Immune Tolerance Induction (immune + tolerance_induction)

Distribution by Scientific Domains


Selected Abstracts


Immune tolerance induction with high von Willebrand factor/factor VIII content ratio concentrate in children with haemophilia A and high-responding inhibitor

HAEMOPHILIA, Issue 2 2009
H. PLATOKOUKI
No abstract is available for this article. [source]


Low-dose immune tolerance induction for paediatric haemophilia patients with factor VIII inhibitors

HAEMOPHILIA, Issue 2 2008
A. UNUVAR
Summary., The development of an inhibitor against factor VIII (FVIII) is a serious complication in children with haemophilia A. Immune tolerance induction (ITI) therapy is generally considered to be the best approach to eradicate the inhibitor. In this paper, the low-dose (,50 IU kg,1 twice or three times weekly with plasma-derived factor concentrates) ITI regimen used in Turkey is discussed. This regimen was given to 21 haemophilia A patients with high titer inhibitors. The median age at the beginning of ITI was 9 years and exposure days were 25. The median pre-ITI historical peak inhibitor titer, and inhibitor titer when ITI started were 80 BU (range 6.0,517), 19.2 BU (range 3.6,515), respectively. Complete immune tolerance was defined as the time at which at least two negative inhibitor assays was obtained with no anamnestic response. Our two cases were not reached in follow-up period. Immune tolerance could be achieved in 5 of 19 (26.3%) patients within a median time of 6 months. Partial tolerance was obtained in 7 patients while treatment failed in spite of significant decreased inhibitor levels in the other patients. A relapse developed in one immune-tolerized patient, one year later. The level of inhibitor titer at the beginning of ITI (,10 BU), the pre-ITI historical peak inhibitor titer (<50 BU), and the time between the first diagnosis inhibitor to starting ITI (<12 months) were main factors in the success (complete or partial tolerance) of ITI. In conclusion, the outcome of low-dose ITI protocol was not satisfactory in this retrospective study. [source]


Cyclosporin A can achieve immune tolerance in a patient with severe haemophilia B and refractory inhibitors

HAEMOPHILIA, Issue 1 2007
D. C. A. CROSS
Summary., Immune tolerance induction (ITI) is described in a patient with severe haemophilia B complicated by the presence of an inhibitor. A number of ITI regimes were attempted without success and the patient suffered from frequent relapses and bleeding episodes. Successful ITI was achieved with the additional use of cyclosporin A. The patient developed nephrotic syndrome although had a negative Bethesda titre at this time. When cyclosporin A therapy was ceased, the inhibitor titre rose and the patient suffered again from bleeding episodes. Cyclosporin A was reintroduced at a lower dose. The patient has now received cyclosporin A for 10 years, during which time he has relapsed three times for short periods (2 weeks). He is also on prophylaxis with factor IX three times a week with preinfusion levels >1% and without bleeding. [source]


Immune tolerance induction in patients with haemophilia A with inhibitors: a systematic review

HAEMOPHILIA, Issue 4 2003
J. Wight
Summary., In some patients with haemophilia A, therapeutically administered factor VIII (FVIII) comes to stimulate the production of antibodies (inhibitors) which react with FVIII to render it ineffective. As a result, FVIII cannot be used prophylactically and patients become liable to recurrent bleeds. There are two elements to the management of patients with inhibitors: the treatment of bleeding episodes, and attempts to abolish inhibitor production through the induction of immune tolerance. This paper reports a systematic review of the best available evidence of clinical effectiveness in relation to immune tolerance induction (ITI) in patients with haemophilia A with inhibitors. Owing to the lack of randomized controlled trials on this topic, broad inclusion criteria with regard to study design were applied in order to assess the best available evidence for each intervention. As a result of the clinical and methodological heterogeneity of the evidence, it was not appropriate to pool data across studies; instead, data were synthesized using tabulation and qualitative narrative assessment. The International Registry provides the most reliable estimate of the proportion of successful cases of ITI [48.7%, 95% confidence interval (CI) 42.6,52.7%]. The duration of effect is unclear, but relapses appear to be infrequent. The International Registry shows a rate of relapse of 15% at 15 years. The comparative effectiveness of different protocols is uncertain, as no trials have been undertaken which compare them directly. However, the evidence suggests that the Bonn protocol may be more effective than the Malmö or low-dose protocols. There is no good evidence that immunosuppressive drug regimens are effective. [source]


Factor VIII gene (F8) mutations as predictors of outcome in immune tolerance induction of hemophilia A patients with high-responding inhibitors

