Tacrolimus (FK506) and cyclosporine reduce the uptake and transport of particles into rabbit Peyer???s patches1

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Abstract
Tacrolimus (FK) and cyclosporine (Cs) are potent immunosuppressants that effectively prevent the rejection of transplanted organs including liver and small intestine. Our study examined the effects of these immunosuppressants on Peyer’s patches, which play an important role in mucosal immune response through uptake and transport of enteric microorganisms and macromolecules in the gut-associated lymphoid tissues. After administration of FK and Cs, we assessed changes in lymphoid follicle structure and quantified the uptake and transport of particles in the follicle associated epithelium (FAE) including M cells, using fluorescent latex microspheres in rabbit Peyer’s patches. Rabbits, five in each group, received oral administration of FK (3.2 mg/kg), Cs (10 mg/kg), or phosphate-buffered saline daily for 7 days. After 2 days of withdrawal, rabbits were anesthetized, and received injections with 2 ml of the suspension of 0.5-μm fluorescent microspheres (1010/ml) into ligated intestinal segments containing Peyer’s patches. After 2 hr of gentle agitation, segments were removed, rinsed, fixed with periodate-lysine-2% paraformaldehyde, frozen, and sections were stained with fluorescent phalloidin to label brush border actin filaments. The size of the lymphoid follicles in each group was measured under a light microscope. The number of microspheres in follicles was assessed in graphically defined areas of follicles from each group. In addition, immunohistochemical analysis of CD43 and MHC-II positive cells in FAE of lymphoid follicles of each group was performed. FK and Cs significantly reduced the height of lymphoid domes and the height and width of follicles, as compared to those of controls. In both FK and Cs groups, the numbers of microspheres that adhered, were taken up and were transported into lymphoid follicles were smaller than in controls, indicating that their movement rates into deep layers were markedly reduced. Furthermore, FK and Cs reduced the mean numbers of CD43 and MHC-II positive cells in FAE per unit area (mm2) as compared with controls. These findings suggest that FK and Cs may produce immunosuppressive effects, at least in part, through reduction of the uptake and transport of particles into Peyer’s patches, and by reduction of the number of immunoreactive cells in FAE of Peyer’s patches.