Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1995-06-06
2003-05-20
Schwadron, Ronald B. (Department: 1644)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S007210, C435S007200, C435S007100, C436S506000, C436S510000, C436S536000, C436S811000, C530S387300, C530S387900, C530S388150, C530S388220, C530S388750, C530S389600, C530S391100, C530S391300, C530S391700, C530S866000, C530S867000, C530S868000
Reexamination Certificate
active
06566082
ABSTRACT:
TECHNICAL FIELD
This invention relates to methods for the specific depletion of activated T-lymphocytes particularly those belonging to the CD4
+
subclass. Such activated T-lymphocytes e.g. CD4
+
T-lymphocytes, are implicated in a number of conditions in humans including multiple sclerosis and transplant rejection. In particular, this invention provides a treatment in which activated T-lymphocytes e.g. CD4
+
T-cells involved in a particular disease or condition are depleted while the non-activated T-lymphocyte e.g. CD4
+
T-cells repertoire is unaffected.
BACKGROUND OF INVENTION
The CD4
+
T-lymphocyte (herein referred to as the CD4
+
T-cell) is the central player in the immune system because of the “help” it provides to other leukocytes in fighting off infection and potential cancerous cells. CD4
+
T-cells play essential roles in both humeral and cell-mediated immunity and additionally they act during parasite infection to promote the differentiation of eosinophils and mast cells. If the CD4
+
T-cell population is depleted (as is the case in AIDS patients) the host is rendered susceptible to a number of pathogens and tumours that do not ordinarily pose a threat to the host.
While CD4
+
T-cells thus play an important beneficial role in disease prevention, the aberrant function of these cells can produce serious problems. In some individuals, the aberrant function of CD4
+
T-cells leads to autoimmunity and other disease states (Swanborg, R. H., 1984; Cush, J. J., and Lipsky, P. E., 1988; Caspi et al., 1988). Autoimmune diseases in which CD4
+
T-cells have been implicated include multiple sclerosis, rheumatoid arthritis and autoimmune uveitis (see generally, Steinman, L., 1993). In essence these diseases involve an aberrant immune response in which the immune system is subverted from its normal role of attacking invading pathogens and instead attacks the host body tissues, leading to illness and even death. The targeted host tissues vary between autoimmune diseases, for example, in multiple sclerosis the immune system attacks the white matter of the brain and spinal cord, in rheumatoid arthritis the immune system attacks the synovial lining of the joints. Activated CD4
+
T-cells have also been implicated in other illnesses, including rejection of transplant tissues and organs and in the development of CD4
+
T-cell lymphomas.
Investigations into conditions caused by aberrant CD4
+
T-cell activity are focused on several animal models, and in particular on a number of experimentally induced autoimmune diseases. Research on these experimentally induced diseases in animals is premised on the idea that they will provide information useful in the treatment of the corresponding human diseases. In pursuit of this goal, it has been shown that CD4
+
T-cells are responsible for several experimentally induced autoimmune diseases in animals, including experimental autoimmune endephalomyelitis (EAE), collagen induced arthritis (CIA), and experimental autoimmune uveitis (EAU).
EAE is induced by autoimmunizing animals against myelin basic protein (MBP, a component of the white matter of the brain and the spinal cord) and produces the same clinical symptoms observed in multiple sclerosis: demyelination and paralysis. Proof of the value of the EAE model as a comparative model for multiple sclerosis has been provided by evidence showing that these conditions share a causative nexus: Steinman and co-workers showed that the predominant cell type found in the brain lesions of multiple sclerosis patients is CD4
+
T-cells (Oksenberg, J. R., et al., 1990) and that the T-cell receptor (the molecule responsible for antigen recognition) associated with the cells in these brain lesions had the same 3 amino acid binding motif for antigen recognition as on the CD4
+
T-cells responsible for causing experimental autoimmune. encephalomyelitis (EAE) (Oksenberg, J. R., et al., 1993). All the evidence thus suggests that the EAE model will be useful in testing therapies for multiple sclerosis.
Research on a number of the experimentally induced autoimmune diseases, including EAE, CIA and EAU, has shown that antibodies that bind CD4
+
T-cells when injected in vivo can inhibit the development of these diseases as well as inhibit transplantation rejection (Swanborg, R. H. 1983; Cobbold, S. P. et al., 1984; Steinman, L, 1993). This antibody-mediated effect depletes or inactivates all CD4
+
cells in the body (the antibodies that bind to the CD4
+
cells presumably block the activity of the cells and also target the CD4
+
cells for destruction by the immune system.) This strategy has shown some success with rheumatoid arthritis and is now being tested for multiple sclerosis (see generally, Steinman, L., 1993).
While it appears that therapeutic approaches that destroy the CD4
+
T-lymphocyte population might be effective in ameliorating these autoimmune diseases, this approach has one very major drawback. The treatment not only inhibits the function of those CD4
+
T-cells that are antigen reactive and thus involved in the autoimmune disease process, but also the CD4
+
T-cells that are quiescent and not involved in the disease. Since CD4
+
T-cells are important in the general immune response (protecting the body against infectious agents), destruction of the entire CD4
+
T-cell population leaves the patient severely immunocompromised and hence highly susceptible to infection. A preferable approach would be to remove only those CD4
+
T-cells that are actively involved in the auto-immune response, leaving the remaining CD4
+
T-cell population available for their normal role in the immune system.
This method of treatment has not yet been achieved. It is therefore an object of the present invention to provide a method of specifically depleting the population of activated CD4
+
T-cells in a patient without affecting the quiescent CD4
+
T-cell population.
SUMMARY OF THE INVENTION
In one aspect the present invention provides a method by which autoantigen specific T-cells, especially for example activated CD4
+
T-cells, can be specifically eliminated in vivo, while leaving the quiescent population of T-cells especially for example unactivated CD4
+
T-cells intact. This invention therefore provides a treatment useful for T-cell mediated especially for example activated CD4
+
T-cell mediated autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, sarcoidosis and autoimmune uveitis, graft versus host disease (GVHD) and/or inflammatory bowel disease. This invention also provides a method for eliminating other undesired immune responses caused by activated T-cells especially for example activated CD4
+
T-cells such as rejection of transplanted tissue and organs in transplant recipients. Furthermore, the present invention provides a method of specifically eliminating activated CD4
+
T-cell lymphomas from the body. The present invention also provides a method for early diagnosis of conditions mediated by activated T-cells especially for example activated CD4
+
T-cells by detecting the presence of autoreactive T-cells at the site of autoimmune lesions and potentially harmful T-cell lymphomas. This early diagnosis provides an indication that the methods of treatment provided by the present invention may be effective and can facilitate earlier treatment of the condition than might otherwise be possible.
The present invention is also based on the discovery that a particular protein antigen, termed OX-40 (herein referred to as the OX-40 antigen), is specifically expressed on the cell surface of antigen activated T-cells especially for example activated CD4
+
T-cells. In particular, using the EAE disease model in rats, this antigen was shown to be expressed on the surface of activated autoantigen-specific CD4
+
T-cells present at the site of inflammation (the spinal cord in this disease model) but absent on CD4
Vandenbark Arthur A.
Weinberg Andrew D.
Klarquist & Sparkman, LLP
Schwadron Ronald B.
LandOfFree
T-cell antigens, and their use in diagnosis and treatment of... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with T-cell antigens, and their use in diagnosis and treatment of..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and T-cell antigens, and their use in diagnosis and treatment of... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3078308