tacrolimus and Edema

TAFRO syndrome is a systemic inflammatory disorder characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis, renal dysfunction, and organomegaly. In contrast to that in multicentric Castleman disease, interleukin-6 targeting strategies seem ineffective in some TAFRO syndrome cases; however, the optimal treatment remains unclear. Here, we report 2 cases of TAFRO syndrome, where 1 with cardiomyopathy, successfully treated with tacrolimus. This is the first case report of successful treatment with tacrolimus in TAFRO syndrome.. Both patients (cases 1 and 2) developed fever, anasarca, thrombocytopenia, renal dysfunction, and mild hepatosplenomegaly.. In both patients, lymph node pathology revealed mixed type Castleman disease-like features, and bone marrow showed reticulin myelofibrosis. TAFRO syndrome was diagnosed based on the patients' laboratory, clinical, and pathologic findings. In case 2, we observed a rare complication of cardiomyopathy with no evidence of takotsubo cardiomyopathy or viral myocarditis.. In case 1, tocilizumab combined with glucocorticoids was ineffective and caused septic shock; additionally, cyclosporine A was discontinued because of hepatotoxicity. However, tacrolimus was effective in resolving TAFRO syndrome without any adverse events. In case 2, tacrolimus completely reversed TAFRO syndrome and was also effective in cardiomyopathy.. This report suggests that tacrolimus is potentially effective and safe as an initial treatment and a glucocorticoid-sparing agent. Our literature review shows that calcineurin inhibitors, including tacrolimus, may be effective in TAFRO syndrome. Since previous studies indicate a role of Th1 inflammation in TAFRO syndrome pathogenesis, tacrolimus may, therefore, be effective in treating TAFRO syndrome.

Topics: Adolescent; Aged; Bone Marrow; Calcineurin Inhibitors; Cardiomyopathies; Castleman Disease; Cyclosporine; Edema; Female; Fever; Fibrosis; Glucocorticoids; Hepatomegaly; Humans; Interleukin-6; Male; Primary Myelofibrosis; Renal Insufficiency; Splenomegaly; Syndrome; Tacrolimus; Thrombocytopenia; Treatment Outcome

Topics: Administration, Topical; Animals; Antigens, Dermatophagoides; Child; Child, Preschool; Cyclosporine; Dermatitis, Atopic; Desensitization, Immunologic; Eczema; Edema; Humans; Immunoglobulin E; Male; Pyroglyphidae; Tacrolimus

Chlorthalidone is a very effective antihypertensive drug, but it has not been studied prospectively in kidney transplant recipients with hypertension. Recent data indicate that calcineurin inhibitors activate the thiazide-sensitive sodium chloride cotransporter, providing further rationale to test thiazides in this population.. Randomized noninferiority crossover trial (noninferiority margin, -2.8mmHg).. Hypertensive kidney transplant recipients using tacrolimus (median duration, 2.4 years after transplantation; mean estimated glomerular filtration rate, 63±27 [SD] mL/min/1.73m. Amlodipine (5-10mg) and chlorthalidone (12.5-25mg) for 8 weeks (separated by 2-week washout).. Average daytime (9 am to 9 pm) ambulatory SBP.. Blood pressure and laboratory parameters.. 88 patients underwent ambulatory blood pressure monitoring, of whom 49 (56%) with average daytime SBP>140mmHg were enrolled. 41 patients completed the study. Amlodipine and chlorthalidone both reduced ambulatory SBP after 8 weeks (mean changes of 150±12 to 137±12 [SD] vs 151±12 to 141±13mmHg; effect size, -4.2 [95% CI, -7.3 to 1.1] mmHg). Despite these similar blood pressure responses, chlorthalidone reduced proteinuria by 30% (effect size, -65 [95% CI, -108 to -35] mg/g) and also reduced physician-assessed peripheral edema (22% to 10%; P<0.05 for both). In contrast, chlorthalidone temporarily reduced kidney function and increased both serum uric acid and glycated hemoglobin levels.. Open-label design, short follow-up, per-protocol analysis.. Chlorthalidone is an antihypertensive drug equally effective as amlodipine after kidney transplantation.

