Drug – bio-affecting and body treating compositions – Extract – body fluid – or cellular material of undetermined... – Blood
Reexamination Certificate
1999-11-20
2002-04-30
Huff, Sheela (Department: 1642)
Drug, bio-affecting and body treating compositions
Extract, body fluid, or cellular material of undetermined...
Blood
C530S388250, C530S388100
Reexamination Certificate
active
06379708
ABSTRACT:
This invention relates generally to the field of immunotherapy and, more specifically, to methods for enhancing host immune responses.
BACKGROUND OF THE INVENTION
The immune system of mammals has evolved to protect the host against the growth and proliferation of potentially deleterious agents. These agents include infectious microorganisms such as bacteria, viruses, fungi, and parasites which exist in the environment and which, upon introduction to the body of the host, can induce varied pathological conditions. Other pathological conditions may derive from agents not acquired from the environment, but rather which arise spontaneously within the body of the host. The best examples are the numerous malignancies known to occur in mammals. Ideally, the presence of these deleterious agents in a host triggers the mobilization of the immune system to effect the destruction of the agent and, thus, restore the sanctity of the host environment.
The destruction of pathogenic agents by the immune system involves a variety of effector mechanisms which can be grouped generally into two categories: innate and specific immunity. The first line of defense is mediated by the mechanisms of innate immunity. Innate immunity does not discriminate among the myriad agents that might gain entry into the host's body. Rather, it responds in a generalized manner that employs the inflammatory response, phagocytes, and plasma-borne components such as complement and interferons. In contrast, specific immunity does discriminate among pathogenic agents. Specific immunity is mediated by B and T lymphocytes and it serves, in large part, to amplify and focus the effector mechanisms of innate immunity.
The elaboration of an effective immune response requires contributions from both innate and specific immune mechanisms. The function of each of these arms of the immune system individually, as well as their interaction with each other, is carefully coordinated, both in a temporal/spatial manner and in terms of the particular cell types that participate. This coordination results from the actions of a number of soluble immunostimulatory mediators or “immune system stimulators” (Reviewed in, Trinchieri, et al.,
J. Cell. Biochem
. 53:301-308 (1993)). Certain of these immune system stimulators initiate and perpetuate the inflammatory response and the attendant systemic sequelae. Examples of these include, but are not limited to, the proinflammatory mediators tumor necrosis factors &agr; and &bgr;, interleukin-1, interleukin-6, interleukin-8, interferon-&ggr;, and the chemokines RANTES, macrophage inflammatory proteins 1-&agr; and 1-&bgr;, and macrophage chemotactic and activating factor. Other immune system stimulators facilitate interactions between B and T lymphocytes of specific immunity. Examples of these include, but are not limited to, interleukin-2, interleukin-4, interleukin-5, interleukin-6, and interferon-&ggr;. Still other immune system stimulators mediate bidirectional communication between specific immunity and innate immunity. Examples of these include, but are not limited to, interferon-7, interleukin-1, tumor necrosis factors &agr; and &bgr;, and interleukin-12. All of these immune system stimulators exert their effects by binding to specific receptors on the surface of host cells, resulting in the delivery of intracellular signals that alter the function of the target cell. Cooperatively, these mediators stimulate the activation and proliferation of immune cells, recruit them to particular anatomical sites, and permit their collaboration in the elimination of the offending agent. The immune response induced in any individual is determined by the particular complement of immune system stimulators produced, and by the relative abundance of each.
In contrast to the immune system stimulators described above, the immune system has evolved other soluble mediators that serve to inhibit immune responses (Reviewed in, Arend, W. P.,
Adv. Int. Med
. 40:365-394 (1995)). These “immune system inhibitors” provide the immune system with the ability to dampen responses in order to prevent the establishment of a chronic inflammatory state with the potential to damage the host's tissues. Regulation of host immune function by immune system inhibitors is accomplished through a variety of mechanisms as described below.
First, certain immune system inhibitors bind directly to immune system stimulators and, thus, prevent them from binding to plasma membrane receptors on host cells. Examples of these types of immune system inhibitors include, but are not limited to, the soluble receptors for tumor necrosis factors &agr; and &bgr;, interferon-&ggr;, interleukin-1, interleukin-2, interleukin-4, interleukin-6, and interleukin-7.
Second, certain immune system inhibitors antagonize the binding of immune system stimulators to their receptors. By way of example, interleukin-1 receptor antagonist is known to bind to the interleukin-1 membrane receptor. It does not deliver activation signals to the target cell but, by virtue of occupying the interleukin-1 membrane receptor, blocks the effects of interleukin-1.
Third, particular immune system inhibitors exert their effects by binding to receptors on host cells and signalling a decrease in their production of immune system stimulators. Examples include, but are not limited to, interferon-&bgr;, which decreases the production of two key proinflammatory mediators, tumor necrosis factor-&agr; and interleukin-1 (Coclet-Ninin et al.,
Eur. Cytokine Network
8:345-349 (1997)), and interleukin-10, which suppresses the development of cell-mediated immune responses by inhibiting the production of the immune system stimulator, interleukin-12 (D'Andrea, et al.,
J. Exp. Med
. 178:1041-1048 (1993)). In addition to decreasing the production of immune system stimulators, certain immune system inhibitors also enhance the production of other immune system inhibitors. By way of example, interferon-&agr;
2b
inhibits interleukin-1 and tumor necrosis factor-&agr; production and increases the production of the corresponding immune system inhibitors, interleukin-1 receptor antagonist and soluble receptors for tumor necrosis factors &agr; and &bgr; (Dinarello, C. A.,
Sem. in Oncol
. 24(3 Suppl. 9):81-93 (1997).
Fourth, certain immune system inhibitors act directly on immune cells, inhibiting their proliferation and function, thereby, decreasing the vigor of the immune response. By way of example, transforming growth factor-&bgr; inhibits a variety of immune cells, and significantly limits inflammation and cell-mediated immune responses (Reviewed in, Letterio and Roberts,
Ann. Rev. Immunol
. 16:137-161 (1998)). Collectively, these various immunosuppressive mechanisms are intended to regulate the immune response, both quantitatively and qualitatively, to minimize the potential for collateral damage to the host's own tissues.
In addition to the inhibitors produced by the host's immune system for self-regulation, other immune system inhibitors are produced by infectious microorganisms. For example, many viruses produce molecules which are viral homologues of host immune system inhibitors (Reviewed in, Spriggs, M. K.,
Ann. Rev. Immunol
. 14:101-130 (1996)). These include homologues of host complement inhibitors, interleukin-10, and soluble receptors for interleukin-1, tumor necrosis factors &agr; and &bgr;, and interferons &agr;, &bgr; and &ggr;. Similarly, helminthic parasites produce homologues of host immune system inhibitors (Reviewed in, Riffkin, et al.,
Immunol. Cell Biol
. 74:564-574 (1996)), and several bacterial genera are known to produce immunosuppressive products (Reviewed in, Reimann, et al.,
Scand. J. Immunol
. 31:543-546 (1990)). All of these immune system inhibitors serve to suppress the immune response during the initial stages of infection, to provide advantage to the microbe, and to enhance the virulence and chronicity of the infection.
A role for host-derived immune system inhibitors in chronic disease also has been established. In the majority of cases, this
Howell Mark Douglas
Leber Leland Charles
Selinsky Cheryl Lynn
Cytologic, LLC
Helms Larry R.
Huff Sheela
Sheridan & Ross P.C.
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