tacrolimus and Colitis

A 31-year-old woman with systemic lupus erythematosus and lupus nephritis was treated with prednisone and immunosuppressants. After her lupus nephritis symptoms worsened, both high-dose steroid and cyclophosphamide pulse therapy were administered. The patient developed an intestinal perforation, and laparoscopic Hartmann's surgery was performed on the sigmoid colon. Serum Cytomegalovirus (CMV) antigen C7HRP was detected, and the patient was diagnosed with CMV colitis and underwent a colon resection. Severe hematochezia continued despite ganciclovir administration, and the patient underwent laparoscopic total colectomy and partial ileostomy. CMV enteritis should be considered in patients treated with prednisone and immunosuppressants and those who have abdominal pain and hematochezia. Immunocompromised patients with intestinal perforation due to CMV enteritis have a poor prognosis. We report a case with along with the results of a literature review.

Topics: Adult; Antiviral Agents; Betamethasone; Colitis; Colon, Sigmoid; Cytomegalovirus; Cytomegalovirus Infections; Enteritis; Female; Ganciclovir; Gastrointestinal Hemorrhage; Humans; Immunocompromised Host; Immunosuppressive Agents; Intestinal Perforation; Lupus Nephritis; Prednisolone; Tacrolimus

Immune checkpoint inhibition with the anti-CTLA-4 antibody ipilimumab and the anti-PD-1 antibodies nivolumab and pembrolizumab has improved survival in metastatic melanoma, lung cancer and renal cancer. Use of these agents holds promise in other malignancies. The augmented immune response enabled by these agents has led to a particular group of side effects called immune-related adverse events (irAEs). The main irAEs include diarrhea, colitis, hepatitis, skin toxicities and endocrinopathies such as hypophysitis and thyroid dysfunction. The anti-PD-1 antibodies have a different toxicity profile to ipilimumab with fewer high grade events. This article identifies the rates of common and uncommon irAEs associated with each immune checkpoint inhibitor (ICPI) and their timing of onset, focusing mainly on the experience in melanoma and lung cancer. An approach to management for each class of irAE is provided.

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Antineoplastic Agents; Carcinoma, Renal Cell; Chemical and Drug Induced Liver Injury; Colitis; CTLA-4 Antigen; Cyclosporine; Diarrhea; Drug Eruptions; Humans; Immunosuppressive Agents; Infliximab; Ipilimumab; Kidney Neoplasms; Lung Neoplasms; Melanoma; Mycophenolic Acid; Neoplasms; Nivolumab; Pituitary Diseases; Programmed Cell Death 1 Receptor; Skin Neoplasms; Tacrolimus; Thyroiditis

The choice between ciclosporin (CsA), infliximab (IFX) and surgery for severe colitis not responding to intensive intravenous treatment, is challenging. With the advent of vislizumab and alternatives such as tacrolimus or leucocytapheresis, decisions will get harder. This article reviews the evidence for each intervention, draws attention to disparities in the definition of severe colitis between different trials and gives practical guidance. Early medical decision making is critical. Standard intensive treatment with intravenous steroids is still the first-line approach. Progress should be monitored objectively using a simple predictive index. Rescue therapy with CsA (oral 5 mg/kg or 2 mg/kg iv) or IFX (5 mg/kg) should be started on the third day of intensive treatment if predictive factors are poor (e.g. C-reactive protein > 45 mg/L). Physicians should discuss with their patients that there is just one attempt at rescue therapy, because only one patient death, as a consequence of delayed colectomy, changes the balance of benefit between medicine and surgery.

Topics: Anti-Inflammatory Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Colectomy; Colitis; Cyclosporine; Humans; Immunosuppressive Agents; Infliximab; Practice Patterns, Physicians'; Tacrolimus

The management of acute severe ulcerative colitis depends on early recognition of the unwell patient with colitis, the prompt initiation of treatment and objective assessment of the likelihood of medical failure. This deters 'hopeful expectation' in an attempt to avoid surgery. Intravenous corticosteroids remain first-line therapy but are completely effective in only 40%, partially effective in 30% and around 30% come to colectomy. The decision to use ciclosporin or infliximab for those with a poor response to steroids should be made at an early stage, often 3 or 4 days after starting intensive therapy. Decision-making is becoming more difficult with agents such as visilizumab, tacrolimus and the technique of leucocytapheresis as further options. Nevertheless, intravenous corticosteroids and timely colectomy have reduced mortality from nearly 30% to < 1% in specialist centres. Ciclosporin has delayed the need for urgent colectomy in many patients, but long-term follow-up suggests the majority come to colectomy within 7 years. Long-term outcome with newer agents, including infliximab, is not yet known.

Topics: Acute Disease; Adrenal Cortex Hormones; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Colitis; Humans; Infliximab; Tacrolimus

To determine the efficacy of 0.1% tacrolimus ointment in patients with perianal Crohn's disease (CD).. This prospective randomized trial enrolled 20 patients with perianal CD as anal fissures and rectal fistulas. The inclusion criteria were rectovaginal or extrasphincteric fistulas and purulent leakages. A study group comprised 11 patients, including 9 with anal fissures and 2 with fistulas. A control group included 9 patients, including 8 with fissures and 1 with fistulas. The study group received systemic therapy with azathioprine 2 mg/kg/day and tacrolimus ointment 2 mg/day; the control group had systemic therapy with azathioprine 2 mg/kg/day, hormone ointment 1 mg/day, and metronidazole suppositories 250 mg/day. Control examination and perianal CD activity index (PCDAI) determination were done 6 and 12 weeks after therapy initiation.. At 6 weeks after beginning the study, local examination revealed the signs of anal fissure epithelialization in 5 (45.5%) of the 11 patients in the study group and in 3 (33.3%) of the 9 patients in the control one. At 12 weeks, fissure epithelialization and fistula obliteration were stated in 6 (54%) patients in the study group and in 3 (33%) of the 9 patients in the control group. At 12 weeks, PCDAI in the study and control groups was 2.00 and 4.44 scores (p = 0.01).. The findings suggest that topical 0.1% tacrolimus ointment versus antibacterial suppositories and hormone ointments is effective in treating patients with perianal CD. Topical 0.1% tacrolimus ointment therapy caused a reduction in PCDAI.. Цель исследования. Определить эффективность мази такролимус (0,1%) у больных с перианальными поражениями при болезни Крона (БК). Материалы и методы. В проспективное рандомизированное исследование включили 20 больных БК с перианальными поражениями в виде трещин анального канала и свищей прямой кишки. Критериями исключения являлись ректовагинальные свищи, экстрасфинктерные свищи и наличие гнойных затеков. Основную группу составили 11 пациентов, из которых трещины анального канала отмечались у 9, свищи - у 2. В контрольную группу входили 9 пациентов, из которых трещины имелись у 8, свищи - у 1. Пациенты основной группы получали системную терапию азатиоприном (2 мг/кг/сут) и мазь такролимус (1 мг/сут), пациенты контрольной группы - системную терапию азатиоприном (2 мг/кг/сут), гормональную мазь (1 мг/сут) и свечи с метронидазолом (250 мг/сут). Контрольный осмотр и определение индекса активности перианальной БК (PCDAI) проводили через 6 и 12 нед от начала терапии. Результаты. Через 6 нед от начала исследования при местном осмотре у 5 (45,5%) из 11 пациентов основной группы и у 3 (33,3%) из 9 контрольной отмечалось появление признаков эпителизации анальной трещины. Через 12 нед эпителизация трещин и облитерация свищей констатированы у 6 (54%) больных из 11 основной группы и у 3 (33%) из 9 больных контрольной. PCDAI через 12 нед в основной группе составил 2,00 балла, в контрольной группе - 4,44 балла (р=0,01). Заключение. По результатам проведенного исследования выявлена эффективность местного использования мази такролимус (0,1%) у больных с перианальными поражениями при БК по сравнению с антибактериальными свечами и гормональными мазями. Местная терапия такролимусом (0,1%) способствовала снижению PCDAI.