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 11 2009
A. COPPOLA
Summary.,Background:, Immune tolerance induction (ITI) is the only therapeutic approach that can eradicate factor VIII (FVIII) inhibitors in patients with hemophilia A. Predictors of ITI outcome are still debated, and the role of F8 gene mutations in this is not well established. Objectives: To investigate the relationship between F8 genotype and ITI outcome in patients with severe hemophilia A and high-responding inhibitors. Patients and Methods:F8 mutations were identified in 86 patients recruited as part of the Italian ITI registry (the PROFIT study). ITI outcome was centrally reviewed according to the following definitions: success (undetectable inhibitor and normal FVIII pharmacokinetics), partial success (inhibitor titer < 5 BU mL,1 and/or abnormal FVIII pharmacokinetics), and failure. Results:F8 mutations known to be associated with a high risk of inhibitor development (large deletions, inversions, nonsense mutations and splice site mutations) were found in 70 patients (81%); among these, the intron 22 inversion was present in 49 patients (57%). In 16 patients (19%) lower-risk F8 defects (small insertions/deletions and missense mutations) were identified. The latter group of patients showed a significantly higher ITI success rate than those carrying high-risk mutations [13/16 (81%) vs. 33/70 (47%); risk ratio 1.7, 95% confidence interval (CI) 1.1,2.1, P = 0.01]. On multivariate analysis, the mutation risk class remained a significant predictor of success [adjusted odds ratio (OR) 6.2, 95% CI 1.1,36.0, P = 0.04], as were inhibitor titer at ITI start (< 5 BU mL,1, OR 11.8, 95% CI 3.5,40.2, P < 0.001), and peak titer during ITI (< 100 BU mL,1, OR 11.4, 95% CI 3.2,40.8, P < 0.001). Conclusions: ITI success is influenced by F8 genotype. This knowledge should contribute to the stratification of prognosis, and to the clinical choices made for ITI in patients with high-responding inhibitors. [source]


Ethanol lock therapy for the treatment of catheter-related infections in haemophilia patients

HAEMOPHILIA, Issue 6 2009
M. RAJPURKAR
Summary., Central venous access devices (CVAD) are increasingly being used for optimal delivery of clotting factor concentrates in patients with haemophilia with poor peripheral venous access. The utility of CVAD is particularly well recognized in young patients starting factor prophylaxis and in patients with inhibitors undergoing immune tolerance induction (ITI). A catheter-related infection (CRI) remains the most common complication of CVAD in haemophilia patients and is the most frequent indication for its removal. Additionally, in some patients the infection results in significant morbidity and mortality and also contributes to failure of the ITI regimen. Ethanol-lock therapy (ELT) is a treatment modality that has been used to treat CRI in patients with indwelling catheters for home parenteral nutrition and chemotherapy. The aim of this study was to report the success in treating CRI in haemophilia patients using ELT. Three severe haemophilia A patients undergoing ITI regimen who developed CVAD infections resistant to conventional management with antibiotics were treated by ELT according to the institutional technique. All three patients responded well to ELT with clearance of the CVAD infection. There were no adverse side effects. To our knowledge, this is the first report of ELT in patients with haemophilia. The role of ELT needs to be investigated in larger studies for treatment of CRI in patients with bleeding disorders. [source]


Forum on: the role of recombinant factor VIII in children with severe haemophilia A

HAEMOPHILIA, Issue 2 2009
M. FRANCHINI
Summary., The development of recombinant FVIII (rFVIII) products, fuelled by the need for improved safety of treatment arising from the dramatic widespread blood-borne virus transmission in the 1970,1980s revolutionized the care of children with haemophilia A over the last two decades. The larger availability of perceived safer replacement therapy associated with the introduction of rFVIII products reassured the haemophilia community and there was a strong push in some Western countries to treat haemophilic children only with rFVIII. Moreover, this significantly contributed in the 1990s to the diffusion outside Northern Europe of prophylactic regimens implemented at an early age to prevent bleeding and the resultant joint damage (i.e. primary prophylaxis), together with the possibility of home treatment. These changes led to a substantial improvement of the quality of life of haemophilic children and of their families. The general agreement that primary prophylaxis represents the first-choice treatment for haemophilic children has been recently supported by two randomized controlled trials carried out with rFVIII products, providing evidence on the efficacy of early prophylaxis over on-demand treatment in preserving joint health in haemophilic children. However, the intensity and optimal modalities of implementation of prophylaxis in children, in particular with respect to the issue of the venous access, are still debated. A number of studies also supports the role of secondary prophylaxis in children, frequently used in countries in which primary prophylaxis was introduced more recently. With viral safety now less than an issue and with the more widespread use of prophylaxis able to prevent arthropathy, the most challenging complication of replacement therapy for children with haemophilia remains the risk of inhibitor development. Despite conflicting data, there is no evidence that the type of FVIII concentrate significantly influences the complex multifactorial process leading to anti-FVIII alloantibodies, whereas other treatment-related factors are likely to increase (early intensive treatments due to surgery or severe bleeds) or reduce (prophylaxis) the risk. Although the optimal regimen is still uncertain, eradication of anti-FVIII antibodies by immune tolerance induction (ITI), usually with the same product administered at inhibitor detection, should be the first-choice treatment for all patients with recent onset inhibitors. This issue applies particularly to children, as most patients undergo ITI at an early age, when inhibitors usually appear. The availability of a stable and long-lasting venous access represents a leading problem also in this setting. These and other topics concerning rFVIII treatment of haemophilic children were discussed in a meeting held in Rome on 27 February 2008 and are summarized in this report. [source]


