Receiving Cyclosporine Treatment Research Articles

Assessment of hearing levels in children with nephrotic syndrome

ObjectiveDue to the similarities in the physiological mechanisms and antigenicity of the kidney and cochlea, they are simultaneously affected by certain diseases and drugs. Therefore, the purpose of this study was to investigate whether the hearing functions of patients with nephrotic syndrome (NS) were affected by the severity of the disease and the cyclosporine treatment. MethodsThe sample of this study consisted of 87 participants, including 65 patients (130 ears) with NS and 22 age- and sex-matched normal hearing children (44 ears). Based on the severity of the disease, the patients were divided into two groups: infrequently relapsing nephrotic syndrome (IRNS) and steroid-dependent or frequently relapsing nephrotic syndrome (SD/FRNS). Their audiologic tests, including Pure-tone Audiometry and Distortion-Product Otoacoustic Emission (DPOAE), were compared with the tests of the control group. In addition, the audiologic tests of the NS patients who received cyclosporine were compared with those who did not. ResultsIn the pure-tone audiometry, there were statistically significant differences between the IRNS, SD/FRNS, and control groups at 2000, 4000 Hz, and pure-tone average (PTA). Hearing levels of the SD/FRNS group at 2000, 4000 Hz, and PTA were higher than those of the control group. At 6000 Hz in pure-tone audiometry, there was a very weak positive correlation between the hearing level and the number of relapses. At 250 Hz and PTA, hearing levels of the group that received cyclosporine were higher compared to the group that did not receive it. In DPOAE, there was no significant difference between the groups according to the severity of the disease and the use of cyclosporine. ConclusionDuring the follow-up of the patients with NS, their hearing functions should be questioned, especially in patients with SD/FRNS and receiving cyclosporine treatment.

PB1950: MASS CYTOMETRY ANALYSIS IDENTIFIES T CELL IMMUNE SIGNATURE FOR APLASTIC ANEMIA AND PREDICTS RESPONSE TO CYCLOSPORINE

Background: Aplastic anemia (AA) is a bone marrow failure syndrome attacked by autologous T cells. Cyclosporine is often taken for non-severe AA which is accounting for 80% of AA. Although effective, the response rate to cyclosporine is only around 50%. Emerging data support that T cell subpopulations, expression of transcription factors and immune checkpoint molecules are critical to regulate pathophysiology of AA. It’s also verified that T cell egress and activation play an important role in autoimmune diseases. Aims: We hypothesis that defining T cell immune signature will facilitate the development of predicting cyclosporine response and exploring novel immune-based therapeutics. Methods: Here, we performed mass cytometry for phenotypic and functional immune analysis on clinical samples from AA patients receiving cyclosporine treatment and demonstrated a significant heterogeneity on expression of inhibitory molecules, T cell trafficking and cytokines. Results: T-cell expression of cytotoxic T lymphocyte antigen 4 (CTLA-4) was upregulated following response to cyclosporine and a lower level of CTLA-4 on CD8+ T cells was correlated to better treatment response. Moreover, higher expression of sphingosine-1-phospharylation receptor 1 (S1P1) on naïve T cells and higher level of interleukin-9 (IL-9) on T helpers predicted a worse response to cyclosporine. Therefore, this immune signature has a strong predictive value for clinical response. Summary/Conclusion: Collectively, our study suggests that immune-based analysis may predict clinical response to cyclosporine and provide a therapeutic strategy to improve the treatment of AA.

Opportunistic Invasive Cutaneous Fungal Infections Associated with Administration of Cyclosporine to Dogs with Immune-mediated Disease.

