Potent inhibition of cytokine production from intestinal lamina propria T cells by phosphodiesterase-4 inhibitory thalidomide analogues

In Crohn's disease, intestinal lamina propria (LP) T cells overproduce TNF- alpha and IFN-gamma, and clinical and animal studies indicate that this is pathogenic. Thalidomide influences cytokine production by leukocytes, inhib iting macrophage TNF-alpha and is beneficial in treating Crohn's disease. C hemical ana, logues have been synthesized that may lack teratogenic and oth er side effects of thalidomide. We tested three analogues [selective cytoki ne inhibitory drugs (SelCIDs) A, B, and C, all potent PDE4 inhibitors] for effect on TNF-alpha, IFN-gamma, and IL-10 production by and on proliferatio n of intestinal LP mononuclear cells after T-cell stimulation and results w ere compared with those for peripheral blood leukocytes (PBL). While thalid omide itself had little effect, the SelCIDs were potent inhibitors, with re lative inhibitory potencies: A greater than or equal toB > >C. The LP T cel ls were less sensitive to inhibition by the SelCIDs than were PBL. Since hi ghly pre-activated PBL were even less sensitive, activation state alone can account for the responsiveness of intestinal LP T cells. Thalidomide analo gues could play a role in treating Crohn's disease and other inflammatory d isorders.