The North American Immune Tolerance Registry: contributions to the thirty-year experience with immune tolerance therapy

HAEMOPHILIA, Issue 1 2009
D. DIMICHELE
Summary., The North American Immune Tolerance Registry (NAITR) began in 1992 as a project of the ISTH Factor VIII/IX Subcommittee with the goal of further determining immune tolerance induction (ITI) practices in Canada and the United States. This retrospective registry study, published in 2002, was limited in its capacity to provide definitive answers to many unresolved ITI practice issues. Nonetheless, it played a role in developing guidelines for current ITI practice and in generating hypotheses that must now be examined through rigorous prospective data collection efforts. For haemophilia A, the logical next step has been the initiation of international prospective randomized studies of ITI outcome relative to factor VIII (FVIII) dose and purity for subjects with high titre inhibitors. Both trials will additionally provide platforms for translational study of the immunology of tolerance, a prelude to the next generation of safe and effective tolerizing strategies. For the less common problem of FIX inhibitor eradication, prospective randomized studies will not be a feasible way to confirm the NAITR observations. Coordinated international efforts will still be required to prospectively collect data on ITI outcome to document new potentially effective therapeutic strategies for inhibitor eradication. These registries will hopefully also serve to identify potential subjects for scientific studies of immunology of haemophilia B-related allergic phenomena, a devastating complication of FIX antibody development. [source]


Haemophilia care then, now and in the future

HAEMOPHILIA, Issue 2009
J. OLDENBURG
Summary., Epidemiological data show the benefits of dramatically improved haemophilia care in all life-stages. There are improved administration techniques and dosing regimens, a shift from on-demand treatment to prophylaxis, successful treatment protocols for immune tolerance induction in patients with inhibitors and enhanced approaches to overall patient management. Improvements also include the introduction of virus inactivation methods for plasma derived clotting factor concentrates and the development of recombinant factor VIII therapy, which practically eliminated the risk of infectious disease transmission. Recombinant factor concentrates are recommended as treatment of choice by several guidelines today. All these developments have resulted in increased health-related quality of life and life expectancy in haemophilia patients, who are transitioning from childhood to adulthood with healthy joints and an overall healthy status today. Because of increased life expectancy, these patients are expected to experience age-related clinical problems that were not previously observed in this population. With respect to this, the spectrum of haemophilia care will be extended to diseases of older ages with the need of including further disciplines in comprehensive haemophilia care programmes. Despite these advances, the short half-life of factor VIII, requiring re-administration every 2 or 3 days and the development of inhibitors remains a challenge. Bayer's research and development currently focuses on the optimization of recombinant coagulation factors to address these challenges. Haemophilia care has experienced significant improvements within the past decades. Novel technologies and continued clinical research have facilitated the development of treatment regimen that resulted in dramatic increases in the life expectancy and quality of life of haemophilia patients. To set the scene for the following papers dealing with haemophilia care from paediatrics to geriatrics, developments behind these improvements and some aspects of future research will be presented in this paper. [source]


Low-dose immune tolerance induction for paediatric haemophilia patients with factor VIII inhibitors

HAEMOPHILIA, Issue 2 2008
A. UNUVAR
Summary., The development of an inhibitor against factor VIII (FVIII) is a serious complication in children with haemophilia A. Immune tolerance induction (ITI) therapy is generally considered to be the best approach to eradicate the inhibitor. In this paper, the low-dose (,50 IU kg,1 twice or three times weekly with plasma-derived factor concentrates) ITI regimen used in Turkey is discussed. This regimen was given to 21 haemophilia A patients with high titer inhibitors. The median age at the beginning of ITI was 9 years and exposure days were 25. The median pre-ITI historical peak inhibitor titer, and inhibitor titer when ITI started were 80 BU (range 6.0,517), 19.2 BU (range 3.6,515), respectively. Complete immune tolerance was defined as the time at which at least two negative inhibitor assays was obtained with no anamnestic response. Our two cases were not reached in follow-up period. Immune tolerance could be achieved in 5 of 19 (26.3%) patients within a median time of 6 months. Partial tolerance was obtained in 7 patients while treatment failed in spite of significant decreased inhibitor levels in the other patients. A relapse developed in one immune-tolerized patient, one year later. The level of inhibitor titer at the beginning of ITI (,10 BU), the pre-ITI historical peak inhibitor titer (<50 BU), and the time between the first diagnosis inhibitor to starting ITI (<12 months) were main factors in the success (complete or partial tolerance) of ITI. In conclusion, the outcome of low-dose ITI protocol was not satisfactory in this retrospective study. [source]


