Sarcoidosis and lymphoma, both AIDS and non-AIDS-associated, are relatively common human immunoproliferative diseases that may be complicated by a derangement of endogenous vitamin D metabolism. The development of active vitamin D metabolite- mediated hypercalciuria and/or hypercalcemia in patients with these diseases is a morbid (and sometimes life-threatening) event that requires immediate interventive therapy. The cellular source and structural identity of the offending vitamin D metabolite in sarcoidosis are known to be the macrophage and 1,25- dihydroxyvitamin D (1,25(OH)2-D), respectively; in lymphoma neither the source nor the identity of the hypercalcemia-causing metabolite is known.
The specific aims of the current application are to: 1) comprehend the mechanism(s) by which 1,25-(OH)2-D synthesis is regulated in sarcoid macrophages by the use of inhibitory agents that can be used safely in the treatment of patients with the disease; 2) define the source, identity, and regulation of the active vitamin D metabolite synthesized in some patients with lymphoma; and 3) explore the role of retroviruses, including the AIDS virus (HIV), in modulating the expression of active vitamin D metabolite synthesis by human immune cells. To investigate the deregulation of vitamin D metabolism in sarcoidosis and lymphoma we will employ primary cultures of pulmonary alveolar macrophages and lymphoma cell lines, respectively, established from hypercalcemic/hypercalciuric patients with sarcoidosis and lymphoma. Vitamin D metabolism in vitro will be performed by HPLC analysis of lipid extracts of cells incubated with (3H)25-hydroxyvitamin D3. Infection of established cell lines of immune cell origin with human retrovirus will be employed to probe the molecular mechanism underlying the putative 1-hydroxylase in inflammatory cells. The long term goals of this work are to: 1) isolate and characterize the putative 1-hydroxylase in human immune cells; 2) clone the cDNA(S) and gene(s) which encode the hydroxylase and/or proteins that are transactivators of the enzyme; and 3) more clearly define a potential contributory role for endogenously-synthesized active vitamin D metabolites in acquired immune deficiency states including sarcoidosis and AIDS.
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