Topics: Aged; Amlodipine; Antihypertensive Agents; Blood Pressure Monitoring, Ambulatory; Chlorthalidone; Cross-Over Studies; Edema; Female; Glomerular Filtration Rate; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Proteinuria; Tacrolimus; Treatment Outcome

To evaluate the efficacy of the novel topical immune modulator tacrolimus in chronic uninfectious otherwise therapy-resistant external otitis (EO).. Prospective clinical study.. There were 53 patients aged 5 to 83 years. An ear wick containing 0.1% tacrolimus ointment (Protopic) was inserted into the external auditory canal every 2nd to 3rd day. Altogether, the wick was changed three times. The pre-, intra- and posttherapeutic state of the clinical parameters otalgia, edema, otorrhea, erythema, pruritus, and desquamation was rated by means of a 6-point score system. Treatment efficiency was evaluated on the basis of follow-up investigations at 3-month intervals, a standardized findings sheet, and photograph documentation.. The short-term results showed a clear improvement in 85% of the patients and significant reductions of the severity levels for all clinical parameters investigated (P < .001). Concerning the long-term results, a one-time treatment cycle led to complete healing in 46% of the patients throughout a follow-up of 10 to 22 months. Of the patients, 54% had recurrent EO events with significantly extended mean symptom-free intervals. Reapplied tacrolimus treatment patterns attenuated the relapsing course of disease and significantly reduced the number of EO episodes. Within the observation period, no relevant side effects were observed, except for a local feeling of heat, occasional skin burning, and itching.. The topical application of 0.1% tacrolimus ointment in the outer ear canal appears to be an effective and well-tolerated new option in corticosteroid-free treatment of chronic therapy-resistant EO.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cerebrospinal Fluid Otorrhea; Child; Child, Preschool; Drug Resistance, Bacterial; Earache; Edema; Erythema; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Otitis Externa; Otoscopy; Prospective Studies; Pruritus; Tacrolimus; Treatment Outcome

A 75-year-old man visited our Collagen Disease Department because of a fever, edema in the lower legs, and arthralgia. He presented with peripheral arthritis of the extremities and was negative for rheumatoid factor, leading to a diagnosis of RS3PE syndrome. A search for malignancy was performed, but no obvious malignant findings were found. After starting treatment with steroid, methotrexate, and tacrolimus, the patient's joint symptoms improved, but after five months, enlarged lymph nodes throughout the body were observed. A lymph node biopsy revealed a diagnosis of other iatrogenic immunodeficiency-associated lymphoproliferative disorders/angioimmunoblastic T-cell lymphoma (OI-LPD/AITL). After discontinuation of methotrexate and follow-up, no lymph node shrinkage was observed, and the patient had strong general malaise, so chemotherapy was started for AITL. After the start of chemotherapy, the patient's general symptoms improved quickly. RS3PE syndrome is a polyarticular, rheumatoid factor-negative, polyarticular synovitis with symmetric dorsolateral hand-palmar symmetric indentation edema that occurs mainly in elderly patients. It is also noted as a paraneoplastic syndrome, with 10%-40% of patients having malignant tumors. When our patient was diagnosed with RS3PE syndrome, a search for malignancy was performed, but there were no findings suggestive of malignant disease. However, after methotrexate and tacrolimus administration was started, the patient developed rapid lymph node enlargement, and the pathology showed AITL. The possibility of AITL as an underlying disease and RS3PE syndrome as a paraneoplastic syndrome, or conversely, OI-LPD/AITL associated with immunosuppressive therapy for RS3PE syndrome is considered. We herein report this case, as sufficient recognition is required for a proper diagnosis to be made and treatment of RS3PE syndrome to be performed.

Topics: Aged; Edema; Humans; Immunoblastic Lymphadenopathy; Immunosuppression Therapy; Lymphoma, T-Cell; Male; Methotrexate; Paraneoplastic Syndromes; Rheumatoid Factor; Tacrolimus

Tyrosine kinase inhibitors (TKI) are an effective treatment option for chronic myeloid leukemia (CML). The most common associated adverse effects of TKI include thrombocytopenia, neutropenia, nausea, vomiting, and diarrhea. Facial edema is a rare adverse reaction that may cause significant psychological burden. Treatment is life-long in many cases therefore it is vital to have options available to manage these adverse effects.. We present a 70-year-old female with a medical history of CML, diabetes, hypertension, and hypercholesterolemia who presented to our dermatology clinic for chief complaint of worsening edematous facial rash beginning after initiation of dasatinib. We were able to achieve significant improvement with a regimen that allowed her to remain on dasatinib.. We treated the patient with a novel, unreported regimen of topical metronidazole 1% gel to be applied every morning and topical tacrolimus 0.1% ointment to be applied twice daily. She had significant improvement with the treatment and was continued on this topical regimen indefinitely.. Previous reports of treatment options available for TKI-associated facial edema include topical and systemic corticosteroids, which can cause long-term side effects int the context of long-term TKI use. Our patient achieved an acceptable reduction in facial edema and rash with our combination regimen of metronidazole gel and tacrolimus ointment. We present the only such case of successful treatment of facial edema associated with a tyrosine kinase inhibitor. We encourage future studies on the efficacy and safety of this regimen to treat this adverse effect.