Topics: Adult; Anal Canal; Colitis; Crohn Disease; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Prospective Studies; Tacrolimus; Treatment Outcome; Young Adult

Tacrolimus is a potent immunomodulator that is effective in the systemic treatment of inflammatory bowel diseases (IBD). However, potential toxicity and systemic (side) effects after oral intake limit its use. We investigated the local applicability and safety of tacrolimus for distal colitis.. Patients with refractory left-sided colitis or proctitis were treated for 4 weeks with a daily tacrolimus 2-4 mg enema or 2 mg suppository. Safety of local tacrolimus treatment was assessed by measurement of whole blood tacrolimus trough levels by monitoring liver and kidney function and blood glucose levels. Efficacy of treatment was assessed by comparing the disease activity index (DAI) in ulcerative colitis (UC) patients and endoscopic and histologic appearances before and after 4 weeks of treatment.. Nineteen patients with left-sided colitis (n = 7) or proctitis (n = 12) were treated. Two patients with left-sided colitis had Crohn's disease (CD), the other 17 patients had UC. None of the patients developed side effects. Blood trough levels of tacrolimus were too low to induce systemic immune suppression. Thirteen of 19 patients (3/5 left-sided UC, 0/2 left-sided CD, and 10/12 proctitis) showed clinical improvement of disease activity after 4 weeks of local tacrolimus treatment. Moreover, a significant improvement of histological appearance was observed in the suppository-treated group.. This study demonstrates that local colonic application of tacrolimus 2-4 mg daily in patients with refractory distal colitis is feasible, probably safe, and potentially efficacious, and therefore opens the need for a further, randomized trial.

Topics: Adult; Colitis; Female; Humans; Immunosuppressive Agents; Male; Recurrence; Suppositories; Tacrolimus; Treatment Outcome

Tacrolimus is a common immunosuppressant used in solid organ transplant recipients. Although most patients develop diarrheal symptoms, data regarding patterns of injury in patients taking tacrolimus are limited. We performed this study to characterize tacrolimus-related features of colonic injury. We retrospectively identified colonic samples from 20 patients receiving tacrolimus monotherapy. Records were reviewed for symptoms, endoscopic findings, other medications, and infections. None of the patients had gastrointestinal infections or used other drugs known to cause colonic injury; none had received mycophenolate within 6 months of presentation. Cases were evaluated for the nature and distribution of inflammation and crypt abnormalities, including distortion, destruction, and apoptosis. Eighteen (90%) patients were solid organ transplant recipients. Seventeen (85%) had gastrointestinal symptoms, particularly diarrhea (75%). More than 50% had endoscopic colitis and 15% had ulcers and/or erosions. Most (90%) cases showed regenerative epithelial changes; apoptotic crypt cells were present in 55% and numerous in 10% of cases. Neutrophilic cryptitis was present in 60% of cases; 35% showed crypt destruction. Plasma cell-rich lamina propria inflammation and crypt distortion were observed in 40% and 25% of cases, respectively. There was no correlation between therapy duration and features of chronic injury. We conclude that tacrolimus can cause symptomatic colitis. Histologic abnormalities are often mild, featuring regenerative crypts and scattered apoptotic debris. However, 40% of symptomatic patients have chronic colitis, most likely reflecting drug-induced immune dysregulation. Pathologists should be aware of these associations because colitis often resolves with decreasing drug dosage rather than treatment directed toward inflammatory bowel disease.

Topics: Adolescent; Adult; Aged; Biopsy; Calcineurin Inhibitors; Child; Child, Preschool; Chronic Disease; Colitis; Colon; Colonoscopy; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Prognosis; Retrospective Studies; Tacrolimus; Young Adult

An attempt to use combination therapy with anti-tumor necrosis factor α (TNFα) antibodies and tacrolimus (TAC) has been tried to induce remission in ulcerative colitis (UC). However, the optimal dose of TAC in combination therapy with anti-TNFα antibodies (TAC + anti-TNFα therapy) remains unclear. We examined the efficacy of various doses of TAC + anti-TNFα therapy in a mouse colitis model. Dextran sulfate sodium induced colitis model mice were divided into an anti-TNFα antibody monotherapy group and the groups that received various doses of TAC + anti-TNFα therapy. The nuclear factor expression of activated T-cells, cytoplasmic 1 (NFATc1) in the nuclei and the mRNA expression of inflammatory cytokines were assessed by immunohistochemistry and RT-PCR, respectively. The serum anti-TNFα antibody concentration was measured with an enzyme-linked immunosorbent assay. The colon length and histological severity were significantly improved in the groups that received any dose of TAC + anti-TNFα therapy. The nuclear expression of NFATc1 was inversely proportional to the administered doses of TAC. The expression levels of inflammatory cytokines tended to decrease in proportion to the dose of TAC. The serum concentration of anti-TNFα antibodies in the high-dose TAC + anti-TNFα therapy was significantly higher than those in the other groups. Low-dose TAC exerted its immunosuppressive effect on T-cells, and additionally, high-dose TAC maintained the serum anti-TNFα antibody concentration. When administered in combination with anti-TNFα antibodies, the dose of TAC should be adjusted according to the disease severity.

