Relationship between Mean Fluorescence Intensity and C1q/C3d-fixing capacities of anti-HLA antibodies

Background

Complement-binding assays are proposed to better stratify the risk of antibody-mediated rejection associated-graft failure. Despite promising clinical results, some have suggested that the MFI of anti-HLA antibodies may influence these tests.

Individualized scheme of immunoadsorption for the recurrence of idiopathic focal segmental glomerulosclerosis in the graft: a single center experience

Abstract

Objectives: To explore the role of immunoadsorption (IA) for the treatment of idiopathic focal segmental glomerulosclerosis (FSGS) recurrence in the renal allograft, if applied in a personalized manner. Methods: We studied patients with end-stage renal disease (ESRD) due to idiopathic FSGS, transplanted between 2001 and 2010. Patients with FSGS recurrence were treated with daily sessions of IA for the first week, followed by an every other day scheme and then individualized tapering until discontinuation. Complete remission was defined as a reduction of 24-h proteinuria to ≤0.5?g/day and partial remission as a reduction of 24-h proteinuria to 50% or more from baseline. Results: Of the 18 renal transplant recipients with ESRD due to idiopathic FSGS, 12 (66.7%) experienced disease recurrence in a mean time of 0.75 months post-transplantation (KTx), with a mean proteinuria of 8.9?g/day at the time of recurrence. The mean recipient age was 30.8 years; the mean donor age was 47.4 years, while living related donors provided the allograft in seven cases. Four of the patients received therapy with rituximab in addition to IA. During a mean time of follow-up of 48.3 months, seven patients (58.3%) achieved complete remission, and five (41.7%) partial remission. At the end of follow-up, eight patients (66.7%) had functioning grafts, being in sustained remission, in contrast to four patients (33.3%), who ended up in ESRD because of FSGS recurrence. Conclusions: IA was shown efficacious in a small series of patients with recurrent FSGS in the graft. Renal function remained stable in eight of the 12 patients with FSGS recurrence.     

Major surgery in a severe haemophilia A patient with high titre inhibitor: use of the thrombin generation test in the therapeutic decision

Summary. In haemophilia patients with inhibitor, elective orthopaedic surgery is usually performed under recombinant activated factor VII (rFVIIa). We report here the case of a severe haemophilia A patient with a high inhibitor who needed a bilateral total knee arthroplasty. Recombinant FVIIa was previously shown to be ineffective for the treatment of muscle and joint bleedings, and he had a history of excessive postoperative bleeding under activated prothrombin complex concentrate (APCC). Thrombin generation test (TGT) was used to assess the efficacy of Factor Eight Inhibitor Bypassing Activity (FEIBA). Insufficient correction of thrombin-generating capacity was observed after administration of 75 U kg(-1) FEIBA. In a multidisciplinary environment, a bilateral total knee arthroplasty was performed using a protocol combining immunoadsorption of inhibitors preoperatively associated with FVIII replacement during a first phase followed by FEIBA when the inhibitor reappeared. To our knowledge this is the first direct application of TGT in the management of haemophilia patients with inhibitor, which indicated that a sequential use of immunoadsorption, FVIII and FEIBA was the most appropriate treatment to perform this major elective surgery. This case demonstrates that this combined protocol can be safely used to cover major surgery in inhibitor patients. In addition, it also suggests that TGT may have a major contribution in the decision-making process of the most adapted therapy for the treatment of such high-risk patients.     

Inhibition of the human tissue plasminogen activator in plasma from different species

The rate and extent of complex formation between protease inhibitors present in plasma from different species and a human plasminogen activator purified to homogeneity from the supernatant of a human melanoma cell line was studied in vitro. The fibrinolytic activity of the one-chain plasminogen activator disappeared from human, cat and rabbit plasma with a half-life of 100 minutes. By means of antibodies directed against purified protease inhibitors the main inhibitor in human, cat, dog and rabbit plasma was identified as ₂-antiplasmin. ₂-macroglobulin and Cl-esterase-inhibitor functioned as inhibitors to a lesser extent. The main inhibitor in rat plasma was ₂-macroglobulin. The plasma half-life was 3 (rabbit and human) to 10 (dog and rat) times shorter for the two-chain form than for the one-chain form of the plasminogen activator molecule. It is also concluded that, with respect to plasma elimination of the fibrinolytic activity, among the common laboratory animals, the rabbit is the most suitable animal available for the study of fibrinolysis.     