Topics: Aged; Antineoplastic Agents; Dasatinib; Edema; Exanthema; Face; Female; Gels; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Metronidazole; Ointments; Protein Kinase Inhibitors; Tacrolimus

The appearance of edema limits the use of everolimus de novo together with tacrolimus and steroids in kidney transplantation. We aimed to investigate the frequency and characteristics of patients with edema and compare them according to the type of immunosuppression.. We studied 150 kidney transplant recipients between 2015 and 2017 based on receiving everolimus de novo (group A) or mycophenolic acid derivatives (group B).. We analyzed 50 patients in group A and 100 in group B. Follow-up was 26.2 ± 10 months. Fifty-six patients presented edema (37.3%): 54% in group A and 29% in group B (P = .003). Edema was mild in 74% of patients in group A and 57.1% in group B. The probability of edema was 10.1%, 22.4%, and 41% at 3, 6, and 12 months, respectively, in group A vs 10.1%, 20.3%, and 25.4% in group B (P = .006). Patients were treated mostly with diuretics (14.3% in group A vs 27.6% in group B) and discontinuation of calcium channel blockers (46.4% in group A vs 48.3% in group B). Improvement was 70.4% in group A vs 60.7% in group B; patient worsening was 0% in group A vs 10.7% in group B; and there was no change in 29.6% in group A vs 28.6% in group B. We did not find differences in patient or graft survival in those who presented edema, regardless of the treatment group.. The use of everolimus and standard doses of tacrolimus caused edema in 54% of patients, with no impact on renal function or survival compared with mycophenolic acid derivatives. The edema was mostly of low intensity and improved in most patients.

Topics: Edema; Everolimus; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Mycophenolic Acid; Tacrolimus

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease, and excessive T lymphocyte activation plays a critical role in the development of inflammation. CD147 is an antigen related to T cell activation, CD147 blockade exerts beneficial effects on RA. FK506, also known as tacrolimus, exerts strong immunosuppressive effects by inhibiting T cell activation. In this study, RL73 (an anti-mouse CD147 functional-grade purified antibody) and FK506 were co-administered to mice with collagen-induced arthritis (CIA). As expected, the combination of these two drugs produced superior therapeutic effects than either drug alone and enabled the administration of each drug at a lower dose. Moreover, joint damage and destruction were significantly improved in mice injected with both FK506 and RL73 compared with mice injected with either agent alone. These effects might have been observed because the proportions of CD4 + T and CD8 + T cells in the mouse spleen of the combination regimen were clearly decreased compared with each monotherapy. In addition, the proportions of Th2 subsets in the mouse spleen and peripheral blood were clearly increased, and the serum levels of the cytokines interleukin 4 (IL-4) and IL-10 were markedly increased in mice treated with the combination therapy compared with the other groups of mice. The splenic total number of T lymphocytes also showed that the inhibition of T lymphocytes was the most obvious in the combined treatment group. Based on the results from the present study, combining FK506 and the anti-CD147 mAb might be a new practical therapeutic option for the treatment of RA.

Topics: Animals; Antibodies, Monoclonal; Arthritis, Experimental; Basigin; Body Weight; Chickens; Disease Models, Animal; Drug Therapy, Combination; Edema; Female; Inflammation; Interleukin-10; Interleukin-4; Mice; Spleen; Tacrolimus; Th2 Cells

Topics: Anti-Bacterial Agents; Atrophy; Blepharoptosis; Doxycycline; Edema; Elastin; Female; Humans; Tacrolimus; Treatment Outcome; Young Adult

The aim was to explore the potential application of novel self-assembled nanoparticles cross-linking thermosensitive hydrogels composed of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (Soluplus) and tacrolimus (FK-506) for local therapy of rheumatoid arthritis (RA). The sol-gel transition temperature (T

