allergen or a known self-antigen. While it is believed the prior art shows that conjugates of nonimmunogenic carrier molecules and haptens or DNA may be used to induce B cell tolerance (anergy/unresponsiveness) in allergies and auto-immune diseases, it is also believed that the prior art fails to disclose, nor is it obvious therefrom, that B cell tolerance may be induced for therapeutic purposes in either cancer or microbial infections. On the contrary, the current belief of those skilled in the art is that the humoral response is important, if not critical, in the development of prote

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