Therapeutic Effect Of Tacrolimus Research Articles

Factors associated with changes in tacrolimus blood concentration after food initiation in patients with ulcerative colitis.

The therapeutic effect of tacrolimus against ulcerative colitis (UC) is correlated with its trough blood concentration. Conventionally, oral tacrolimus for the treatment of UC is initiated under fasting conditions; once the symptoms improve, food intake is resumed. Tacrolimus blood concentration decreases with food intake compared with that under fasting conditions. The aim of this study was to explore the characteristics of patients with UC whose tacrolimus blood concentrations tended to decrease after food initiation. Medical data of 13 patients with UC and treated with tacrolimus were retrospectively obtained. The participant characteristics associated with the changes in tacrolimus blood concentrations after food initiation were analyzed using regression analysis based on the rate of decrease in the concentration/dose (C/D) ratio after food initiation. Single regression analysis showed that the number of days required from tacrolimus initiation to food resumption (P = 0.0071) and individual differences in the increase in tacrolimus blood concentration after administration (P = 0.0247) were significantly associated with the rate of decrease in the C/D ratio after food initiation. Furthermore, multiple regression analysis showed a significant effect of the number of days to food resumption (P = 0.0004) and individual differences in the increase in tacrolimus blood concentration after administration (P = 0.0012). The results suggest that the degree of change in blood tacrolimus concentration after food initiation may be related to the severity of the symptoms and pathology of UC. Early identification of participant characteristics may help control tacrolimus blood concentration fluctuations after food initiation.

The Therapeutic Effect of Tacrolimus in a Mouse Psoriatic Model is Associated with the Induction of Myeloid-derived Suppressor Cells.

Topical administration of Tacrolimus (TAC) is efective in the treatment of psoriasis in human patients and in mouse models. Previously, we showed that, though promoting the proliferative expansion of CD4+Foxp3+ regulatory T cells (Tregs), TNFR2 was protective in mouse psoriasis model. We thus examined the role of TNFR2 signal in the efect of TAC in the treatment of mouse psoriasis. To this end, psoriasis was induced in WT, or TNFR1 KO, or TNFR2 KO mice, and the psoriatic mice were treated with or without IMQ. The results showed that TAC treatment potently inhibited the development of psoriasis in WT and TNFR1 KO mice, but not in TNFR2 KO mice. However, the treatment of TAC failed to induce the expansion of Tregs in psoriatic mice. In addition to playing a decisive role in the activation of Tregs, TNFR2 stimulates the generation and activation of myeloid-derived suppressor cells (MDSCs). This led us to found that the topical treatment with TAC markedly increased the number of MDSCs in the spleen of WT and TNFR1 KO mice, but not in TNFR2 KO mice. Consequently, TAC potently decreased serum levels of IL-17A, INF-γ, and TNF and their mRNA levels in the inflamed skin lesion. Therefore, our study for the first time found that the therapeutic efect of TAC in psoriasis is associated with the expansion of MDSCs in a TNFR2-dependent manner.

Comparison of topical application of tea polyphenol versus pimecrolimus versus tacrolimus for the treatment of monobenzone-induced vitiligo-like depigmentation in a mouse model

Objective To compare the therapeutic effect of topical application of tea polyphenol versus pimecrolimus versus tacrolimus for monobenzone-induced vitiligo-like depigmentation in mice. Methods Twenty-five 3-week-old female C57BL/6 mice were randomly and equally divided into 5 groups: negative control group, model group, tea polyphenol group, pimecrolimus group, tacrolimus group. Monobenzone 45% cream was applied to the back of mice in all the five groups except the negative control group once daily for 40 consecutive days to establish a model of vitiligo-like depigmentation. During the induction of depigmentation, the tea polyphenol group, pimecrolimus group and tacrolimus group were topically treated with tea polyphenol, pimecrolimus and tacrolimus respectively, and the model group remaining untreated. The depigmentation of hairs and skin was observed by naked eyes on a daily basis. Tissue specimens were obtained for histological examination from depigmented skin at non-application sites in mice after the end of the experiment. Hematoxylin-eosin staining was conducted to analyze lymphocytic infiltration, reflectance confocal microscopy to observe melanin and melanocytes in skin, and immunofluorescence assay to detect CD8+ T cell infiltration. Results Depigmentation occurred in both application sites and non-application sites of mice in the model group. Compared with the model group, the tacrolimus, pimecrolimus and tea polyphenol groups showed delayed depigmentation, reduced degree and area index of depigmentation, and attenuated lymphocytic infiltration and CD8+ T cell infiltration in depigmented maculae at application sites. In addition, the therapeutic effect of tacrolimus was stronger than that of pimecrolimus and tea polyphenol. Conclusion Tea polyphenol, pimecrolimus and tacrolimus are all effective for the treatment of vitiligo-like depigmentation in mice. Key words: Monobenzone; Tea polyphenol; Tacrolimus; Pimecrolimus; Vitiligo, animal model

Therapeutic effect of Tacrolimus on autoimmune prostatitis in rat model and possible mechanism