Topics: Animals; Arthritis, Experimental; Drug Carriers; Drug Compounding; Drug Liberation; Edema; Hindlimb; Hydrogels; Immunosuppressive Agents; Kinetics; Male; Mice; Mice, Inbred ICR; Nanoparticles; Particle Size; Phase Transition; Poloxamer; Polyethylene Glycols; Polyvinyls; Rats; Rats, Sprague-Dawley; Tacrolimus

To identify the value of magnetic resonance imaging (MRI)-proven bone edema in patients with very early rheumatoid arthritis (RA).. All of the 13 patients included in the study were positive at entry for MRI-proven bone edema of the wrist and finger joints and anti-cyclic citrullinated peptide antibodies or IgM-rheumatoid factor. A tight control approach was applied for 12 months. Plain MRI and radiographs of both wrist and finger joints were examined every 6 months. MRI was scored by the RA MRI scoring (RAMRIS) technique and plain radiographs were scored using the Genant-modified Sharp score. Variables that were correlated with plain radiographic changes at 12 months were examined.. Simplified disease activity index (SDAI) remission was achieved in 7 patients, and a significant reduction in the RAMRIS bone edema score, which declined to <33 % as compared with the baseline, was achieved in 8 out of 13 patients. Four patients showed plain radiographic progression while 9 patients did not. Significant reductions in the RAMRIS bone edema score (p = 0.007) and the time-integrated SDAI (p = 0.031) were the variables involved in plain radiographic progression.. Improvement in bone edema may be associated with protection against structural damage in very early RA patients managed using the tight control approach.

Topics: Adult; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Bone Diseases; Disease Progression; Edema; Female; Finger Joint; Humans; Magnetic Resonance Imaging; Male; Methotrexate; Middle Aged; Radiography; Sulfasalazine; Tacrolimus; Treatment Outcome; Wrist Joint

A 50-year-old female patient, who had had a long-term history of myelodysplastic syndrome and type II diabetes mellitus, had developed acute myelogenous leukemia and received allogeneic bone marrow transplantation (BMT). She was being treated with tacrolimus, methotrexate and prednisolone for prophylaxis and treatment of graft-versus-host disease, and with intensive insulin therapy for better glycemic control. The patient suddenly developed marked leg edema at 27 days after starting intensive insulin therapy (on day 40 after BMT) without coexistence or exacerbation of apparent causes such as renal failure, cardiac dysfunction or leg thrombosis around the onset of leg edema. Interestingly, the leg edema regressed soon after daytime hyperglycemia and intensive insulin therapy were performed. Histopathological examination revealed slight dermal edema and small bullae with little inflammatory infiltration but no signs of autoimmune blistering diseases or vasculitis. These findings indicate that the present case may be considered a form of so-called insulin edema occurring during intensive insulin therapy after BMT.

Topics: Bone Marrow Transplantation; Diabetes Mellitus, Type 2; Edema; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Insulin; Leg; Methotrexate; Middle Aged; Myelodysplastic Syndromes; Prednisolone; Skin Diseases; Tacrolimus; Treatment Outcome

We report a 10-yr-old boy who developed CIPS after a second allogeneic BMT for severe aplastic anemia. He received the second BMT from the same HLA-matched sibling donor 16 months after the first BMT due to secondary graft failure. The preparative regimen for the second BMT consisted of fludarabine, cyclophosphamide, and anti-thymocyte globulin. Prophylaxis for acute GVHD was tacrolimus and oral PSL. Engraftment was achieved on day 15. On day 19, he suddenly complained of intermittent pain in the bilateral lower limbs. Electric shock-like pain continued for a few minutes in succession. This intractable pain was not ameliorated by various analgesic drugs including pentazocine. MRI demonstrated bone marrow edema with high T2 signal intensity in the femur. He was diagnosed as CIPS based on his symptoms and MRI findings. The trough concentration of tacrolimus (10.1 ng/mL) at the onset of CIPS was within the therapeutic range. Bouts of severe pain naturally resolved after day 43 without the discontinuation of tacrolimus. CIPS is a rare complication in HSCT. This is the first non-malignant, and the first pediatric, case who developed CIPS after HSCT.