Topics: Animals; Antibodies, Monoclonal; Colitis; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Drug Therapy, Combination; Immunosuppressive Agents; Male; Mice, Inbred BALB C; Tacrolimus

The present study aimed at constructing an oral nanoparticle delivery system loaded with tacrolimus (FK506) for effective treatment of inflammatory bowel disease. A FK506/HP-β-CD inclusion compound was prepared by grinding to increase drug solubility. To address the side- effects in non-target organs and systemic toxicity of FK506, pH-responsive Eudragit S100 (ES100) and hyaluronic acid (HA) with high affinity to CD44 receptor were adsorbed onto the surface of chitosan (CS) nanoparticles loaded with FK506/HP-β-CD through electrostatic interactions to obtain FK506@ES100/HA/CS/HP-β-CD nanoparticles (FK506@EHCh NPs). Caco-2 cells and Raw 264.7 macrophages were used to confirm the lack of cytotoxicity and good uptake ability of the newly generated nanoparticles. FK506@EHCh NPs significantly suppressed secretion of TNF-α, IL-1β and IL-6 by LPS-activated Raw 264.7 macrophages. A dextran sodium sulfate (DSS)-induced inflammatory bowel disease (IBD) murine model was established to further confirm the colon targeting and in vivo efficacy of oral IR-775@EHCh NPs. Based on the collective results, we conclude that packaging FK506 into active targeting nanocarriers sensitive to pH facilitates concentration of the drug within the sites of intestinal inflammation and improves the drug levels in target tissues, thus avoiding systemic side-effects and improving efficacy. In view of the promising results obtained in this study, the potential of EHCh nanoparticles for drug delivery and targeted treatment of inflammatory bowel disease warrants further investigation.

Topics: Animals; Caco-2 Cells; Colitis; Drug Delivery Systems; Humans; Hydrogen-Ion Concentration; Mice; Nanoparticles; Tacrolimus

Inflammatory bowel disease is a chronic or remitting/relapsing intestinal inflammation, which comprises Crohn's disease and ulcerative colitis (UC). Severe UC is a life-threatening condition that requires corticosteroids (CS) as a first-line rescue therapy. Some patients are refractory to CS and may require alternative immunosuppressive therapy. Oral tacrolimus (FK506), an immunosuppressive agent, has been reported to be effective in the management of severe refractory UC, but it can cause serious adverse effects. This work aims to study the effect of tacrolimus delivered by a colon-targeted delivery system (CTDS) in a dextran sulfate sodium (DSS)-induced animal model of colitis.. We developed and evaluated an oral CTDS of tacrolimus (FK506) loaded pH-dependent polymeric microspheres, composed of Eudragit® S100 as a pH-sensitive polymer using the oil-in-water emulsion method. The physicochemical properties and drug release profiles of these microparticles in gastrointestinal tract (GIT) conditions were examined. A DSS-induced colitis rat model was used to evaluate the potential remedial and in vivo distribution of microspheres.. The pH-microspheres prevented a burst drug release in acidic pH conditions and showed sustained release at a colonic pH. The in vivo distribution study in the rat GIT demonstrated that pH-microspheres were successfully delivered to the inflamed colon. Moreover, it also demonstrated a significant decrease of disease activity and expression of proinflammatory cytokines, such as tumor necrosis factor α, interleukin-1β (IL-1β), and IL-6, and minimized the histological and morphometric changes.. The results confirmed the efficacy of tacrolimus (FK506) CTDs in the management of DSS-induced colitis.

Topics: Administration, Oral; Animals; Colitis; Colon; Cytokines; Delayed-Action Preparations; Dextran Sulfate; Disease Models, Animal; Drug Carriers; Drug Delivery Systems; Hydrogen-Ion Concentration; Immunosuppressive Agents; Male; Microspheres; Polymethacrylic Acids; Rats; Rats, Wistar; Tacrolimus

Immunosuppression is necessary after solid organ transplantation. The non-infectious side effects associated with many of these agents are not well understood. We report a case of colitis, most resembling inflammatory bowel disease, that persisted despite withdrawal of tacrolimus and mycophenolate mofetil and transition to alternative agents. The patient was treated for clostridium difficile without improvement. Endoscopic biopsies demonstrated non-specific inflammation without evidence of active infection. An extensive immunologic and oncologic workup was negative. Ultimately, we trialed the administration of infliximab, a monoclonal antibody that inhibits TNF-alpha receptors that is commonly used in the treatment of inflammatory bowel disease. With infliximab treatment, the patient experienced rapid resolution of his disease and has remained in remission.

Topics: Antibiotics, Antineoplastic; Antirheumatic Agents; Biopsy; Child, Preschool; Colitis; Colonoscopy; Drug Therapy, Combination; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Infliximab; Male; Mycophenolic Acid; Tacrolimus

Chronic immunosuppression may increase the risk of post-transplant infection and medication-related injury and may also be responsible for the increased risk of gastrointestinal complications in kidney transplant recipients. Differentiating the various forms of post-transplant colitis is challenging, since most have similar clinical and histological features. This study evaluated the incidence of post-transplant gastrointestinal complications during screening colonoscopy. Kidney transplant recipients undergoing a colonoscopy for any reasons in the period 2014-2018 were included. Among the 134 patients completing the colonoscopy, 74 patients (56%) had an abnormal finding: an adenoma was found in 25 patients (18.6%), while 19 patients (14.1%) had colitis. Mycophenolic acid/related colitis was the most common colitis (6%), while 7 patients (5.2%) developed a

Topics: Adenoma; Age Distribution; Aged; Anemia; Colitis; Colonoscopy; Colorectal Neoplasms; Diarrhea; Diverticulosis, Colonic; Early Detection of Cancer; Female; Gastrointestinal Hemorrhage; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Inflammatory Bowel Diseases; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Tacrolimus; Time Factors

Epithelial to mesenchymal transition (EMT) occurs when cells lose morphological features of epithelial cells, such as cell-to-cell adhesion, and gain features of mesenchymal cells, including elongation and flattening. These cells also lose expression of epithelial immunohistochemical markers. In this report, we present a 55-year-old Caucasian male patient who underwent orthotopic heart transplant and immunosuppressant therapy with tacrolimus and mycophenolic acid. Seven and a half months later, an endomyocardial biopsy revealed a hypercellular, atypical lesion. Evaluation was negative for acute cellular rejection and post-transplant lymphoproliferative disorder. Histopathologic features and immunohistochemical stains were consistent with EMT. We subsequently identified four additional cases of EMT in patients who underwent orthotopic heart transplantation and received a similar immune suppression regimen. EMTs have been reported to occur in lung and kidney allografts; however, this is the first known report describing this entity in a heart transplant recipient.