免疫吸附法治疗多发性硬化的研究

目的探讨免疫吸附法（Immunoadsorption,IA）治疗多发性硬化（multiple sclerosis,MS）的临床疗效和不良反应。方法将该院神经内科收治的多发性硬化患者43例随机分为两组,观察组22例,对照组21例,观察组在常规治疗的基础上采用IA治疗,对照组采用传统治疗,疗程4周,比较两组患者治疗后神经功能的恢复程度（EDSS评分）、不良反应,以及血浆免疫球蛋白（IgG,IgA,IgM）、补体C3、脑脊液寡克隆区带（CSF-OB）的改变情况。结果两组MS患者于治疗4周后神经功能均有不同程度的恢复,总有效率均达90%以上,观察组显效率（68.18%）比对照组（38.10%）更为明显,差异有统计学意义（P〈0.05）;观察组治疗后血浆免疫球蛋白和补体C3明显降低（P〈0.01）,与对照组比较差异有统计学意义（P〈0.01）,而对照组的变化不明显,差异无统计学意义（P〉0.05）;治疗前两组MS患者的总体CSF-OB阳性率为32.56%,治疗后总体CSF-OB阳性率为23.26%,差异无统计学意义（P〉0.05）。结论免疫吸附法能显著降低MS患者血浆免疫球蛋白和补体C3水平,有效恢复多发性硬化患者受损的神经功能,不良反应少,优于传统的药物治疗,值得临床借鉴。     

Myocardial regeneration in heart failure: integrated development of biological therapeutic approaches

Heart failure currently constitutes one of the greatest health problems in the Western world. Its incidence, far from diminishing or even remaining stable, is actually still increasing in association with the aging of the population and its lifestyle. A better knowledge of physiopathological mechanisms has allowed for the development of new therapeutic focal points and lines of research. Nevertheless, its treatment is complex and encompasses a multidisciplinary approach. Patients in an advanced stage still have a very high mortality rate in spite of receiving optimum medical care. The development of new therapeutic techniques that afford a better prognosis has therefore been essential. Of these, and leaving aside surgical treatments, myocardial regeneration by means of cellular therapy, new concepts in tissue engineering and their results, and the applications of new advances in the field of immunomodulation have all recently experienced development. In this article, the aim is to bring the latest concepts in the physiopathology and humoral response of cardiac failure up to date as well as doing the same with the therapeutic approaches in this area.     

Improved treatment of sudden hearing loss by specific fibrinogen aphaeresis

The etiology of sudden sensorineural hearing loss is still unclear and is thought to result from disturbances of microcirculation, infectious causes, or autoimmune disorders. So far standard therapy did not show clear improvement over spontaneous remission rate, which is assumed to be about 50% [Nakashima et al., Acta. Otolaryngol. Stockh. 514:14-16, 1994; Schuknecht and Donovan, Arch. Otorhinolaryngol. 243:1-15, 1986; Harris and Sharp, Laryngoscope 100:516-524, 1990; Mayot et al., Clin. Immunol. Immunopath. 68:41-45, 1993; Gussen, Ann. Otol. Rhinol. Laryngol. 85:94-100, 1976]. Elevated blood viscosity due to high fibrinogen levels is supposed to cause decreased cochlear blood flow and thus initiate sudden hearing loss. The specific lowering of fibrinogen immediately decreases plasma viscosity exactly to the desired extent and should lead to improved cochlear blood flow [Suckfüll et al., Acta. Otolaryngol 119:763-766, 1999; Suckfüll, Lancet 360:1811-1817, 2002; Walch et al., Laryngol. Rhino. Otol. 75:641-645, 1996; Suckfüll et al., Otol. Neurotol. 23:309-311, 2002]. In a prospective uncontrolled pilot study on 36 patients with unilateral sudden onset sensorineural hearing loss (SHL) we tried to establish that 1-3 specific fibrinogen aphaereses alone improve recovery of hearing and that it is possible to lower fibrinogen to the target of 80-100 mg/dl without important side effects. Pure tone audiometry was carried out immediately before and after each aphaeresis as well as at 2 and 4 weeks and 6 months after treatment. Sixteen patients recovered spontaneously before undergoing fibrinogen adsorption. All 20 aphaeresis patients improved during immunoadsorption; in 60% of patients auditory thresholds returned to normal after the first immunoadsorption and treatment could be discontinued, in another 20% of patients complete recovery was reached after 4 weeks. The mean plasma fibrinogen concentration of the 20 patients before the first aphaeresis session was 308.1 +/- 51.5 mg/dl. Immediately after the first treatment session, the fibrinogen concentration was lowered to 100.7 +/- 25.3 mg/dl (P < 0.001). The second and third sessions also showed highly significant reductions in plasma fibrinogen. No important side effects were seen.In conclusion, specific fibrinogen adsorption is a promising new treatment modality that should be tested in a prospective, randomized controlled trial in patients with sudden hearing loss.     