Topics: Adult; Anemia, Aplastic; Antilymphocyte Serum; Bone Marrow Transplantation; Calcineurin Inhibitors; Child; Cyclophosphamide; Edema; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Male; Middle Aged; Pain; Tacrolimus

Topics: Adult; Brain; Brain Diseases; Edema; Female; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Radiography; Stem Cell Transplantation; Syndrome; Tacrolimus; Treatment Outcome

An in vivo study in Wistar albino rats with injured spinal cord.. Department of Neurosurgery, Biochemistry and Pathology, Gazi University, Ankara, Turkey.. The aim of this study was to investigate and compare the effects of FK506 an immunosupressive agent with methylprednisolone (MP) on lipid peroxidation (LP) in injured spinal cord tissue.. A total of 28 adult healthy Wistar albino rats were subjected to traumatic spinal cord injuries (SCI) by using an aneurysmal clip compression technique, and they were divided into four groups. The G1 group (n=8) received FK506 (1 mg/kg); the G2 group (n=8) received FK506 (1 mg/kg) and MP (30 mg/kg); the G3 group (n=6) received only MP (30 mg/kg); and the G4 group (n=6) received no medication. The injured spinal cord tissue was studied by means of lipid peroxides, malondialdehyde (MDA), with thiobarbituric acid reaction and additionally the FK506 (G1); the MP (G3) groups were studied for histopathologic alterations 72 h after SCI with eight separate animals.. Although LP values of G1, G2, G3 showed no statistical difference between intergroup analyses (P=0.547), a histopathological examination revealed that in the group that received MP, the oedema pattern was more significant than the group that received FK506. Another interesting finding was the presence of polymorphonuclear leucocytes in the MP group, whereas no infiltration was found in the FK506 group.. Analysis of the results indicated that FK506 is a valuable pharmacological agent that could be used to decrease the LP and polymorphonuclear leucocyte infiltration and inflamatory reactions in the injured spinal cord tissue.

Topics: Animals; Chemotaxis, Leukocyte; Disease Models, Animal; Down-Regulation; Drug Synergism; Drug Therapy, Combination; Edema; Free Radicals; Immunosuppressive Agents; Lipid Peroxidation; Male; Malondialdehyde; Methylprednisolone; Nerve Degeneration; Oxidative Stress; Rats; Rats, Wistar; Spinal Cord; Spinal Cord Injuries; Tacrolimus

Septic arthritis (SA) typically occurs in young children, often from Staphylococcus. With chronic immunosuppression, however, pathogens may be atypical. A 15-year-old African-American female developed Mycoplasma hominis SA in her right hip 2 months following cadaveric renal transplant (Tx). Her presentation was subtle and indolent, without fever or leukocytosis. Although reported in adult Tx recipients, M. hominis infections have not been described in pediatric recipients. Early immunosuppression (basiliximab, prednisone, tacrolimus, mycophenolate mofetil and Thymoglobulin) may have increased her susceptibility to M. hominis. Optimal therapy for M. hominis SA is not well established and relapses occur. This patient underwent joint incision and drainage, treatment for 8 weeks with doxycycline and levofloxacin guided by in vitro sensitivities, and a reduction in immunosuppression. She has been free of ongoing infection for 3 years with stable graft function (Cr 1.1 mg/dL) on moderate immunosuppression with prednisone, tacrolimus and MMF.

Topics: Adolescent; Arthritis, Infectious; Doxycycline; Edema; Female; Graft Survival; Hip; Humans; Immunocompromised Host; Immunosuppressive Agents; Inflammation; Kidney Transplantation; Levofloxacin; Magnetic Resonance Imaging; Mycophenolic Acid; Mycoplasma hominis; Ofloxacin; Pelvis; Prednisone; Radiography; Tacrolimus; Treatment Outcome

We investigated the effects of 1-4% ointments of metronidazole and tinidazole (derivatives of nitroimidazole) on models of inflammatory dermatitis evoked by antigen, hapten and monoclonal anti-dinitrophenol (DNP) IgE antibody in mice. Metronidazole and tinidazole ointments (1) suppressed the late-phase reaction (LPR) of biphasic ear edema in mice sensitized with ovalbumin (OA), (2) suppressed trinitrochlorobenzene-induced inflammatory dermatitis, (3) suppressed the immediate phase reactions and LPR in mice passively sensitized with anti-DNP IgE mAb, and (4) enhanced vascular permeability and the number of scratching reactions, presumably due to itching, in passively sensitized mice. These results strongly indicate that metronidazole and tinidazole 1-4% ointments possess antiinflammatory, immunosuppressive and anti-itching effects, and have the potential for clinical use in the treatment of human inflammatory skin diseases including atopic dermatitis in addition to rosacea and acne vulgaris.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antigens; Antipruritics; Capillary Permeability; Dermatitis; Dermatologic Agents; Disease Models, Animal; Edema; Humans; Immunosuppressive Agents; Male; Metronidazole; Mice; Ointments; Ovalbumin; Picryl Chloride; Pruritus; Tacrolimus; Tinidazole