Topics: Colitis; Diagnosis, Differential; Endocardium; Epithelial-Mesenchymal Transition; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Tacrolimus

Enteric-coated formulations using Eudragit® polymers have been extensively used for delivering drugs to the lower gastrointestinal tract. However, these drug-delivery systems cannot accurately deliver the therapeutic cargoes to colon because of early degradation of the polymers at alkaline pH of the small intestine. Here, we describe a precise method of delivering drugs to inflammation sites in colon using an oral drug delivery system. Tacrolimus (FK506)-loaded microspheres were prepared using a thioketal-based polymer that releases drug in response to reactive oxygen species (ROS), which are abundantly produced at the sites of inflammation in acute colitis. Orally-administered FK506-loaded thioketal microspheres (FK506-TKM) led to a substantial accumulation of FK506 in inflamed colon and effectively alleviated dextran-sulfate sodium (DSS)-induced murine colitis. At the molecular level, FK506-TKM significantly inhibited infiltration of CD4

Topics: Animals; Cell Differentiation; Cell Movement; Colitis; Dendritic Cells; Disease Models, Animal; Drug Delivery Systems; Drug Liberation; Immunosuppressive Agents; Inflammation; Mice; Mice, Inbred C57BL; Microspheres; Polymethacrylic Acids; Reactive Oxygen Species; Tacrolimus; Th1 Cells; Th17 Cells

We hypothesized that the gut microbiota influences survival of murine cardiac allografts through modulation of immunity. Antibiotic pretreated mice received vascularized cardiac allografts and fecal microbiota transfer (FMT), along with tacrolimus immunosuppression. FMT source samples were from normal, pregnant (immune suppressed), or spontaneously colitic (inflammation) mice. Bifidobacterium pseudolongum (B. pseudolongum) in pregnant FMT recipients was associated with prolonged allograft survival and lower inflammation and fibrosis, while normal or colitic FMT resulted in inferior survival and worse histology. Transfer of B. pseudolongum alone resulted in reduced inflammation and fibrosis. Stimulation of DC and macrophage lines with B. pseudolongum induced the antiinflammatory cytokine IL-10 and homeostatic chemokine CCL19 but induced lesser amounts of the proinflammatory cytokines TNFα and IL-6. In contrast, LPS and Desulfovibrio desulfuricans (D. desulfuricans), more abundant in colitic FMT, induced a more inflammatory cytokine response. Analysis of mesenteric and peripheral lymph node structure showed that B. pseudolongum gavage resulted in a higher laminin α4/α5 ratio in the lymph node cortical ridge, indicative of a suppressive environment, while D. desulfuricans resulted in a lower laminin α4/α5 ratio, supportive of inflammation. Discrete gut bacterial species alter immunity and may predict graft outcomes through stimulation of myeloid cells and shifts in lymph node structure and permissiveness.

Topics: Allografts; Animals; Anti-Bacterial Agents; Cell Line, Tumor; Colitis; Cytokines; Disease Models, Animal; Fecal Microbiota Transplantation; Female; Gastrointestinal Microbiome; Graft Rejection; Graft Survival; Heart Transplantation; Humans; Immunity, Innate; Immunosuppressive Agents; Lymph Nodes; Mice; Myocardium; Pregnancy; RAW 264.7 Cells; Tacrolimus; Treatment Outcome

Tacrolimus is an immunosuppressive agent that has been proposed in the treatment of severe ulcerative colitis. The present study examined the effectiveness and safety of tacrolimus in treating refractory Crohn disease (CD) colitis in children.. All children treated by oral tacrolimus for CD colitis at a tertiary pediatric center were included in the study. All patients were refractory to steroids and infliximab. Clinical response (decreased pediatric CD activity index [PCDAI] >15 and PCDAI <30) and remission (PCDAI <10) were monitored at 2, 4, 6, 12, and 24 months after induction. Tacrolimus blood levels and adverse effects were also noted.. Among 220 patients with CD, 8 children (including 3 girls, median age 14 [9.5-18] years) were registered with a median PCDAI of 58.7 (32.5-65) before tacrolimus initiation. In patients treated with tacrolimus, the overall clinical response rates were 6/8, 3/8, 2/8, 2/8, and 1/8 with a remission rate of 4/8, 0/8, 0/8, 2/8, and 0/8 at 2, 4, 6, 12, and 24 months, respectively. At 2 months, the PCDAI scores were lower than those at induction (median 11.2; P = 0.004) with the mean whole plasma level of tacrolimus being 8.75 ng/mL (5.9-10 ng/mL). Adverse events occurred in 6 of 8 patients, including renal dysfunction, insulin-dependent diabetes, paresthesia, and tremor. Tacrolimus interruption was required in 2 cases.. Tacrolimus could be considered to transiently treat refractory CD colitis. Tacrolimus could be used as a "bridge" toward another medical option in pediatric CD, although its adverse events are frequent.

Topics: Acute Disease; Administration, Oral; Adolescent; Child; Colitis; Crohn Disease; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Retrospective Studies; Severity of Illness Index; Tacrolimus; Treatment Outcome

Serious gastrointestinal complications arising 13 years after the initiation of posttransplant immunosuppressant therapy with mycophenolate mofetil are reported.. Over a three-month period, a male heart transplant recipient who had taken oral mycophenolate mofetil (2 g daily) for 13 years as part of an immunosuppressant maintenance regimen developed diarrhea and weight loss leading to renal failure and metabolic acidosis. There was no evidence of opportunistic infection, and immunostaining for cytomegalovirus yielded negative results. Colonoscopy revealed areas of congested, erythematous, and nodular mucosa. Histological examination of mucosal biopsy specimens revealed pathological abnormalities typical of those seen in cases of mycophenolate mofetil-associated colitis. On discontinuation of mycophenolate mofetil use, the patient's diarrhea resolved and his renal function improved. Colitis, diarrhea, and other gastrointestinal complications are commonly reported in patients receiving mycophenolate mofetil, an immunosuppressant widely used to prevent rejection of solid organ or bone marrow transplants; however, the onset of such symptoms after more than a decade of continuous use of the drug has not been previously reported. This case suggests that mycophenolate mofetil toxicity should be considered in the evaluation of late-onset posttransplant diarrhea regardless of the duration of therapy.. A 33-year-old man maintained on mycophenolate mofetil for 13 years after heart transplantation developed diarrhea, weight loss, and acute kidney injury over a three-month period. Colonoscopy and biopsy revealed pathological changes consistent with mycophenolate mofetil toxicity, and the patient's symptoms resolved after the drug was discontinued.

