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Conventional Immunosuppression (conventional + immunosuppression)
Selected AbstractsFurther experience with the use of 6-thioguanine in patients with Crohn's diseaseINFLAMMATORY BOWEL DISEASES, Issue 10 2008Azhar Ansari MD Abstract Background: 6-Thioguanine (6-TG) is efficacious in patients with Crohn's Disease (CD) failing conventional immunosuppression but there are reports of hepatotoxicity. We report our experience of the safety and efficacy of 6-TG in a series of patients with CD. Methods: A retrospective study of patients with CD who failed thiopurines ± methotrexate between 2001 and 2006 was performed. Indications for 6-TG were; active disease, to allow infliximab withdrawal, steroid sparing, or fistula closure. Patients underwent regular review and those treated longer than 1 year were advised to have liver magnetic resonance imaging (MRI) and liver biopsy. Results: All 30 patients treated with 6-TG during the period were included. The median dose and duration of 6-TG was 40 mg daily and 21.5 months, respectively. Initial clinical response was achieved in 18/30 (60%). Eleven of 29 (38%) (1 unrelated death) remained in remission at a median 44 months follow-up. Seven of 30 (23%) discontinued 6-TG due to adverse effects; 7/30 (23%) patients developed abnormal liver function tests (LFTs) during treatment, mostly transient and mild. One patient developed a portal hypertensive syndrome resolving on cessation of 6-TG. Of 11 liver biopsies, none showed nodular regenerative hyperplasia (NRH). The median red blood cell 6-thioguanine nucleotide (6-TGN) level was 807 pmol/108. Conclusions: 6-TG has good clinical efficacy for third-line immunosuppression in CD but hepatotoxicity remains a concern. However, previous reports of NRH in 6-TG-treated inflammatory bowel disease patients have not been substantiated by this cohort. (Inflamm Bowel Dis 2008) [source] Orthotopic liver transplantation using low-dose tacrolimus and sirolimusLIVER TRANSPLANTATION, Issue 8 2001Vivian C. McAlister MB Although sirolimus (SRL) binds the immunophilin FK506-binding protein-12 (FKBP-12) with greater avidity than tacrolimus (TAC), animal studies have shown that SRL and TAC act synergistically to prevent rejection. Dose-related toxicity is more often the cause of TAC discontinuation than rejection. We hypothesized that SRL would allow for a substantial reduction in the concomitant dose of TAC after liver transplantation to levels less than the threshold for toxicity. A series of 56 liver transplant recipients were administered a combination of SRL and TAC (target trough levels, 7 and 5 ng/mL, respectively). Planned weaning of steroids commenced after 3 months. Pharmacokinetic (PK) studies were undertaken. Patient and graft survival were 52 patients (93%) and 51 grafts (91%), with a follow-up of 23 months (range, 6 to 35 months). One episode (1.8%) of hepatic artery thrombosis was seen. The rate of acute cellular rejection was 14%. No extra treatment was administered in 3 of 8 patients, and the other 5 episodes responded to a single course of steroids. Cytomegalovirus infection occurred in 4 patients (7%). Renal function, glucose control, and lipid metabolism are near normal in 47 patients (84%) without additional medication. Steroid elimination is completed in 51 patients (91%). Bioavailability of SRL and TAC varied between transplant recipients, but trough levels strongly correlated with the area under the curve (r2 = 0.82 and r2 = 0.84, respectively). Simultaneous administration did not affect the PK profile of the drugs at this dose. The ratio of trough level to daily dose correlated between SRL and TAC. The synergistic effect seen in animal models also occurs in clinical liver transplant recipients on SRL-TAC combination immunosuppression. A low-dose combination of SRL and TAC should be compared with conventional immunosuppression in a multicenter, randomized, controlled trial. [source] Infliximab (Remicade?) in uveitis: a reviewACTA OPHTHALMOLOGICA, Issue 2009A ABU EL ASRAR Tumor necrosis factor (TNF)-, has been implicated as an important mediator in autoimmune ocular inflammatory disease pathogenesis as shown by animal studies and its detection in the ocular fluids of patients with uveitis. Blockade of TNF-, has emerged as one of the most promising therapies in autoimmune diseases including uveitis. Currently, there are three TNF-, antagonists: two monoclonal antibodies (infliximab and adalimumab) and a soluble receptor that binds soluble TNF-, (etanercept). Infliximab is a chimeric monoclonal antibody directed against TNF-,. It binds with high affinity to both the soluble and the membrane-bound TNF-, and inhibits a broad range of biologic activities of TNF-,. Binding to membrane TNF-, can mediate programmed cell death. Several studies reported that infliximab therapy was rapidly effective and safe treatment for refractory noninfectious uveitis including childhood uveitis and is indicated as rescue therapy for relapses of ocular inflammation or as maintenance therapy when conventional immunosuppression fails. It also allowed a reduction of corticosteroids and immunosuppressive drugs required to control the disease. However, repeated infusions are required to maintain long-term remission. Moreover, infliximab administration is costly and requires hospital admission. Adalimumab, fully humanized monoclonal anti- TNF-, antibody, was also found to be effective and safe therapy for the management of refractory