To investigate the effects of prophylactic and therapeutic treatments with FK506 (tacrolimus), an immunosuppressive drug that specifically inhibits T cell activation, and methotrexate (MTX) on inflammatory cytokines, tumor necrosis factor (TNF)-a, interleukin (IL)-1beta, and IL-6 levels in rat adjuvant-induced arthritis (AIA).. AIA was induced in female Lewis rats. Arthritis was assessed by hindpaw swelling. TNF-a, IL-1beta, and IL-6 levels in paw extracts were determined by ELISA. To assess the effects on cytokine levels, rats were treated prophylactically with FK506 (3 mg/kg) or MTX (0.1 mg/kg) from day 1 to day 17, and therapeutically with FK506 (5 mg/kg) or MTX (1 mg/kg) from day 15 to day 17 (3-day treatment) or day 15 to 20 (6-day treatment) by oral administration.. TNF-a, IL-1beta, and IL-6 levels in paw tissue were found to significantly increase between day 15 and day 21 after adjuvant injection, when the arthritis was in a developed stage. Prophylactic treatment with FK506 and MTX suppressed arthritis and reduced the levels of those inflammatory cytokines. FK506 caused a marked reduction of TNF-a and IL-1beta levels in paw tissue even in short-term (3-day) therapeutic treatment. It reduced all levels of TNF-a, IL-1beta, and IL-6 in paws in 6-day therapeutic treatment. In contrast, therapeutic treatment with MTX affected neither TNF-a or IL-6 levels in paws. MTX reduced IL-1beta levels only in the 6-day treatment.. FK506 is more effective than MTX in reducing elevated levels of inflammatory cytokines TNF-a, IL-1beta, and IL-6 in established stages of AIA. Our findings suggest that inhibition of T cell activation results in a rapid reduction of inflammatory cytokine levels even after the arthritis is established in AIA.

Topics: Animals; Arthritis, Experimental; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Edema; Enzyme-Linked Immunosorbent Assay; Female; Hindlimb; Immunosuppressive Agents; Interleukin-1; Interleukin-6; Methotrexate; Rats; Rats, Inbred Lew; Tacrolimus; Tumor Necrosis Factor-alpha

Because interferon-gamma, interleukin-4, and interleukin-5 have been identified at the mRNA and protein levels in the lesional skin of patients with atopic dermatitis, we investigated the roles played by granulocytes as effector cells in allergic inflammation by using two unique murine skin models. In vitro generated Th1 and Th2 cells from naïve splenocytes of antiovalbumin T cell receptor transgenic BALB/C mice were adoptively transferred with ovalbumin into the ear pinnae or air-pouches produced in the back skin of naïve, nontransgenic BALB/C mice. The injection of Th1 cells with ovalbumin induced delayed type ear swelling that peaked at 48 h, whereas that of Th2 resulted in ear swelling that peaked at a much earlier time, 24 h. Histologic study of the swollen ear skin and granulocytes recruited into the air-pouch demonstrated that, although the Th1-induced inflammation caused a neutrophil-predominant infiltrate with few eosinophils, larger numbers of eosinophils accumulated in the Th2-induced inflammation. Using these murine models, we further evaluated the effects of drugs used for the treatment of atopic diseases. The results showed that FK506 administration could effectively reduce skin inflammation induced by either Th cells. Interestingly, the neutrophil elastase inhibitor ONO-6818 efficiently inhibited Th1-induced inflammation. In contrast, a leukotriene receptor antagonist, ONO-1078, specifically suppressed Th2-induced inflammation. We also found that each ONO drug exerted direct influence on specified granulocytes, as neither affected in vitro production of relevant Th cytokines. Thus, we succeeded in developing animal skin inflammation models in which we can evaluate the contribution of protein antigen-specific Th1 or Th2 cells through the action of granulocytic effector cells.