Topics: Adult; Colitis; Colon; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Mycophenolic Acid; Tacrolimus

The dextran sulfate sodium (DSS)-induced model of colitis is a commonly used model of inflammatory bowel disease (IBD) in animals. However, there were few studies on the therapeutic efficacy of drugs for IBD after the onset of colitis in this model. We established a semi-chronic model of DSS-induced colitis in mice and used it to assess the therapeutic efficacy of agents for IBD.. Colitis was induced by administration of 3% DSS in drinking water to mice for 7days followed by 5days of normal drinking water.. Ulcerative colitis (UC)-like symptoms including diarrhea, bloody stools and body-weight loss were observed from days 3 to 5, and continued until day 12 after DSS administration. Persistent colitis was associated with sustained local production of cytokines and was characterized by infiltration of inflammatory cells, crypt loss and erosion in the distal colon. These features are similar to those found in patients with UC. In this model, anti-tumor necrosis factor (TNF)-α antibody or anti-interleukin (IL)-12/23p40 antibody significantly ameliorated colitis when administered after the onset of colitis. However, treatment with FK506, prednisolone or sulfasalazine provided limited therapeutic benefit.. The DSS-induced colitis established here showed similar symptomatic and histopathological features to those seen in human UC. This model may be available for predicting the clinical efficacy of candidate compounds for UC.

Topics: Animals; Anti-Inflammatory Agents; Antibodies; Colitis; Cytokines; Dextran Sulfate; Disease Models, Animal; Female; Gastrointestinal Agents; Immunosuppressive Agents; Inflammatory Bowel Diseases; Mice; Mice, Inbred C57BL; Peroxidase; Prednisolone; Sulfasalazine; Tacrolimus

Nuclear factor of activated T cells (NFAT) plays a critical role in the development and function of immune and non-immune cells. Although NFAT is a central transcriptional regulator of T cell cytokines, its role in macrophage specific gene expression is less defined. Previous work from our group demonstrated that NFAT regulates Il12b gene expression in macrophages. Here, we further investigate NFAT function in murine macrophages and determined the effects of a cell permeable NFAT inhibitor peptide 11R-VIVIT on experimental colitis in mice. Treatment of bone marrow derived macrophages (BMDMs) with tacrolimus or 11R-VIVIT significantly inhibited LPS and LPS plus IFN-γ induced IL-12 p40 mRNA and protein expression. IL-12 p70 and IL-23 secretion were also decreased. NFAT nuclear translocation and binding to the IL-12 p40 promoter was reduced by NFAT inhibition. Experiments in BMDMs from IL-10 deficient (Il10(-/-)) mice demonstrate that inhibition of IL-12 expression by 11R-VIVIT was independent of IL-10 expression. To test its therapeutic potential, 11R-VIVIT was administered systemically to Il10(-/-) mice with piroxicam-induced colitis. 11R-VIVIT treated mice demonstrated significant improvement in colitis compared to mice treated with an inactive peptide. Moreover, decreased spontaneous secretion of IL-12 p40 and TNF in supernatants from colon explant cultures was demonstrated. In summary, NFAT, widely recognized for its role in T cell biology, also regulates important innate inflammatory pathways in macrophages. Selective blocking of NFAT via a cell permeable inhibitory peptide is a promising therapeutic strategy for the treatment of inflammatory bowel diseases.

Topics: Active Transport, Cell Nucleus; Animals; Bone Marrow Cells; Colitis; Cytokines; Disease Models, Animal; Green Fluorescent Proteins; Inflammation; Interferon-gamma; Interleukin-10; Interleukin-12 Subunit p40; Lipopolysaccharides; Macrophages; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Fluorescence; NFATC Transcription Factors; Nitric Oxide Synthase Type II; Promoter Regions, Genetic; RNA, Messenger; Tacrolimus

Salmonellosis caused by Salmonella enteritidis is an acute and in most cases zoonotic disease, but chronic human carriers are also known. Mostly, affected persons recover without treatment, but severe complications occur occasionally. For the first time we report a case of probably food-borne invasive Salmonella enteritidis infection with septic shock in a patient with Tacrolimus treatment, 13 years after renal transplantation, probably acquired by uncooked ground pork meat.

Topics: Aged; Animals; Colitis; Cooking; Food Microbiology; Foodborne Diseases; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Meat; Opportunistic Infections; Salmonella enteritidis; Salmonella Infections; Shock, Septic; Swine; Tacrolimus; Tomography, X-Ray Computed

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.

Topics: Animals; Colitis; Disease Models, Animal; Dose-Response Relationship, Drug; Immunosuppressive Agents; Inflammation; Interleukin-10; Macrophages; Male; Mice; Mice, Transgenic; Monocytes; Phenotype; Prednisolone; T-Lymphocytes; Tacrolimus; Tumor Necrosis Factor-alpha

We investigated the effect of tacrolimus, a calcineurin inhibitor, on dextran sulfate sodium (DSS)-induced colitis. After inducing colitis in C57BL/6 mice by administering DSS solution as drinking water for 7 d, the animals were treated with tacrolimus. Severity of colonic inflammation was evaluated based on colon weight per unit length. Levels of cytokines (interferon (IFN)-γ, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-12, and tumor necrosis factor (TNF)-α) released from isolated inflamed colons of mice treated with tacrolimus or vehicle were also measured. Treatment with tacrolimus for 14 d reduced the colon weight per unit length and suppressed the release of IFN-γ and IL-1β, but not other cytokines, in inflamed colons of colitic mice compared with vehicle-treated mice. A positive correlation was noted between colon weight per unit length and released level of IFN-γ or IL-1β. The release of IFN-γ and IL-1β was also suppressed after single dosing with tacrolimus to colitic mice. Taken together, these results suggested that tacrolimus ameliorated DSS-induced colitis by suppressing release of IFN-γ and IL-1β from inflamed colon.

