Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 9,10-seco- cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-06-26
2001-09-18
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
9,10-seco- cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
active
06291444
ABSTRACT:
TECHNICAL FIELD
The present invention relates to cell mediated immunity functions in mammals, and more particularly to a method for improving impaired cell mediated immunity in a mammal by the administration of a vitamin D compound, such as vitamin D
3
, its active form 1&agr;,25-dihydroxyvitamin D
3
or other compounds exhibiting vitamin D-like activity, to the mammal for a sufficient period of time to improve or restore the immunity of the mammal.
BACKGROUND AND SUMMARY OF THE INVENTION
Although historically vitamin D has been associated with the regulation of mineral metabolism, it now appears certain that its functions are not confined to this system (Manolagas, Hustmyer, and Yu, (1989) Proc. Soc. Exp. Biol. Med. 191, 238-245). Receptors for the active form of vitamin D, i.e. 1,25-30 dihydroxyvitamin D
3
(1,25-(OH)
2
D
3
) are found in peripheral blood lymphocytes and thymus lymphocytes (Malogagas, Prowedini, and Tsoukas, (1985) Mol. Cell. Endocrinol. 43, 113-122) of rat and human origin. In vitro 1,25-(OH)
2
D
3
decreases one protein while increasing another in activated human lymphocytes (Yu, Hustmyer, Garvey, and Manolagas, C. (1991) Proc. Natl. Acad. Sci. 88, 8347-8351). Furthermore, 1,25-(OH)
2
D
3
in vitro exerts an anti-proliferative action on peripheral blood mono-nuclear cells (Manolagas, Provvedini, Murray, Tsoukas, and Deftos, (1986) J. Clin. Endocrinol. Metab. 63, 394-400), decreases—Interlukin-2 (IL-2) production by phytohemagglutinin-activated human peripheral mononuclear cells and decreases IL-1 activity in monocytes (Manolagas, (1988) in “Vitamin D: Molecular, Cellular and Clinical Endocrinology (Norman, Schaefer, Grigoleit, and Herrath, Eds.), pp. 282-290, Walter de Gruyter, Berlin, N.Y.). Inhibition of immunoglobulin synthesis by 1,25-(OH)
2
D
3
in B-lymphocytes has also been reported (Provvedini, Tsoukas, Deftos, and Manolagas, (1986) J. Immunol. 136, 2734-2740).
Although various biological functions for vitamin D compounds have been discovered, as indicated above, the role of vitamin D and other compounds having vitamin D-like activity on the immune system in mammals is poorly defined. To begin the assessment of the impact of vitamin D and other compounds having vitamin D-like activity on the immune system in vivo, the present disclosure provides a vitamin D deficiency model in mice and then studies the effect of this deficiency on cell mediated immunity. The effect of readministration of vitamin D compounds was then studied to determine whether or not any immune deficiency could be improved or restored.
Severe vitamin D deficiency has been produced in mice as evidenced by severe hypocalcemia and an absence of 25-hydroxyvitamin D
3
in blood. These and vitamin D-sufficient mice were sensitized with dinitrofluorobenzene (DNFB). Sensitivity to DNFB was determined by treatment of one ear with DNFB. The ratio of thickness of the treated ear to that of non-treated ear was used as an index of cell-mediated immune reaction. The incorporation of
3
H-thymidine into DNA of the ear was also used as an index of cell-mediated immunity as was the response of thymus lymphocytes to concanavalin A.
Vitamin D deficiency markedly decreased the ear thickness ratio and
3
H-thymidine incorporation ratio. Similarly, the incorporation of
3
H-thymidine into DNA of Concanavalin A treated thymus lymphocytes was significantly reduced in vitamin D deficiency. These results show that in vivo vitamin D deficiency impairs cell-mediated immunity. The provision of a vitamin D-sufficient diet for 8 weeks corrected the impaired response of the immune system, while vitamin D administration for 3 weeks did not.
Thus, in accordance with the present disclosure, it has been found that lack of vitamin D in vivo impairs cell mediated immunity resulting in an immune deficiency in mammals. Additionally, it has been found that this immune deficiency in mammals may be improved dramatically by the administration of vitamin D compounds such as vitamin D
3
and 1&agr;,25-dihydroxyvitamin D
3
as well as by other compounds having vitamin D-like activity, resulting in restoration if not complete repair of the immune deficiency of the mammal.
It has thus been discovered that a vitamin D compound may be utilized to treat immunodeficiencies categorized as either acquired immunodeficiencies or inherited immunodeficiencies. Acquired immunodeficiencies include human immunodeficiency virus-1 (HIV-1) infection, Herpes virus infections, Epstein-Barr virus infections, lepromatous leprosy and diminished immune capacity resulting from skin burns in burn patients, i.e. burn-related immunodeficiency. Inherited immunodeficiencies include adenosine deaminase deficiency (ADA SCID), purine nucleotide phosphorylase deficiency (PNP SCID), severe combined immune deficiency (IL-2 receptor deficiency, i.e. X-LINKED SCID), DiGeorge syndrome (no thymus), partial DiGeorge syndrome (thymic aplasia) and Bare lymphocyte syndrome (no MHC class I or II molecules to mediate positive selection of T cells in the thymus).
The results of the vitamin D deficiency model presented herein also support the use of vitamin D compounds to treat specific T-cell immunodeficiencies. These T-cell immunodeficiencies include leucocyte adhesion deficiency, lazy-leucocyte syndrome, reticular dysgenesis, and Wiskott-Aldrich syndrome (WAS).
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Abe et al, “22-Oxa-1&agr;,25-Dihydroxyvitamin D3; A New Synthetic Analogue of Vitamin D Having a Potent Immunoregulating Activity Without Inducing Hypercalcemia in Mice,” Calcium Regulation and Bone Metabolism, pp. 146-151, 1990.
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DeLuca Hector F.
Prahl Jean M.
Smith Connie M.
Yang Shouli
Andrus Sceales Starke & Sawall LLP
Criares Theodore J.
Wisconsin Alumni Research Foundation
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