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METHODS AND COMPOSITIONS FOR TREATING T CELL MEDIATED

INFLAMMATORY/AUTOIMMUNE DISEASES AND DISORDERS IN SUBJECTS
HAVING A GLUCOCORTICOID REGULATION DEFICIENCY

BACKGROUND OF THE INVENTION

(1) Field of the Invention:
[0001] The present invention relates to methods and compositions for limiting
morbidity and mortality arising from T cell activation in subjects having a
glucocorticoid regulation deficiency, and more particularly to methods and
compositions for preventing and treating T cell mediated inflammatory/autoimmune
diseases and disorders in subjects having a glucocorticoid regulation deficiency.
(2) Description of the Related Art:
[0002] T cells are lymphocytes that play a key role in the immune system. During
normal immune system function in a vertebrate, the activation of T cells triggers the
production of a number of inflammatory active molecules, including various cytokines
and eicosanoids, including the prostaglandins. The presence of the cytokines in the
hypothalamus and pituitary is known to cause the production of adrenocorticotropic
hormone (ACTH, corticotropin), which acts on the adrenal gland to cause the
production of glucocorticoids. The increased level of glucocorticoids, in turn, down-
regulates the expression of the inflammatory cytokines in the T cells, thereby
modulating the inflammatory immune response in the subject. Dysfunction of the
feedback regulatory effect by glucocorticoids can cause morbidity and death. See,
e.g., Webster, J. I. et al., Annu. Rev. Immunol., 20:125 - 163 (2002).
[0003] The direct or indirect administration of glucocorticoids (GCs) is a mainstay
therapy for treatment of inflammatory conditions, autoimmune diseases, and
lymphomas. Webster, J. I. et al., Annu. Rev. Immunol., 20:125 - 163 (2002).
Consistent with these immunosuppressive effects of steroids, in vivo and in vitro
studies have shown that pharmacologic levels of GCs, acting through the
glucocorticoid receptor (GR), modulate cytokine synthesis and affect T cell and
macrophage function. Almawi, W. Y. et al., J. Leukoc. Biol, 60:563 - 572 (1996).
Additionally, physiologic GCs, which are released at high levels into the blood stream
via cytokine activation of the hypothalamic-pituitary-adrenal (HPA) axis, have also
been shown to be critical in maintaining homeostasis

Teste para tradutor (genética) – Dannemann, Siemsen, Bigler & Ipanema Moreira
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WHAT IS CLAIMED IS:

1. A method of preventing or treating a T cell mediated

inflammatory/autoimmune disease or disorder in a subject having a glucocorticoid
regulation deficiency, where the subject is in need of such treatment, the method
comprising administering to the subject an effective amount of a cyclooxygenase-2
inhibitor or prodrug thereof.
2. A method of preventing or treating morbidity and mortality associated
with T cell activation in a subject having a glucocorticoid regulation deficiency, the
method comprising administering to the subject an effective amount of a
cyclooxygenase-2 inhibitor.
3. A method of limiting morbidity and mortality in a subject having a
glucocorticoid regulation deficiency, the method comprising administering to the
subject an effective amount of a cyclooxygenase-2 inhibitor prior to, during, or after
the subject has undergone a T cell activating process.
4. A method of treating a subject for a T cell mediated
inflammatory/autoimmune disease or disorder, the method comprising administering
an effective amount of a cyclooxygenase-2 inhibitor to a subject having a
glucocorticoid regulation deficiency after the subject has undergone T cell activation
process.
5. The method according to any one of claims 1 through 4, wherein the T
cell activating process comprises the contact of a T cell of the subject with a T cell
activating agent.
6. The method according to claim 5, wherein the T cell activating agent is
selected from the group consisting of a T cell activating antigen and a T cell specific
activating antibody.
7. The method according to any one of claims 1 through 4, wherein the
subject is a vertebrate.
8. The method according to claim 7, wherein the subject is a human.
9. The method according to any one of claims 1 through 4, wherein the
glucocorticoid regulation deficiency comprises one that is due

Teste para tradutor (genética) – Dannemann, Siemsen, Bigler & Ipanema Moreira