Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
1995-04-13
2001-07-03
Housel, James C. (Department: 1641)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Bacterium or component thereof or substance produced by said...
C424S093200, C424S093400, C424S093480, C424S258100, C424S184100, C435S069300, C435S173300, C435S173300, C435S252800, C435S252330
Reexamination Certificate
active
06254874
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to vaccines useful for the prevention or modification of microbial pathogenesis. In particular, this invention relates to vaccines comprising genetically attenuated microbial pathogens.
2. Description of the State of the Art
Microbial pathogens, or disease-producing microorganisms, can infect a host by one of several mechanisms. They may enter through a break in the skin, they may be introduced by vector transmission, or they may interact with a mucosal surface. Disease ensues following infection of the host, when the potential of the pathogen to disrupt normal bodily functions is fully expressed. Some disease-producing microorganisms possess properties, referred to as virulence factors, that enhance their pathogenicity and allow them to invade host or human tissues and disrupt normal bodily functions. The virulence of pathogens, that is, their ability to induce disease, depends in large part on two properties of the pathogen, invasiveness and toxigenicity. Invasiveness refers to the ability of the pathogen to invade host or human tissues, attach to cells, and multiply within the cells or tissues of the host. Toxigenicity refers to the ability of a pathogen to produce biochemicals, known as toxins, that disrupt the normal functions of cells or are generally destructive to cells and tissues.
The means by which vertebrates, particularly birds and mammals, overcome microbial pathogenesis is a complex process. Pathogens that invade the host provoke a number of incredibly versatile and protective systems. The first system that is triggered in response to tissue injury or infection is the complex defense mechanism of inflammation. Key to the inflammatory response is the release of various chemicals, such as histamine, from the injured tissue. Histamine causes blood vessels in the region to dilate, thus increasing local blood flow which results in swelling. The tissue fluid, which becomes loaded with extra clotting proteins from the plasma, begins to coagulate and prevents the normal flow of tissue fluid. As a result, the spread of the pathogen or its toxins is greatly slowed and is more or less confined to the area of tissue injury. In addition to this somewhat mechanical slowing of infection, the various chemicals that are released also serve to guide leukocytes or white blood cells toward the site of injury. The general function of leukocytes is to combat inflammation and infection. Some leukocytes, neutrophils and monocytes, are actively phagocytotic and they ingest microbial pathogens and other foreign material. Other leukocytes, lymphocytes, are key elements in the immune response of the body and are discussed in further detail below.
The rapidity of the inflammatory response is proportional to the extent of tissue destruction. Therefore, as an example, a staphylococcal infection, which produces great tissue destruction, is normally quickly confined by the inflammatory response, while streptococcal infections, which are less destructive, elicit a much slower inflammatory response. As a consequence, the confinement of Streptococcus and its toxins is less likely to be successful, and the pathogenic invasion can continue to spread throughout the body.
If all other barriers fail and the microbial pathogen or its toxins penetrate the body's defenses, as discussed above, and reach the bloodstream, the lymphoid tissue of the spleen, liver, and bone marrow will remove and destroy the foreign material as the blood circulates through these organs. Lymphoid tissue is composed primarily of a meshwork of interlocking reticular cells and fibers. Clinging to the interstices of the tissues are large numbers of leukocytes, more specifically lymphocyte cells, and other cells in various stages of differentiation, such as plasma cells, lymphoblasts, monocyte-macrophages, eosinophils and mast cells. The two main lymphocytes, T cells and B cells, have different and complementary roles in the mediation of the antigen-specific immune response.
The immune response is an exceedingly complex and valuable homeostatic mechanism having the ability to create antibodies against any foreign material or every chemical structure that might appear on the surface of a microbial pathogen or one of its toxic products. These foreign materials, referred to as antigens, elicit the ultimate response of the host, the acquired immune system, which operates by means of antibodies. An antibody is said to be specific as it attacks and binds only the antigen that triggered its production, thereby inactivating the antigen. The antigen contains some molecular species, usually protein or glycoprotein, that is not normally present in the host organism. Therefore, microorganismal cell membranes or toxins produced by the microorganism are considered antigenic in the host because they possess molecular species not normally present there.
The process of T cell and B cell development or differentiation describes the maturational events that begin with pluripotential bone marrow stem cells and end with a diverse population of specialized functioning T cells and B cells which mediate the cellular and humoral immune systems, respectively. In mammals, lymphocytes pass through the thymus gland in the throat where they differentiate into T cells, which mediate the cellular immune system. These cells are capable of killing other cells, and so this system is primarily effective against intracellular virus infections, fungi and parasitic worms. T cells also conduct an immune surveillance by watching the body's own cells for those that are developing into cancers. Other lymphocytes pass through the Peyer's patches, the small masses of lymphoid (lymphocyte-bearing) tissues that are distributed around the intestines, where they appear to differentiate into B cells. The B cells, through the production and release of antibodies (including secretory immunoglobulins of the secretory IgA subclass), which are a class of proteins known to mediate neutralization of extracellular bacteria and viruses.
There is a high degree of cooperation and interaction between these two classes of lymphocytes. T cells are first to detect the presence of antigens, and react quickly to bind the antigens with their surface receptor molecules. Once the antigen is bound, the T cell begins to proliferate by rapidly dividing and by producing the monomeric immunoglobulin that is localized on the membrane surface. The antigen-antibody (ag-ab) complexes that form as antigen molecules attach to these surface antibodies are released from the T cell and are then picked up by macrophage cells. The macrophage cells eventually become covered with ag-ab complexes that protrude from the surface with bound antigens facing away from the cells. The macrophage cells then present the antigens to B cells.
When a B cell binds to an antigen which has never been encountered, the cell undergoes repeated divisions to produce multiple clones. This event is considered a primary response. Within this population of “identical” cells, some mature to become antibody factories that release immunoglobulins into the blood. When they are fully mature, they become identified as plasma cells, cells that are capable of releasing about 2,000 identical antibody molecules per second until they die, generally within 2 or 3 days after reaching maturity. During the developmental changes, the plasma cells switch from producing general IgM type antibodies to producing highly specific IgG type antibodies. Other cells within this group of clones never produce antibodies but function as memory cells, which carry the program for the production of a highly specific IgG antibody that will recognize and bind a specific antibody.
As a consequence of the initial challenge by an antigen there are now many more cells identical to the original B cell or parent cell, each of which is able to respond in the same way to the antigen as the original B cell. Consequently, if the antigen appears a second time, it will encounter one of the
Klose Karl E.
Mekalanos John J.
Hogan & Hartson LLP
Housel James C.
Petersen Steven C.
President and Fellows of Harvard College
Ryan V.
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