noninfectious uveitis. Several studies reported that infliximab was more effective than etanercept in the treatment of refractory uveitis. Perhaps infliximab's ability to target membrane-bound TNF-, in addition to the soluble form may contribute to its increased efficacy in comparison with etanercept for uveitis. [source] Factors contributing to long graft survival in non-heart-beating cadaveric renal transplantation in Japan: a single-center study at Kitasato UniversityCLINICAL TRANSPLANTATION, Issue 6 2002Kazunari Yoshida Yoshida K, Endo T, Saito T, Iwamura M, Ikeda M, Kamata K, Sato K, Baba S. Factors contributing to long graft survival in non-heart-beating cadaveric renal transplantation in Japan: a single-center study at Kitasato University. Clin Transplant 2002: 16: 397,404. © Blackwell Munksgaard, 2002 A total of 107 cadaveric kidneys from non-heart-beating donors (NHBDs) have been transplanted between 1974 and 2000 at Kitasato University Hospital, Sagamihara, Japan. The patient survival of the 107 recipients of cadaveric renal transplants at 1, 5 and 10 yr was 0.857, 0.770 and 0.746, respectively. The 50% graft survival was 3.8 yr. The 5 and 10-yr graft survival was 0.457 and 0.337, respectively. Twenty of the 107 recipients of non-heart-beating cadaveric renal transplantation had graft survival longer than 10 yr. Of these 20 patients, 14 survivors still maintain functioning renal grafts and two died with functioning graft, although the remaining four reverted to dialysis because of chronic rejection and nephropathy. The average graft survival of these 20 patients at the time of study was 13.3 yr and the longest was 21.4 yr. The average serum creatinine level at 10 yr after transplantation was 1.63 mg/dL, almost identical to that at 5 yr post-transplant. The donors aged on average 40.2 yr; 13 were male and seven were female. The youngest donor was 9-yr-old and the oldest was 66. The graft survival was significantly better in the group with donor age younger than 55 yr (Log-rank: p=0.007). The average weight of the renal graft was not different between the long and shorter graft survival groups. The average warm ischemic time and total ischemic time were 9.7 and 539.7 min, respectively. The duration of post-transplant acute tubular necrosis averaged 9.2 days. These parameters tended to be shorter than those in recipients with graft survival >10 yr, but with no statistical significance. The mean numbers of acute rejection (AR) episode within 3 months after transplantation were 0.25 ± 0.66 and 0.92 ± 0.90 (p=0.020) in long survival and shorter survival groups, respectively. Long survivors had a significantly lower incidence of AR. Two of 20 cases received conventional immunosuppression with prednisolone, azathioprine and mizoribin, and 18 had prednisolone and calcineurin inhibitor (CNI). Kaplan,Meier analysis showed a significant contribution of CNI to graft survival (p=0.036). However, the graft survival reduction rate after 1 yr post-transplant did not differ between conventional and CNI immunosuppression. These data suggest that renal grafts retrieved with proper organ procurement procedures from NHBDs may survive long-term and help to overcome donor shortage. [source] The kinetics of CD154 (CD40L) expression in peripheral blood mononuclear cells of healthy subjects in liver allograft recipients and X-linked hyper-IgM syndromeCLINICAL TRANSPLANTATION, Issue 6 2000A Bartlett The costimulatory pathways play a key role in T cell activation during allograft rejection (AR). Inhibition of the T cell costimulatory molecule CD154 (CD40 ligand) has been effective in producing long-term allograft survival in rodents and non-human primates. The role of the CD40-CD154 pathway in human orthotopic liver transplantation (OLT) has not been examined. Aim: To describe the patterns of CD154, CD69 and CD152 (CTLA4) expression in OLT recipients and to determine their temporal relationship to AR. Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from 15 OLT allograft recipients just prior to and for seven consecutive days postoperatively. Gene and protein expression of CD154, CD69 and CD154 were examined by reverse transcription-polymerase chain reaction (RT-PCR) and flow cytometry (FC), respectively. Results: FC failed to demonstrate an up-regulation of CD154 and CD152 protein expression during the first postoperative week. Intracellular FC did not increase the sensitivity. There was an increased level of CD3+CD8+ T cells expressing CD69 at the time of rejection compared to that on day 0. RT-PCR demonstrated a sporadic expression of CD154 and CD69 mRNA, with no correlation to episodes of acute cellular rejection. In vitro stimulation of PBMCs revealed an impaired up-regulation of CD154 in patients receiving conventional immunosuppression compared to healthy controls. The assays were validated using positive and negative controls, including a family with X-linked hyper-IgM syndrome. Conclusion: We found no evidence of spontaneous CD154 gene or protein expression in PBMCs associated with acute rejection episodes following OLT. Immunosuppression resulted in impaired responses to ex vivo stimulation. Lymphocyte costimulatory pathways play a critical role in mediating acute allograft rejection. However, we found no evidence of spontaneous CD154 gene or protein expression in PBMCs associated with acute rejection episodes following OLT. Furthermore, stimulation in vitro resulted in less up-regulation of CD154 than for healthy controls. [source] | ||||||||||