The long-term effects of multidrug immunosuppressive protocols based on calcineurin inhibitors and conversion to rapamycin on the morphology, apoptosis, and proliferation of rat salivary glands

Abstract

Background The effect of multidrug immunosuppressive protocols on the salivary glands is still unknown. This study aimed to determine the influence of immunosuppressive regimens based on calcineurin inhibitors (CNIs) and conversion to rapamycin on the morphology, apoptosis, and proliferation of rat salivary glands. Methods Male rats received cyclosporin A (CsA), tacrolimus (FK-506), mycophenolate mofetil (MMF), rapamycin (Rapa), and prednisone (Pre) according to three-drug protocols: CMP (CsA, MMF, and Pre), CMP/R (CsA, MMF, and Pre with conversion to Rapa), TMP (FK-506, MMF, and Pre), and TMP/R (FK-506, MMF, and Pre with conversion to Rapa). Morphological and immunohistochemical and quantitative analyses of the salivary glands were performed. Results Structural changes in salivary glands were observed in all experimental groups, especially in the submandibular gland. In the salivary glands, the percentages of collagen fibers and TUNEL-, Ki67- and PCNA-positive cells were higher in the experimental groups vs. the control but were lower in the CMP/R and TMP/R groups vs. the CMP and TMP groups, with the exception of collagen fibers in the parotid gland in the TMP/R group vs. the TMP group. Conclusions Long-term administration of CNIs in triple regimens and after conversion to rapamycin monotherapy, causes morphological changes in the salivary glands of rats. Immunosuppressive treatment based on CNIs is associated with an increase in collagen accumulation. The effects of the conversion of treatment with CNIs to rapamycin in immunosuppressive protocols in rat salivary glands lead to decreased fibrosis, apoptosis, and proliferation. These changes may possibly prevent abnormalities resulting from the application of CNIs.