Topics: Animals; Colitis; Colon; Cytokines; Dextran Sulfate; Disease Models, Animal; Immunosuppressive Agents; Male; Mice; Mice, Inbred C57BL; Tacrolimus

T-cells are a main target for antiinflammatory drugs in inflammatory bowel disease. As the innate immune system is also implicated in the pathogenesis of these diseases, T-cell suppressors may not only inhibit T-cell-dependent production of proinflammatory mediators but also affect innate immune cell function. Specifically, these drugs may impair innate immune cell recruitment and activation through inhibition of T-cells or act independent of T-cell modulation. We explored the extent of immune modulation by the T-cell inhibitor tacrolimus in a murine colitis model.. We assessed the effects of tacrolimus on trinitro-benzene sulphonic acid (TNBS) colitis in wildtype and Rag2-deficient mice. The severity of colitis was assessed by means of histological scores and weight loss. We further characterized the inflammation using immunohistochemistry and by analysis of isolated intestinal leukocytes at various stages of disease.. Tacrolimus-treated wildtype mice were less sensitive to colitis and had fewer activated T-cells. Inhibition of T-cell function was associated with strongly diminished recruitment of infiltrating neutrophils in the colon at the early stages of this model. In agreement, immunohistochemistry demonstrated that tacrolimus inhibited production of the neutrophil chemoattractants CXCL1 and CXCL2. Rag2-deficient mice displayed an enhanced baseline level of lamina propria neutrophils that was moderately increased in TNBS colitis and remained unaffected by tacrolimus.. Both the innate and the adaptive mucosal immune system contribute to TNBS colitis. Tacrolimus suppresses colitis directly through inhibition of T-cell activation and by suppression of T-cell-mediated recruitment of neutrophils.

Topics: Adaptive Immunity; Animals; Colitis; Dendritic Cells; Diphtheria Toxin; Disease Models, Animal; Disease Progression; DNA-Binding Proteins; Immunosuppressive Agents; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Neutrophils; Severity of Illness Index; T-Lymphocytes; Tacrolimus

Diarrhea is a frequent complication in patients after solid organ transplantation. We describe two cases of severe new onset colitis in kidney transplant recipients that developed shortly after the introduction of the therapy with prolonged-release formulation of tacrolimus replacing standard twice daily formulation of tacrolimus in one case and cyclosporine A in the second case. Both patients developed severe, intermittent bloody diarrhea with abdominal pain, weight loss, dehydration and worsening graft function that required immediate hospitalization. The symptoms did not diminish after dose reduction or withdrawal of mycophenolic acid derivatives. After excluding bacterial, viral, fungal, and parasite infections, colonoscopy with colonic biopsy was performed in both patients, which revealed features typical of colitis. Both patients received mesalazine until the symptoms stopped. In one of the patients, standard formulation of tacrolimus was immediately reintroduced. The second patient was given everolimus in an acute phase of diarrhea. Although the two cases presented in this report cannot fully support a causal relationship between the prolonged-release tacrolimus and colitis, they should increase awareness among transplant physicians and prompt more close monitoring of such potential side effects as a part of the pharmacovigilance plan for a new formulation of the well-established immunosuppressive drug.

Topics: Adult; Biopsy; Colitis; Colon; Delayed-Action Preparations; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Polycystic Kidney Diseases; Tacrolimus

Tacrolimus is a novel immunomodulator for inflammatory bowel diseases. Immunosuppressive effects of tacrolimus on T cells are well known; however, the effects of tacrolimus on macrophages remain unclear. The aim of this study was to investigate the effects of tacrolimus on activated macrophages and to examine its efficacy in murine colitis models.. Proinflammatory cytokine production from lipopolysaccharide (LPS)-stimulated peritoneal macrophages of IL-10-knockout (KO) mice with and without tacrolimus was measured. We investigated the effects of tacrolimus on nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and caspase activation in macrophages and the induction of apoptosis in macrophages in vitro and examined the in vivo apoptotic effect of tacrolimus on colonic macrophages in IL-10-KO mice. We evaluated the effect of the rectal administration of tacrolimus on colonic inflammation in IL-10-KO mice and dextran sulfate sodium (DSS)-induced colitis in CB.17/SCID mice.. Proinflammatory cytokine production from tacrolimus-treated macrophages was significantly lower than that from untreated cells. Tacrolimus suppressed LPS-induced activation of both NF-κB and MAPK in macrophages and induced apoptosis of macrophages via activation of caspases 3 and 9. Rectal administration of tacrolimus evoked apoptosis of colonic macrophages in IL-10-KO mice. Moreover, the rectal administration of tacrolimus ameliorated colitis in IL-10-KO mice and DSS-induced colitis in CB.17/SCID mice. Gene expression of inflammatory cytokines in colonic mucosa was significantly lower in tacrolimus-treated mice than in untreated mice.. Tacrolimus suppresses the function of activated macrophages and promotes their apoptosis, which may lead to the amelioration of colonic inflammation.

Topics: Animals; Apoptosis; Blotting, Western; Cell Proliferation; Colitis; Cytokines; Dextran Sulfate; Disease Models, Animal; Female; Immunosuppressive Agents; Interleukin-10; Lipopolysaccharides; Macrophages, Peritoneal; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinases; NF-kappa B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tacrolimus

Pathophysiologic changes in mucosal protein expression inflammatory bowel disease (IBD) may affect drug concentration in mucosal tissue making it highly relevant to drug dose at the site of action and subsequently for success of the therapy. Tissue samples from an experimental colitis rat model were mounted in Ussing chambers and intratissue concentrations of diverse compounds were quantified. Studies with healthy versus colitis tissue samples and respective microsomal fractions made it possible to assess the involvement of P-glycoprotein (P-gp) and cytochrome P450 3A (CYP3A) on tissue penetration behavior. P-gp-related efflux was slightly increased for colitis tissue. Metabolism studies exhibited higher tacrolimus and testosterone mucosal metabolism in inflamed tissue. However, similar metabolic activity was observed for healthy and colitis groups with equivalent CYP3A expression levels in respective microsome fractions. Severity of colitis as determined by myeloperoxidase activity was found to have linear correlation to changes in tacrolimus degradation (R2 = 0.8299). It is hypothesized that increased drug metabolism is dependent on the number of cells infiltrating inflamed tissue. A dominant contribution of immune-related cells to observed variations in mucosal drug metabolism has been determined. This observed pathophysiologic mechanism may have a significant influence on available drug concentrations at the inflammation site, thus modifying anti-inflammatory efficiency of the therapy.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Colitis; Cytochrome P-450 CYP3A; Immunosuppressive Agents; Intestinal Mucosa; Male; Microsomes; Peroxidase; Rats; Rats, Wistar; Severity of Illness Index; Tacrolimus; Testosterone

Tacrolimus is a macrolide agent that is now the primary immunosuppressant used in prevention of graft rejection in transplant recipients. It has been found to be superior to cyclosporine (CSA) for rescue therapy as well as for earlier weaning of steroids. Both tacrolimus and CSA share similar toxicity profiles; however, their gastrointestinal side effects have received little attention. We report three cases of eosinophilic colitis in liver transplant recipients, maintained on tacrolimus as immunosuppressive medication post-liver transplantation. These patients also had high serum immunoglobulin (Ig)E levels, eosinophilia and IgE-positive radioallergosorbent test for milk proteins. The colitis appeared to be mediated by food allergies. Each patient had symptomatic improvement following reduced immunosuppression and an appropriately restricted diet. We conclude that tacrolimus may play a role in the initiation of food allergies, leading to eosinophilic colitis. More studies are needed in a controlled setting to identify the prevalence of similar findings among other pediatric liver transplant recipients.