Objective To explore the efficacy of tacrolimus in treating experimental autoimmune prostatitis (EAP) in rat model and the possible mechanism.Methods SD rats were randomly divided into 4 groups:normal control group,EAP model group,low-dose treatment group,high-dose treatment group.According to administration durations,each group was further divided into two subgroups:2-week group and 4-week group.After successful modeling,rats in low-dose treatment group and high-dose group underwent gastric perfusion with 0.2 mg/(kg·day) and 0.8 mg/(kg·day) tacrolimus respectively for 2 and 4 weeks in a successive way.Concentrations of interleukin (IL)-2 and macrophage inflammatory protein-1α (MIP-1α) in the homogenate of prostatic tissue and serum were tested.Histomorphological changes of prostatic tissue,spleen and thymus gland were observed,with their viscera coefficients being calculated.Results After the intervention of tacrolimus,a decrease in inflammatory cells in prostatic tissue was revealed histomorphologically and glandular cavity wall was repaired to some extent.The concentrations of IL2 were ( 156.80 ± 19.11 ),( 124.56 ± 17.20) and ( 114.46 ± 20.65) ng/L in the serum of M2W,L2W and H2W groups,and MIP-1 α concentrations were ( 164.99 ± 22.25 ),( 112.03 ± 19.90) and ( 104.91 ± 11.91 ) ng/L,respectively.As for the homogenate of prostatic tissue,IL-2 and MIP-1α levels stood at (219.26±23.11),(191.56±19.08),(186.63 ±20.90) ng/L,and (216.46 ±18.50),(196.55 ±17.84),( 194.74 ± 18.14) ng/L respectively.In comparison,in M4W,LAW and H4W groups,concentrations of the two substances were ( 156.23 ± 19.83),( 129.27 ± 17.25),( 134.26 ± 16.11 ) ng/L and (157.93 ±34.55),(159.09 ±29.17),(154.54 ±29.85) ng/L,respectively.In the homogenate of prostatic tissue,data were (217.92 ±23.23),(186.07 ± 11.56),(180.37 ± 18.26) ng/L and (209.66 ±14.65),( 186.17 ± 17.79),( 186.16 ± 18.27) ng/L,respectively.All differences were statistically significant except MIP-1α level in the serum of 4-week subgroup.Conclusion Tacrolimus can reduce the number of inflammatory cells in prostatic tissue in EAP rat model,which may be related to its suppression of the production of IL-2 and activation of T cells. Key words: Tacrolimus; Prostatitis; Interleukin-2

Preventive and therapeutic effects of tacrolimus in an interleukin-10-deficient mouse model of colitis

To investigate the preventive and therapeutic effects of tacrolimus on colonic inflammation in interleukin-10-deficient (IL-10(-/-)) mice, which spontaneously develop T-cell-mediated colitis. Tacrolimus or prednisolone, an anti-inflammatory glucocorticoid, was administered to IL-10(-/-) mice with pre- or post-symptomatic colitis. Effects on colonic inflammation were examined by measuring indices of colitis such as colonic weight/length ratio, cell infiltration, and goblet cell depletion. Effects on cytokine production in colonic lamina propria mononuclear cells (LPMCs) isolated from IL-10(-/-) mice were also examined. Tacrolimus prevented development of colitis and improved already-developed colitis. Prednisolone prevented the development of colitis, but had no effect on already-developed colitis. Tacrolimus completely inhibited IFN-γ and TNF-α production of activated T-cells in LPMCs, but only partially inhibited IFN-γ, TNF-α, and IL-12 production of activated monocytes/macrophages in LPMCs. Prednisolone inhibited cytokine production in both cell types but exhibited greater potency on monocytes/macrophages than on T-cells. These results suggest that the preventive and therapeutic effect of tacrolimus in IL-10(-/-) mice colitis might be attributed to the inhibition of colonic T-cell activation rather than monocyte/macrophage activation. T-cell immunosuppression may thus be a promising strategy for treating colonic inflammation.

Microchimerism, donor dendritic cells, and alloimmune reactivity in recipients of Flt3 ligand-mobilized hemopoietic cells: modulation by tacrolimus.

Flt3 ligand (FL) is a potent hemopoietic growth factor that strikingly enhances stem cells and dendritic cells (DC) in vivo. We examined the impact of infusing FL-mobilized bone marrow (BM) cells on microchimerism and anti-donor reactivity in normal and tacrolimus-immunosuppressed, noncytoablated allogeneic recipients. BM from B10 (H2b) mice given FL (10 microg/day; days 0-8; FL-BM) contained a 7-fold higher incidence of potentially tolerogenic immature CD11c+ DC (CD40low, CD80low, CD86low, MHC IIlow) that induced alloantigen-specific T cell hyporesponsiveness in vitro. C3H (H2k) mice received 50 x 106 normal or FL-BM cells (day 0) and tacrolimus (2 mg/kg/day; days 0-12). On day 15, enhanced numbers of donor (IAb+) cells were detected in the thymi and spleens of FL-BM recipients. Tacrolimus markedly enhanced microchimerism, which declined as a function of time. Ex vivo splenocyte proliferative and CTL responses and Th1 cytokine (IFN-gamma) production in response to donor alloantigens were augmented by FL-BM infusion, but reduced by tacrolimus. Systemic infusion of purified FL-BM immature DC, equivalent in number to that in corresponding whole BM, confirmed their capacity to sensitize, rather than tolerize, recipient T cells in vivo. In vitro, tacrolimus suppressed GM-CSF-stimulated growth of myeloid DC from normal BM much more effectively than from FL-BM without affecting MHC class II or costimulatory molecule expression. Infusion of normal B10 BM cells at the time of transplant prolonged C3H heart allograft survival, whereas FL-BM cells did not. A therapeutic effect of tacrolimus on graft survival was observed in combination with normal, but not FL-BM cells. These findings suggest the need for alternative immunosuppressive strategies to calcineurin inhibition to enable the engraftment, survival, and immunomodulatory function of FL-enhanced, immature donor DC.