BackgroundOpportunistic invasive fungal infections (OIFIs) occur in dogs administered immunosuppressive medications. However, the epidemiology of OIFIs among dogs undergoing immunosuppressive treatment is poorly understood. The aims of this study were to (1) estimate the incidence of OIFIs among dogs diagnosed with certain immune‐mediated diseases and treated with immunosuppressive drugs, and (2) determine if administration of particular drug(s) was a risk factor for OIFIs.HypothesisDogs receiving cyclosporine treatment (alone or as part of a multidrug protocol) are at higher risk of developing OIFIs.AnimalsOne hundred and thirteen client‐owned dogs diagnosed with select immune‐mediated diseases: 42 with IMHA, 29 with ITP, 34 with IMPA, and 8 with Evans syndrome.MethodsRetrospective cohort study. Medical records of dogs presenting to the Texas A&M University, Veterinary Medical Teaching Hospital between January 2008 and December 2015, and treated for 1 or more of IMHA, IMPA, ITP, or Evans syndrome were retrospectively reviewed. Dogs that did not develop an OIFI were excluded if they died, were euthanized, or were lost to follow‐up within 120 days of initiation of immunosuppressive treatment.ResultsFifteen dogs of 113 (13%) were diagnosed with an OIFI based on 1 or more of cytology, culture, or histopathology. The odds of developing an OIFI were greater among dogs that were treated with cyclosporine (OR = 7.1, P = 0.017; 95% CI, 1.5–34.4) and among male dogs (OR = 5.1, P = 0.018; 95% CI, 1.4–17.9).Conclusions and Clinical Importance OIFIs were significantly more likely in male dogs and those receiving cyclosporine. It is important to consider OIFIs as a potential complication of immunosuppressive treatment, particularly cyclosporine.

Cyclosporine A treatment for relapsed subcutaneous panniculitis-like T-cell lymphoma: a case with long-term follow-up

Subcutaneous panniculitis-like T-cell lymphoma (SPTL) is a distinctive lymphoma characterized by an infiltration of subcutaneous tissue by neoplastic cytotoxic T cells. There was no distinction between TCR alpha/beta phenotype and TCR gamma/delta phenotype, and anthracycline-based chemotherapy was usually used for both. Here, we report a patient with recurrent SPTL who achieved a second long-term complete remission by repeated cyclosporine A (CsA) treatment. From 2000 to 2001, the patient received anthracycline-based combination chemotherapy. However, the treatment did not induce long-term remission. In 2002, he received cyclosporine treatment for about 6 months. This resulted in a 5-year remission that ended in relapse in 2008. He received CsA treatment once again and attained a second long-term remission. This case suggests that re-treatment with CsA can be a good option for relapsed SPTL cases and can result in long-term remission.

Influence of cyclosporine A on mucociliary system after lung transplantation in rats

To investigate the function of the bronchial mucociliary system in transplanted rat lungs with and without the influence of immunosuppression. Thirty-six rats underwent single-lung transplantation and were divided into two groups, one of which received cyclosporine treatment, and the control group which did not. Cyclosporine was administered subcutaneously in doses of 10 mg/kg daily. The rats were sacrificed 2, 15 or 30 days after transplantation. In situ bronchial mucociliary transport (MCT) and ciliary beat frequency (CBF) were determined proximal and distal to the bronchial anastomosis. Significant progressive improvement on MCT, proximal and distal to the anastomotic site, was also found in the cyclosporine-treated group at 15 and 30 days (p<0.01). No significant change in MCT was found in the control group. CBF behavior in the two groups. Histological analysis showed that rejection was significantly higher in the control group (p<0.05). Cyclosporine has a positive influence on bronchial mucociliary transport but not on CBF due to the effect of the rejection mechanism.

Myoblast-based cardiac repair: Xenomyoblast versus allomyoblast transplantation

We sought to investigate immune cell kinetics in relation to skeletal myoblast survival and heart function improvement after nonautologous skeletal myoblast transplantation in a rat model of myocardial infarction. One week after myocardial infarction, 208 Wistar rats were grouped into group 1 (n = 24, receiving 150 muL of medium only), group 2 (n = 24, receiving 150 muL of medium and cyclosporine [INN: ciclosporin]), group 3 (n = 40, human skeletal myoblast transplantation), group 4 (n = 40, human skeletal myoblast transplantation with cyclosporine treatment), group 5 (n = 40, rat skeletal myoblast transplantation), and group 6 (n = 40, rat skeletal myoblast transplantation with cyclosporine treatment). The hearts were harvested at 10 minutes and 1, 4, 7, and 28 days after cell transplantation. Skeletal myoblast survival was confirmed by means of immunohistochemical studies and quantified by using real-time polymerase chain reaction. Host immune responses were assessed by immunostaining for macrophages and CD4+ and CD8+ lymphocytes. Heart function was evaluated by means of echocardiographic analysis. The majority of macrophages and lymphocytes infiltrated in the acute phase (from day 1 to day 7) and then subsided by day 28. The donor skeletal myoblasts survived and differentiated well in all skeletal myoblast transplantation groups. Allogeneic skeletal myoblasts showed a superior survival rate than xenogeneic skeletal myoblasts (P < .01). Cyclosporine inhibited the infiltration of the immunocytes, enhanced skeletal myoblast survival, and improved heart performance compared with that seen in the groups not receiving cyclosporine treatment (P < .05). Allomyoblasts survive better than do xenomyoblasts after transplantation into infarcted myocardium. After inhibition of immunocyte infiltration by means of immunosuppressive treatment, skeletal myoblast survival is enhanced, with improved heart performance. These findings suggest the feasibility of nonautologous myoblast transplantation with immunosuppressive treatment.

