Immunological tolerance-inducing agent

Details Immunological tolerance-inducing agent Immunological tolerance-inducing agent

1997-04-22

2001-11-27

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, C514S828000, C530S868000

Reexamination Certificate

active

06322796

ABSTRACT:

The present invention relates to an immunological tolerance-inducing agent. Specifically it relates to such an agent comprising a mucosa-binding molecule linked to a specific tolerogen and to a method of inducing immunological tolerance in an individual against a specific antigen, including hapten.
BACKGROUND OF THE INVENTION AND DISCUSSION OF PRIOR ART
Introduction of a foreign substance, in the following referred to as antigen (Ag), including hapten, by injection into a vertebrate organism may result in the induction of an immune response characterized by the production of specific antibodies (products of B lymphocytes) capable of interacting with said Ag and/or the development of effector T lymphocytes and the production of soluble mediators, termed lymphokines, at the site of encounter with said Ag. Antibodies and T lymphocytes do certainly play an essential role in protecting against hostile Ag but can also participate in injurious processes leading to destruction of host tissues. This is the case in autoimmune diseases where antibodies and/or T lymphocytes react with Ag of one's own tissues and damage these. This is also the case in allergic reactions characterized by an exaggerated immune response to certain environmental matters and which may result in inflammatory responses leading to tissue destruction. Moreover, 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) or following introduction of foreign particles (e.g. asbestos). This is also the case in immunoproliferative reactions that follow the introduction into the body of an allograft and lead to its rejection.
One of the primary goals in developing effective therapies against diseases caused by unwanted or tissue damaging immunological reactions such as allograft rejection, autoimmune diseases, tissue destructive allergic reactions to infectious microorganisms or to environmental antigens, is to specifically suppress or decrease to an acceptable level the intensity of deleterious immune processes without affecting the remainder of the immune system.
The subject of immunological tolerance deals with all mechanisms that ensure an absence ofdestructive immune response, be it to one's own body constituents (“self antigens”) or to any given foreign substance.
A long-recognized method of inducing immunological tolerance is the oral administration of antigen which was first demonstrated by Wells for hen egg proteins (Wells, H. 1911. Studies on the chemistry of anaphylaxis III. Experiments with isolated proteins, especially those of hen's egg. J. Infect. Dis. 9:147). The phenomenon, often referred to as “oral tolerance” (because initially documented by the effect of oral administration of Ag), 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 Ag introduced by the systemic route, e. g. by injection. In broad terms, linking 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. As opposed to this, introduction of an antigen into a non mucosal tissue, i.e. for example the skin or the blood, referred to as systemic immunization, often results in an immune response with the characteristics mentioned above, and is referred to as systemic immune response. The phenomenon is highly specific of the Ag introduced by the mucosal route in the sense that hyporesponsiveness can only be documented subsequent to injection of said fed or inhaled Ag but not after injection of a structurally unrelated Ag (provided the latter had not previously been encountered at mucosal sites).
It is believed that ingested antigens are absorbed and processed by specialized cells, including epithelial enterocytes and Peyer's patch M cells, in the gut-associated lymphoid tissue (Owen, R. L., and P. Nemanic. 1978. Antigen processing structures of the mammalian intestinal tract: an SEM study of lymphoepithelial organs. Scanning Electron Microsc. 2: 367-378.). It is also believed that inhaled antigens are taken up by similar types of cells in the airway epithelium (Richardson J, Bouchard R and Ferguson C C. 1976. Uptake and transport of exogenous proteins by respiratory epithelium. Lab. Invest. 35:307-314). Following interaction of the antigen with accessory cells and cognate helper T cells and/or B lymphocytes in the local micro-environment of the gut and of the lung mucosae, an immune response may ensue, the characteristics of which may be influenced by several factors, including the nature of the antigen, the type of accessory cells and lymphocytes involved, and the genetic background of the host. However, ingestion or inhalation of antigens may also result in the development of a state of peripheral immunological tolerance, a situation characterized by the fact that immune responses in non-mucosal tissues will not develop even if the 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. Since this phenomenon is exquisitely specific of the antigen initially ingested or inhaled, and thus does not influence the development of systemic immune responses against other antigens, its use has become an increasingly attractive strategy for preventing and possibly treating illnesses associated 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 Ag, such as the production of antibodies and the development of cell-mediated immune responses to said Ag. 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. 1946. Inhibition of experimental drug allergy by prior feeding of the sensitizing agent. Proc. Soc. Exp. Biol. 61:257-259). It has also been possible to prevent or decrease the intensity of immune reactions to systemically introduced soluble protein antigens and particulate antigens such as red cells in experimental animals and in humans by the oral administration of red cells (Thomas H C and Parrot D M V 1974. The induction of tolerance to soluble protein antigens by oral administration. Immunology 27:631-639; Mattingly, J. and Waksman B. 1978. Immunological suppression after oral administration of antigen. Specific suppressor cells found in rat Peyer's patches after oral administration of sheep erythrocytes and their systemic migration. J. Immunol. 121:1878; Bierme, S. J.; Blank, M.; Abbal, M.; Fournie, A. 1979. Oral Rh treatment for severely immunized mothers. Lancet, 1:605-606).
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 thus been possible to decrease the intensity of experimentally induced autoimmune diseases in a variety of animal systems by mucosal deposition of auto-antigens onto the intestinal (by feeding) or the respiratory mucosa (by aerosolization or intranasal instillation of antigens). Thus, oral administration of collagen type II (a prominent type of collagen found in joint cartilage) has been shown to suppress or decrease the intensity of experimental autoimmune arthritis, a disease that can be induced in certain strains of rodents by injection of collagen type II together with Freund's complete adjuvant or by injection of
Mycobacterium tuberculosis
(a component of the former adjuvant) alone (Thompson, H S G and Staines, N A. 1986. Gastric admi

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