Thalidomide analogue CC-3052 reduces HIV+ neutrophil apoptosis in vitro

Thalidomide has significant immunomodulatory properties and has been used s uccessfully in the treatment of oral ulcers and wasting in HIV patients. Ho wever, its use is limited by its poor bioavailability due to low solubility and short half life in solution, and teratogenic and neurotoxic side-effec ts. Recently, water-soluble analogues of thalidomide with significantly gre ater immunomodulatory activity and reduced side-effects have become availab le. We examined the effect of thalidomide and one analogue, CC-3052, on neu trophil apoptosis following culture for 20 h in vitro. Apoptosis was assess ed by reduced CD16 expression and Annexin V binding using flow cytometry. T halidomide or CC-3052 alone had no effect on neutrophil apoptosis when used at physiological levels. However, when used together with prostaglandin E- 2 (10(-7) m), a potent adenylate cyclase activator, CC-3052 but not thalido mide (both 10(-5) m) reduced apoptosis in neutrophils from normal and HIVdonors. The reduced apoptosis could not be attributed to the ability of CC- 3052 to reduce tumour necrosis factor-alpha (TNF-alpha) production, but may be due to its PDE4 inhibitor properties, as it increased [cAMP](i), and mi micked the effect of increasing [cAMP](i) using dibutryl cAMP, a membrane-p ermeable analogue of cAMP. The results suggest a role for thalidomide analo gue CC-3052 in reducing persistent activation of the TNF-alpha system in HI V without markedly impairing neutrophil viability.