Topics: Child; Colitis; Eosinophilia; Food Hypersensitivity; Humans; Immunoglobulin E; Immunosuppressive Agents; Infant; Liver Transplantation; Male; Tacrolimus

FK506 microparticles providing selective colonic drug delivery were tested for their efficiency in a local treatment to the inflamed gut tissue in inflammatory bowel disease (IBD). Because FK506 proved its distinct mitigating potential in the treatment of IBD, risking, however, severe adverse effects, a more selective delivery to the site of inflammation may further improve efficiency and tolerability.. A model colitis was induced to male Wistar rats by trinitrobenzenesulfonic acid. FK506 was entrapped into microspheres (MS) prepared with the pH-sensitive polymer Eudragit P-4135F in order to allow drug delivery to the colon. Clinical activity score, colon/body weight index, and myeloperoxidase activity were determined to assess the inflammation, and adverse effects of FK506 resulting from its systemic absorption were quantified as well.. The clinical activity score and myeloperoxidase activity decreased after the administration of all FK506-containing formulations. The MS formulations proved to be as efficient in mitigating the experimental colitis as the subcutaneous drug solution (myeloperoxidase activity, MS: 9.64+/-6.6 U/mg tissue; subcutaneous: 7.48+/-6.96 U/mg) and to be superior to drug solution given by oral route (oral: 12.66+/-5.46 U/mg; untreated colitis control: 21.88+/-4.12 U/mg). The FK506 subcutaneous group exhibited increased levels of adverse effects, whereas the FK506-MS group proved its potential to retain the drug from systemic absorption as evidenced by reduced nephrotoxicity.. The development of this selective delivery system for FK506 should be given particular consideration in the treatment of IBD, as it allows therapy that profits from FK506's high immune suppressive effect with a simultaneously reduced nephrotoxicity.

Topics: Animals; Calcineurin; Calcineurin Inhibitors; Colitis; Kidney; Male; Microspheres; Rats; Rats, Wistar; Tacrolimus

Topics: Administration, Topical; Child; Colitis; Humans; Immunosuppressive Agents; Leg Ulcer; Male; Pyoderma Gangrenosum; Tacrolimus; Treatment Outcome

Nanoparticles (NP) are proposed for targeted drug delivery to the inflammation site in severe cases of inflammatory bowel disease where state-of-the-art delivery devices fail. FK506 (tacrolimus) entrapped into NP was administered either orally or rectally to male Wistar rats suffering from a preexisting experimental colitis. Clinical activity score, colon/body weight index, and myeloperoxidase activity were determined to assess the inflammation. Tissue penetration experiments elucidated the processes involved in the proposed new therapeutic approach. The therapeutic effects of FK506 solutions as well as FK506-NP by oral route were minor. The myeloperoxidase activity and colon/body weight ratio decreased significantly (P < 0.05) only after the rectal administration of FK506-NP, whereas treatment by free drug was not different from colitis control in both 2,4,6-trinitrobenzenesulfonic acid and oxazolone colitis model. NP allows an enhanced and selective drug penetration into the inflammation site as opposed to surrounding healthy tissue (healthy: FK506, 109 +/- 18 nmol/cm2; FK506-NP, 51 +/- 13 nmol/cm2; colitis: FK506, 79 +/- 28 nmol/cm2; FK506-NP, 105 +/- 24 nmol/cm2), presumably by protecting the encapsulated drug against influences from efflux systems and mucosal metabolism. The relative drug penetration into the inflamed tissue is about 3-fold higher compared with healthy tissue when using NP as drug carriers. The use of drug-loaded NP offers several advantages compared with standard therapeutic strategies such as a higher selectivity in adhesion to and enhanced drug penetration into the inflamed tissue.

Topics: Animals; Colitis; Creatinine; Drug Delivery Systems; Male; Nanostructures; Oxazolone; Rats; Rats, Wistar; Tacrolimus; Trinitrobenzenesulfonic Acid

The liver was previously shown to play a critical role in oral tolerance induction. A subset of liver-associated-lymphocytes expressing NK1.1 marker (NK1.1+ LAL) have killing activities and it has been suggested that they play a role in immune modulation. FK506 is a powerful immunosuppressive agent affecting T-cell differentiation and function. The exact pathway involved in peripheral tolerance induction using this drug remains unknown. The aim of the present study was to determine the interaction between FK506 and NK1.1+ LAL in induction of peripheral immune tolerance in the experimental colitis model.. Colitis was induced in C57 mice by intracolonic instillation of trinitrobenzenesulfonic acid (TNBS). Mice received five oral doses of colonic proteins extracted from TNBS-colitis colonic wall with and without FK506 treatment. The effect of FK506 treatment on NK1.1+ LAL was tested by cell-sorting and cytotoxicity assay. Colitis was assessed by standard clinical, macroscopic and histologic scores.. Both FK506 treatment and oral tolerance induced a significant increase in NK1.1+ LAL number and cytotoxicity function. FK506 treatment enhanced the effect of oral tolerance on amelioration of disease activity. Orally tolerized mice treated with FK506 had no mortality nor increase in body weight, and manifested significant improvement in disease macroscopic and microscopic scores.. This study shows for the first time that immune tolerance induced by both oral administration of an antigen and by FK506 treatment may be mediated via enhancement of NK1.1+ LAL. This subset of lymphocytes may play an immunoregulatory role in immune tolerance induction.