Ex vivo perfusion of plasma over protein A columns in human mammary adenocarcinoma. Role of the Fc-binding capacity of protein A in the side effects and the tumoricidal response

Plasma of twelve patients presenting with a metastic mammary adenocarcinoma was perfused ex vivo over columns of protein A covalently linked to crystalline silica. The plasma of seven patients (group A) was perfused over columns of protein A exhibiting a normal Fc-binding capacity and the plasma of five (group B) over columns of protein A in which the Fc-binding capacity was destroyed. In group A, all patients experienced acute, easily manageable, side effects (hypotension, chills, mild fever, leucocytosis and pain in tumour sites) during or immediately after the immunoadsorption procedures, and three exhibited an objective partial regression after two to five sessions. In contrast, none of the patients from group B developed any acute side effects and all showed evident progression of their disease during the treatment. Tumour cells in all stages of destruction, sometimes surrounded by extensive fibrosis, were seen in biopsies of patients A. However, focal areas of active tumour proliferation were always present in these patients. These data confirm that ex vivo perfusion over protein A columns of plasma from patients with cancer can induce a tumoricidal response in some instances and show that the Fc-binding capacity of protein A is most probably responsible for the necrolytic response and the side effects.     

Successful removal of pathogenic autoantibodies in pemphigus by immunoadsorption with a tryptophan-linked polyvinylalcohol adsorber

BACKGROUND: Autoantibodies against the glycoproteins desmogleins 1 and 3 which are components of the desmosomal adhesion complex have been shown to be responsible for the loss of epidermal adhesion characteristic of pemphigus. Elimination of these antibodies should clinically improve the pathology of this group of severe autoimmune blistering skin disorders. OBJECTIVES: To gather information about the efficacy of immunoadsorption in the reduction of pathogenic serum autoantibodies against desmogleins 1 and 3 and to evaluate the clinical benefit of immunoadsorption in the treatment of pemphigus. PATIENTS AND METHODS: Nine patients with pemphigus and detectable circulating desmoglein antibodies were included in this open trial. Two immunoadsorption treatments separated by a 48-h interval were performed per patient. Anti-desmoglein 1 and 3 antibodies in the patients' sera were monitored by enzyme-linked immunosorbent assay and indirect immunofluorescence before and following each immunoadsorption. In addition, the efficacy of the tryptophan-linked polyvinylalcohol adsorber in removing antidesmoglein antibodies was directly evaluated. RESULTS: IgG antibodies against desmogleins 1 and 3 were effectively eliminated from the patients' plasma upon passage through the adsorber and levels of serum autoantibodies were significantly reduced by immunoadsorption. A single immunoadsorption treatment led to a reduction of antidesmoglein autoantibodies of about 30%. Clinically, mucosal and cutaneous lesions improved allowing for a reduction of the systemic immunosuppressive treatment with glucocorticoids. CONCLUSIONS: Immunoadsorption with tryptophan-linked polyvinylalcohol adsorbers holds promise as a highly effective and safe adjuvant therapeutic regimen in pemphigus.