Immune parameters of mice bearing human head and neck cancer.

A xenogeneic human head and neck squamous cell carcinoma (HNSCC) model in immunocompetent mice was evaluated for its requirement of cyclosporine for progressive tumor growth. Tumor growth and T cell functions were assessed in mice receiving cyclosporine treatment for various lengths of time. Tumor cells were injected s.c. on day 1 and cyclosporine was injected i.p. daily on days 1, 1-7, 1-14, 1-21, or for the entire 28 days of tumor growth. All mice developed tumors. These tumors were confirmed to be squamous carcinomas of human origin histologically and by positive staining for human MHC class I antigen expression. Tumors were largest in mice that received cyclosporine for days 1-21 or days 1-28. Increased tumor size was associated with increased serum levels of tumor-reactive antibodies, an increased intratumoral frequency of CD4+ and CD8+ cells, but a diminished production of interleukin-2 (IL-2) by the tumor infiltrate. Also correlating with increasing tumor size was splenomegaly, a decline in the frequency, but not the absolute levels, of splenic CD4+ and CD8+ cells, and a diminished capacity to proliferate in response to concanavalin A and to be stimulated to secrete IL-2. The HNSCC tumors contributed to the immune decline since T cell functions were more depressed in the tumor bearers than in control mice receiving only cyclosporine treatment. These results demonstrate that human HNSCC tumor xenografts can grow in mice even with limited cyclosporine treatment, and that the survival of these xenografts may, in part, be due to a tumor-induced decline in select T cell functions.

Orthodontic therapy in the patient treated with cyclosporine

Cyclosporine is an immunosuppressive drug that is gaining widespread use in the treatment of a variety of disorders. Gingival hyperplasia, a common side effect of cyclosporine therapy, has significant implications for orthodontic treatment, especially as the drug becomes more widely used to treat diseases prevalent in adolescents. A 5-year study of a group of patients with type 1 diabetes who were receiving cyclosporine treatment revealed a series of findings that are of importance to the orthodontist, including the potential for orthodontic appliances to increase the severity of the induced gingival enlargement and the potential of the gingival hyperplasia to complicate orthodontic therapy. Guidelines to minimize the degree of cyclosporine-induced gingival enlargement in the orthodontic patient are suggested.

Investigations on the metabolic pathways of cyclosporine: I. Excretion of cyclosporine and its metabolites in human bile—isolation of 12 new cyclosporine metabolites

1. Cyclosporine metabolites of known and unknown structures were isolated, by semi-preparative h.p.l.c., from human bile from the T-tube of liver-grafted patients, who received cyclosporine treatment. Their structures were elucidated by FAB mass spectrometry and 1H-n.m.r. spectroscopy. 2. Twelve of the cyclosporine metabolites, with known chemical structures, were isolated and identified using authentic standard material. 3. Four isolated fractions contained tri-hydroxylated metabolites; two fractions contained di-hydroxylated, demethylated metabolites; one fraction contained a tri-hydroxylated, demethylated metabolite; and one fraction a mono-hydroxylated, demethylated metabolite. The exact metabolism sites were partially defined. 4. Two carboxylated cyclosporine metabolites, of which one was hydroxylated in an unknown position, were isolated. 5. One new metabolite proved to be a glucuronylated phase II metabolite. Deglucuronylation of this metabolite by beta-glururonidase yielded metabolite AM1c. The proposed structure was AM1c-Glc; is a proposed extension of the Hawk's Cay nomenclature of the cyclosporine metabolites for glucuronylated metabolites. 6. One of the unknown metabolites was hydroxylated in two positions of amino acid 1. The proposed nomenclature was 'AM11d', where '1d' indicates hydroxylation at the delta C of amino acid 1. 7. A metabolite with an aldehyde functional group at amino acid 1, which had two isomeric forms, was isolated. I.r.-spectroscopy indicated that isomerism may be caused by conjugation of the aldehyde group with the double bond between C6 and C7 of amino acid 1.