Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Patent
1996-01-18
2000-12-05
Yucel, Remy
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
A61K 39395
Patent
active
061563129
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The invention deals with an agent, able to affect the hyperactivated immununological effector cells and with its use.
Different situations and disorders of humans are associated with a hyperactivated state of the immunological effector cells, caused e.g. by cytokines; such effector cells lose their ability to respond to new specific signals. The immune system is impaired or even switched off in such situations. This occurs e.g. following a persistent stimulation during a prolonged infection or in situations of cell hyperactivation due to an excessive release of endogenous cytokines. The term "immunological effector cells" comprises e.g. T cells, macrophages/monocytes, NK cells and other immunological cells.
A variety of immunological processes include on the cellular level the cyclic adenosine phosphate (cAMP) which is produced by the enzyme adenylate cyclase (AC) from adenosine triphosphate (ATP). The cAMP plays as "second messenger" a central role in the hormonal regulation as well as in the metabolism (through activation of protein kineses, e.g. protein kinase A (PKA). The PKA phosphorylates proteins which in turn depress the immune response. In this way, the hyperactivation of effector cells results in the down regulation of the immune function.
This reaction cascade is regulated by the production of cyclic guanosine monophosphate (cGMP) which antagonizes the cAMP. This reaction cascade is also influenced by the group of G-protein coupled receptors, comprising receptors such as adrenergic, muscarinic, histamine, serotonin and adenosine receptors. The G-proteins (guanine nucleotide-binding proteins) are able to stimulate (Gs) or to inhibit (Gi) the production of second messengers. By affecting either the Gs- or the Gi-receptors, the stimulation of AC and herewith the cAMP-production can be regulated. Situations with a disturbed equilibrium are e.g. cancer, viral diseases and autoimmune disorders, as well as the inducing and disease-maintaining component of the atherosclerosis.
SUMMARY OF THE INVENTION
The objective of the invention was to provide an agent, able to fight with such disorders and to restore the susceptibility of the hyperactivation-depressed immune system for signals and a normal immune response. This objective can be achieved by an agent, capable to affect the hyperactivated immunological effector cells which comprises (I) a Ca-antagonist, and (II) an agent, able to decrease the intracellular cAMP/cGMP-ratio. Surprisingly, it could be found out that such a combination reduced or prevented the hyperactivation of effector cells. In this way, these cells re-acquire their susceptibility for specific signals and show a normal immune reaction. It could be shown that hyperactivated cells contain an excess of calcium ions and are characterized by an increased cAMP/cGMP-ratio.
According to the invention, the principle of the agent is the prevention of Ca.sup.2+ -influx and reduction of cAMP/cGMP-ratio in immune effector cells. This can be achieved by the combination of component I and II. Surprisingly, in this way, diseases as different as cancer, autoimmune disorders, arteriosclerosis which seems to need an autoimmune promotor for its provocation, further bacterial, viral, including retro viral infections, as well as some "modern" diseases, based on immunological derailment or deviations, e.g. the CFS (chronic fatigue syndrome) can be treated. All these situations and disorders appear to contain--in the immunological sense--common disregulation elements. These common elements are e.g. a persistent or excessive activation of certain leukocyte-subpopulations, mostly macrophages and helper T cells, as well as suppressor cells. During a simultaneous hyperactivation of macrophages and helper T cells, as observed in HIV-patients, a mutual stimulation of both interdependent leukocyte-subpopulations can occur.
A further common element is the deblockade of blastogenically pretransformed T4 and plasma (B) cells as consequence of preceding, persistent latent or manifest immun
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