Topics: Animals; Cells, Cultured; Chromones; Dermatitis, Atopic; Disease Models, Animal; Ear; Edema; Enzyme Inhibitors; Eosinophils; Hypersensitivity; Immunosuppressive Agents; Leukotriene Antagonists; Male; Mice; Mice, Inbred BALB C; Neutrophils; Ovalbumin; Oxadiazoles; Pyrimidinones; Skin; Tacrolimus; Th1 Cells; Th2 Cells

Anti-arthritic effect of FTY720, a novel immunosuppressant, was compared with those of immunosuppressants cyclosporin A and tacrolimus in adjuvant-induced arthritis in rats.. Male LEW rats.. FTY720 (0.03-0.3 mg/kg), cyclosporin A (1-10 mg/kg) or tacrolimus (0.3-3 mg/kg) were orally administered to rats for 21 days beginning on the day (day 0) of adjuvant inoculation. In addition, the anti-arthritic effect of FTY720 (0.3 mg/kg) and cyclosporin A (10 mg/kg) were evaluated by administration to animals for 5 consecutive days (days 2-6, 6-10, and 10-14).. Adjuvant-induced arthritis was produced by intradermal injection of 0.5 mg heat-killed Mycobacterium tuberculosis. Hindpaw edema was measured plethysmographically. The day of arthritis onset was determined macroscopically. Bone degradation was determined by radiography. Peripheral blood leukocytes were classified microscopically.. All test compounds inhibited the incidence of arthritis, hindpaw edema and bone destruction. In addition, FTY720 but not cyclosporin A or tacrolimus markedly decreased the number of peripheral blood lymphocytes. FTY720 treatment on days 6 to 10 inhibited the bone destruction and hindpaw edema.. These results suggest that the anti-arthritic effect of FTY720 in this adjuvant-induced arthritic model was more potent than those of cyclosporin A and tacrolimus. FTY720 administered on days 6 to 10 showed the inhibitory effect on the bone destruction and hindpaw edema. FTY720 may be effective in the treatment of rheumatoid arthritis.

Topics: Animals; Arthritis, Experimental; Cyclosporine; Edema; Fingolimod Hydrochloride; Immunosuppressive Agents; Leukocyte Count; Lymphocytes; Male; Monocytes; Mycobacterium tuberculosis; Neutrophils; Osteolysis; Propylene Glycols; Rats; Rats, Inbred Lew; Sphingosine; Tacrolimus

A possible new common action of immunosuppressants, besides suppression of the genes for cytokines like interleukin-2, was investigated in in vivo models. Dexamethasone (0.1 mg/kg, s.c.) failed to suppress ischemic paw edema in mice 1 h after its injection, but maximal suppression was achieved at 3 h (20%) whereafter the suppression decreased at 6 and 18 h (11% and 10%). Pretreatment with oral FK506 (chemical name is recently donated as tacrolimus, 0.1 mg/kg) resulted in 38%, 52%, 23% and 17% suppression at 1, 3, 6 and 18 h, respectively. Cyclosporin A (1 mg/kg), rapamycin (0.1 mg/kg) and deoxyspergualin (1 mg/kg) showed a similar pattern of suppressions after dexamethasone. Transforming growth factor-beta1 (TGF-beta1, 0.3 microg/kg, i.p.) maintained the suppression elicited by an immunosuppressant (42-58%) at 6 h after dexamethasone, whereas transforming growth factor-beta1 and/or an immunosuppressant were not suppressive. Suppression, irrespective of the agent that elicited it, was blocked by nitric oxide (NO) synthase inhibitor, anti-oxidant enzymes and cycloheximide. Endogenous nitric oxide or oxyradicals are essential for the action of dexamethasone in vivo. The four immunosuppressants bound to specific heat-hock proteins (hsp) in the glucocorticoid receptor complex and might enhance the synthesis of anti-inflammatory protein(s).

Topics: Animals; Anti-Inflammatory Agents; Cyclosporine; Dexamethasone; Drug Interactions; Edema; Hindlimb; Immunosuppressive Agents; Ischemia; Male; Mice; Nitric Oxide; Superoxides; Tacrolimus

Topics: Animals; Edema; Graft Rejection; Ileum; Intestinal Mucosa; Intestine, Small; Jejunum; Microscopy, Video; Monitoring, Physiologic; Rats; Rats, Inbred BN; Rats, Inbred Lew; Tacrolimus; Time Factors; Transplantation, Homologous

Dark Agouti (DA) and Lewis rat strains were tested for susceptibility to collagen-induced arthritis (CIA) and for development of cellular and humoral immune responses to type II collagen (CII). All of the DA rats developed arthritis following a single intradermal injection of more than 20 microg of CII (130-150 microg/kg rat weight) and showed a swelling rate of more than 100% in the hind paws. The swelling rate showed little deviation among the animals. There was a strong correlation between the severity of the arthritis and the strength of the immune response to CII in DA rats with CIA. Following immunization with even 800 microg of CII (3.8-4.2 mg/kg rat weight), Lewis rats showed a maximum rate of hind paw swelling of only 45%. In the pharmacological studies, prednisolone, indomethacin, FK-506 and mizoribine all suppressed arthritis in DA rats. These findings suggest that DA rats are more susceptible to CIA than Lewis rats and that CIA in DA rats as well as in Lewis rats is serviceable as an experimental animal model of rheumatoid arthritis.

