Immunological tolerance-inducing agent

Details Immunological tolerance-inducing agent Immunological tolerance-inducing agent

2000-07-25

2002-04-02

Swartz, Rodney P (Department: 1645)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Bacterium or component thereof or substance produced by said...

C424S241100, C424S275100, C424S282100, C424S810000, C514S885000, C530S868000

Reexamination Certificate

active

06365163

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to inflammatory reactions caused by certain infectious microorganisms. Specifically, it relates to an agent comprising a mucosa-binding molecule linked to a specific antigen derived from a microorganism, which is useful in inducing systemic immunological tolerance to the specific antigen and thus preventing or treating deleterious inflammatory reactions caused by the microorganism.
BACKGROUND OF THE INVENTION
Introduction of a foreign substance, herein referred to as an antigen (Ag), including a hapten, by injection into a vertebrate organism can result in the induction of an immune response. Typically, an immune response involves the production of specific antibodies (products of B lymphocytes) capable of interacting with the antigen and/or the development of effector T lymphocytes and the production of soluble mediators, termed lymnphokines, at the site of encounter with the antigen. Antibodies and T lymphocytes play essential roles in protecting against a hostile antigen; under certain circumstances, however, they also participate in injurious processes in response to an antigen that lead to destruction of host tissues. For example, the local reaction of antibodies and/or T lymphocytes with an antigen derived from an infectious microorganism at certain anatomical sites can cause extensive tissue damage. This is the case in chronic inflammatory reactions that develop as a result of ineffective elimination of foreign materials, as in certain infections (e.g. tuberculosis, schistosomiasis, and infections caused by Chlamydia,
Helicobacter pylori, Pneumocystis carinii,
etc.) where immunoproliferative reactions develop at the site(s) of microbial colonization.
To develop vaccines effective against infectious microorganisms that cause destructive immunological reactions, it is desirable, on the one hand, to specifically prevent or reduce the rate of entry of the microorganisms into internal organs (or the uptake of potentially harmful components, such as toxins derived from these microorganisms), and, on the other hand, to specifically suppress (or decrease to an acceptable level) the intensity of deleterious immune processes without affecting the remainder of the immune system.
The most frequent portals of entry of common microbes are the mucosal surfaces covering the digestive tract, the respiratory tract, the urogenital tract, the eye conjunctiva, the inner ear, and the ducts of exocrine glands, which collectively represent the largest (400 m
2
) organ system in upper vertebrates. Endowed with powerful mechanical and physicochemical cleansing mechanisms, these surfaces are further protected by a specialized immune system that guards them against potential insults from the environment. This system, termed “mucosa-associated lymphoid tissue” (MALT), is the largest mammalian lymphoid organ system, and represents a well-known example of a compartmentalized immunological system. Through the compartmentalization of its afferent and efferent limbs, MALT functions essentially independently from the systemic immune apparatus, the latter system comprising peripheral lymphoid organs such as the blood, the bone marrow, the spleen, peripheral lymph nodes, and the thymus. This notion explains why systemic injection of immunogens is relatively ineffective at inducing an immune response in mucosal tissues.
The predominant component of the immune response expressed by MALT is the elaboration of secretory immunoglobulin A (SIgA), the predominant Ig class in human external secretions and one that provides specific immune protection for mucosal tissues. SIgA antibodies provide “immune exclusion” of bacteria and viruses, bacterial toxins, and other potentially harmful molecules, and have also been reported to neutralize certain viruses directly, to mediate antibody-dependent cell-mediated cytotoxicity (in cooperation with macrophages, lymphocytes and eosinophils), and to interfere with the utilization of growth factors for bacterial pathogens in the mucosal environment.
In contrast to the systemic immune apparatus, which is in a sterile compartment and responds vigorously to most invaders, the mucosal immune system guards organs that are replete with foreign matter including microorganisms. It follows that, upon encounter with a given antigen, the mucosal immune system must select appropriate effector mechanisms and regulate the intensity of its response so as to avoid bystander tissue damage and depletion of the immune response capacity.
In addition to inducing local SIgA antibody responses, ingestion or inhalation of antigens (mucosal route) may also result in the development of a state of peripheral immunological tolerance. Tolerance is characterized by a lack of immune responses in non-mucosal tissues when an antigen initially encountered in the digestive tract mucosa or the respiratory mucosa is reintroduced in the organism by a non-mucosal route such as by parenteral injection. Mucosal administration of antigens is in fact a long-recognized method of inducing immunological tolerance (Wells, H.,
J. Infect. Dis.
9:147, 1911). The phenomenon, often referred to as “oral tolerance” because it was initially documented by the effect of oral administration of antigen, is characterized by the fact that animals fed or having inhaled an antigen become refractory or have diminished capability to develop a systemic immune response when re-exposed to said antigen introduced by the systemic route, e.g., by injection. In broad terms, application of an antigen onto a mucosal membrane or into a mucosal tissue, be it the intestine, the lung, the mouth, the genital tract, the nose, or the eye, can induce the phenomenon of systemic immunological tolerance. By contrast, introduction of an antigen into a non-mucosal tissue, such as, for example, by a subcutaneous or intravenous route (referred to as systemic immunization) often results in an affirmative systemic immune response.
The phenomenon of “oral tolerance” is highly specific for the antigen that was introduced by the mucosal route. That is, hypo-responsiveness can only be documented subsequent to injection of the same antigen used to tolerize, but not after injection of a structurally unrelated antigen that had not been encountered previously at mucosal sites.
The specificity of oral tolerance for the initially ingested or inhaled antigen, and the lack of effect on the development of systemic immune responses against other antigens, makes it an increasingly attractive strategy for preventing and treating illnesses associated with or resulting from the development of untoward and/or exaggerated immunological reactions against specific antigens encountered in non-mucosal tissues.
The phenomenon of mucosally induced systemic tolerance may involve all types of immune responses known to be inducible by the systemic introduction of antigen, such as the production of specific antibodies and the development of cell-mediated immune responses to the antigen. Mucosally induced immunological tolerance has therefore been proposed as a strategy to prevent or to reduce the intensity of allergic reactions to chemical drugs (Chase, M. W.,
Proc. Soc. Exp. Biol.
61:257-259, 1946). It has also been possible in experimental animals and in humans to prevent or decrease the intensity of immune reactions to systemically introduced soluble protein antigens and to particulate antigens such as red cells by the oral administration of red cells (Thomas H. C. et al.,
Immunology
27:631-639, 1974; Mattingly, J. et al.,
J. Immunol.
121:1878, 1978; Bierme, S. J. et al.,
Lancet,
1:605-606, 1979). The phenomenon of mucosally induced systemic tolerance can be utilized to reduce or suppress immune responses not only against foreign antigens but also against self antigens, i.e., components derived from host tissues.
It has also been shown that the enteric administration of schistosome eggs in mice prevented the development or decreased the intensity of hepatic and intestinal granulomatous reactions, which are chronic T cell-mediate

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