Topics: Animals; Antigens; Antigens, Ly; Antigens, Surface; Colitis; Immune Tolerance; Immunosuppression Therapy; Immunosuppressive Agents; Lectins, C-Type; Liver; Lymphocyte Subsets; Male; Mice; Mice, Inbred C57BL; NK Cell Lectin-Like Receptor Subfamily B; Proteins; Tacrolimus; Trinitrobenzenesulfonic Acid

Topics: Colitis; Colon; Creatinine; Cyclosporine; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Ischemia; Kidney Transplantation; Middle Aged; Muromonab-CD3; Mycophenolic Acid; Tacrolimus

The objective of this study was to quantitatively characterize the effects FK506 on the pathophysiology observed in a model of chronic granulomatous colitis in rats and compare these effects to those obtained with cyclosporin A (CyA). Chronic granulomatous colitis was induced in female Lewis rats via intramural (subserosal) injections of peptidoglycan/polysaccharide (PG/PS) into the distal colon. Rats then received daily injections (i.m.) of either vehicle for CyA (0.5 ml/kg cremophor), CyA in vehicle (25 mg/kg), saline (0.5 ml/kg) or FK506 (1 mg/kg in saline), beginning 7 days after PG/PS injection and continuing for an additional 2 weeks. On day 21, we found that the intramural injection of PG/PS produced a chronic colitis that was associated with hepatic and splenic granulomatous inflammation. Daily treatment with CyA or FK506 beginning 7 days after the induction of colitis resulted in significant inhibition in colonic mucosal permeability, colonic myeloperoxidase activity and plasma nitrate/nitrite levels when compared with their vehicle or untreated controls. In some instances, we noticed a significant vehicle-dependent anti-inflammatory activity. The incidence of peritoneal adhesions as well as the presence of hepatic and splenic granulomas induced by PG/PS were also significantly reduced in both the CyA- and FK506-treated groups. Taken together, these data suggest that immunosuppressive therapy is effective at attenuating both the colitis as well as the extraintestinal inflammation induced by PG/PS. We conclude that FK506 may be useful in the treatment of certain types of inflammatory bowel disease.

Topics: Animals; Blood Pressure; Body Weight; Colitis; Colon; Cyclosporine; Female; Granulomatous Disease, Chronic; Intestinal Mucosa; Liver; Nitrates; Nitrites; Organ Size; Peptidoglycan; Polysaccharides; Rats; Rats, Inbred Lew; Spleen; Tacrolimus

Topics: Adolescent; Autoimmune Diseases; Biopsy; Chronic Disease; Colitis; Diarrhea; Duodenum; Gastroenteritis; Humans; Immunosuppressive Agents; Male; Rectum; Tacrolimus

Topics: Biopsy; Child; Colitis; Colon; Female; Humans; Immunosuppressive Agents; Remission Induction; Sigmoidoscopy; Tacrolimus

To assess the effects of FK506, a newly developed immunosuppressant, on experimental colitis in rats.. Experimental colitis was induced by a single colonic instillation of hapten 2,4,6-trinitrobenzene sulphonic acid (TNB) in anaesthetized rats. Rats received 30 mg TNB dissolved in 0.25 mL of 50% ethanol, and were sacrificed on day 5 following 4 days dosing with FK506 (0.25, 0.5, 1.0, 2.0 mg/kg, s.c.) or vehicle. Mucosal prostanoid concentrations were determined using high performance liquid chromotography. Tissue myeloperoxidase activities were measured. The effects of FK506 on superoxide radical formation by neutrophils in both rats and humans were also estimated in vitro.. Administration of FK506 significantly reduced the colonic damage in a dose-dependent manner. Activities of myeloperoxidase and concentrations of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), PGF2 alpha and PGE2 in colonic tissue increased significantly following induction of experimental colitis, however, FK506 did not affect these changes. FK506 reduced stimulant-induced superoxide radical formation by neutrophils in rats and humans.. FK506 decreased superoxide radical generation by neutrophils, which might contribute to the lessening of colonic damage in this model.

Topics: Animals; Colitis; Colon; Male; NADH, NADPH Oxidoreductases; NADPH Oxidases; Peroxidase; Rats; Rats, Wistar; Superoxides; Tacrolimus

Administration of dextran sulfate sodium (DSS) solutions to rats induced colitis which resembled mucosal lesions of human ulcerative colitis. Recent reports have shown that some cytokines are related to the pathogenesis of ulcerative colitis. In the present report, we describe the production of two cytokines in colitis mucosa in this DSS model. Using a cytotoxicity assay and a radioimmunoassay, we observed significant increases in levels of tumor necrosis factor-alpha (TNF-alpha) in the colitis mucosa and detected interleukin-1 alpha in the mucosa of 3 of 5 DSS rats and an increase in TNF-alpha had a tendency to be inhibited by treatment with FK506. Immunohistochemical investigation of DSS mucosa showed that the number of activated T cells increased at the earlier phase of inflammation. Luminol-dependent chemiluminescence values and myeloperoxidase activities were increased in the late phase of colitis and were suppressed by the FK506 treatment. These findings may support the role of TNF-alpha and T-cell activation in the pathogenesis of DSS colitis.

Topics: Animals; Colitis; Dextran Sulfate; Interleukin-1; Intestinal Mucosa; Luminescent Measurements; Lymphocyte Activation; Male; Peroxidase; Rats; Rats, Wistar; T-Lymphocytes; Tacrolimus; Tumor Necrosis Factor-alpha

Intestinal epithelial permeability can be modulated by the immune system and can be greatly increased by transepithelial migration of neutrophils. Since immunosuppressants have been reported to inhibit the ability of neutrophils to migrate, we assessed the effects of two immunosuppressants on epithelial permeability and granulocyte infiltration in a model of acute colitis. Epithelial permeability was measured at 3 and 6 h after induction of colitis in the rabbit by intracolonic administration of trinitrobenzene sulfonic acid. At these times, blood-to-lumen leakage of 51Cr-EDTA was elevated by approximately 8- and 18-fold, respectively, above levels observed in healthy controls. Pretreatment with either of the immunosuppressants (cyclosporin A and L-683,590) significantly reduced the changes in 51Cr-EDTA leakage observed at the latter time point. These drugs also significantly attenuated granulocyte infiltration of the colon after induction of colitis, as measured by tissue myeloperoxidase activity. Unlike the immunosuppressants, misoprostol, a prostaglandin analogue, attenuated the increases in colonic permeability but had no effect on granulocyte infiltration in this model. These results demonstrate that two structurally unrelated immunosuppressants are capable of markedly reducing neutrophil infiltration and the colonic permeability changes observed in an experimental model of acute colitis, although the mechanisms through which these effects are produced remain unclear.

Topics: Animals; Colitis; Colon; Cyclosporine; Disease Models, Animal; Epithelium; Immunosuppressive Agents; Male; Misoprostol; Neutrophils; Permeability; Peroxidase; Rabbits; Tacrolimus; Trinitrobenzenesulfonic Acid