Topics: Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibody Formation; Arthritis; Collagen; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Enzyme-Linked Immunosorbent Assay; Female; Hindlimb; Hypersensitivity, Delayed; Immunosuppressive Agents; Indomethacin; Injections, Intradermal; Prednisolone; Rats; Rats, Inbred Lew; Rats, Inbred Strains; Ribonucleosides; Species Specificity; T-Lymphocytes; Tacrolimus

Topics: Animals; Animals, Newborn; Cyclosporine; Edema; Female; Graft Rejection; Graft Survival; Guanidines; Heart Transplantation; Hemorrhage; Immunosuppressive Agents; Male; Methotrexate; Necrosis; Papio; Splenectomy; Swine; Tacrolimus; Time Factors; Transplantation, Heterologous

Topics: Administration, Oral; Cardiomyopathy, Hypertrophic; Cyclosporine; Echocardiography; Edema; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Middle Aged; Tacrolimus

To use mice to examine the effects of cyclosporine and tacrolimus (FK 506) on two forms of acute pancreatitis often seen after clinical organ transplantation.. In the first experiment, male CD-1 mice received cyclosporine (10 mg/kg), tacrolimus (0.32 mg/kg), or saline solution (control) subcutaneously once a day for 10 days. On the 11th day, acute edematous pancreatitis was induced by ceruletide (cerulein). In the second experiment, female ICR mice were fed with a choline-deficient, ethionine-supplemented (CDE) diet for 72 hours to induce necrotizing pancreatitis. After 30 hours on the CDE diet, the mice received cyclosporine (10 mg/kg), tacrolimus (0.32 mg/kg), or saline solution (control) subcutaneously twice daily for 3 days.. The pancreatic dry-to-wet weight ratios after ceruletide injections significantly decreased in mice treated with cyclosporine but did not with tacrolimus. Cyclosporine also significantly increased serum amylase levels, but tacrolimus did not. Cyclosporine or tacrolimus alone did not produce pancreatitis. In the CDE diet groups there was a significant difference in survival among the cyclosporine-treated, the tacrolimus-treated, and the control groups.. Cyclosporine or tacrolimus given alone does not induce acute pancreatitis. In contrast, cyclosporine can adversely affect the course of acute edematous pancreatitis, and both immunosuppressants may worsen the survival of mice with acute hemorrhagic necrotizing pancreatitis. This study also demonstrated that the deteriorating effect of tacrolimus is less potent than that of cyclosporine.

Topics: Acute Disease; Animals; Ceruletide; Choline Deficiency; Cyclosporine; Edema; Ethionine; Female; Male; Mice; Necrosis; Pancreatitis; Tacrolimus

An immunosuppressant FK506 binds with a component (hsp 56) of glucocorticoid receptor (GR) complex. Dexamethasone (Dex) never suppressed histamine paw edema of mice before 1 hr after its dosing as new protein(s) synthesis is required. However, FK506 (0.01-10 mg/kg, oral) 1.5 hr before 0.1 mg/kg Dex (s.c.), suppressed edema at 30 min. This suppression and that at 3 hr, were abolished by nitric oxide (NO) synthesis inhibitors (1-300 mg/kg). Nitroprusside (NO donor), catalase and molybdate (GR complex stabilizing protease inhibitor) enhanced the suppression. FK506, not cyclosporin A, was demonstrated for the first time in vivo to enhance GR and a hypothesis is proposed that FK506 might enhance GR and AP-1 signalings in a system reciprocally controlled by NO and H2O2.

Topics: Animals; Arginine; Catalase; Dexamethasone; Dose-Response Relationship, Drug; Drug Synergism; Edema; Gene Expression; Histamine; Hydrogen Peroxide; Male; Mice; Mice, Inbred Strains; NG-Nitroarginine Methyl Ester; Nitric Oxide; Reactive Oxygen Species; Receptors, Glucocorticoid; Tacrolimus; Translocation, Genetic