FEIBA® safety profile in multiple modes of clinical and home-therapy application

HAEMOPHILIA, Issue 2004
H. Luu
Summary., The development of neutralizing antibodies to factor VIII or IX therapeutic concentrates remains the most serious and challenging complication in the management of patients with haemophilia A and B. FEIBA®, Anti-Inhibitor Coagulant Complex, is an activated prothrombin complex concentrate that has been used to treat patients with such complications for almost 30 years. The mechanism of action of FEIBA® has been proposed to involve simultaneous FVIII/FIX inhibitor bypassing action in the common, intrinsic and extrinsic coagulation pathways. FEIBA® is derived from human plasma that undergoes stringent viral screening followed by significant viral inactivation and removal. To date, there have been no confirmed reports of transmission of hepatitis A, B or C, or of human immunodeficiency viruses associated with the use of the current, vapour-heat-treated FEIBA® concentrate. The incidence of thrombotic adverse events recorded in the Baxter pharmacovigilance database for the 10-year postmarket period (1990,99) was approximately 4 : 100 000 infusions of FEIBA®. Almost all documented thrombotic events with FEIBA® occurred with doses that exceeded dosing recommendations, and known risk factors for cardiovascular disease were evident in more than 80% of the patients involved. Overall, clinical data have shown FEIBA® to be safe and well-tolerated for use in a wide variety of clinical settings, including treatment of bleeding episodes, management of surgical procedures, home therapy, long-term prophylaxis, and prophylaxis during immune tolerance induction, when used according to dosing guidelines. [source]


The management of inhibitors in haemophilia A: introduction and systematic review of current practice

HAEMOPHILIA, Issue 4 2003
S. Paisley
Summary., Haemophilia is the commonest bleeding disorder in the UK, affecting approximately 5400 people, almost all of them male. In haemophiliacs, reduced levels, or absence, of factor VIII (FVIII) cause bleeding episodes, typically into joint spaces or muscles. Haemophilia is generally treated with exogenous FVIII. However, in some haemophiliacs, therapeutically administered FVIII comes to be recognized as a foreign protein, stimulating the production of antibodies (inhibitors), which react with FVIII to render it ineffective. Alternative treatment strategies then have to be used to manage bleeding episodes. In addition, strategies have been developed to attempt to abolish inhibitor production through the induction of immune tolerance. A systematic review was undertaken of current international practice for the clinical management of haemophilia A patients with inhibitors to FVIII, concentrating on literature published from 1995 onwards. Although it can be difficult to determine what constitutes current practice, current guidelines indicate that immune tolerance induction is seen as desirable, with the choice of regimen dependent on patient characteristics, familiarity with regimens and cost. Various approaches, based on similar factors, are used to control bleeding episodes. [source]


Immune tolerance induction in patients with haemophilia A with inhibitors: a systematic review

HAEMOPHILIA, Issue 4 2003
J. Wight
Summary., In some patients with haemophilia A, therapeutically administered factor VIII (FVIII) comes to stimulate the production of antibodies (inhibitors) which react with FVIII to render it ineffective. As a result, FVIII cannot be used prophylactically and patients become liable to recurrent bleeds. There are two elements to the management of patients with inhibitors: the treatment of bleeding episodes, and attempts to abolish inhibitor production through the induction of immune tolerance. This paper reports a systematic review of the best available evidence of clinical effectiveness in relation to immune tolerance induction (ITI) in patients with haemophilia A with inhibitors. Owing to the lack of randomized controlled trials on this topic, broad inclusion criteria with regard to study design were applied in order to assess the best available evidence for each intervention. As a result of the clinical and methodological heterogeneity of the evidence, it was not appropriate to pool data across studies; instead, data were synthesized using tabulation and qualitative narrative assessment. The International Registry provides the most reliable estimate of the proportion of successful cases of ITI [48.7%, 95% confidence interval (CI) 42.6,52.7%]. The duration of effect is unclear, but relapses appear to be infrequent. The International Registry shows a rate of relapse of 15% at 15 years. The comparative effectiveness of different protocols is uncertain, as no trials have been undertaken which compare them directly. However, the evidence suggests that the Bonn protocol may be more effective than the Malmö or low-dose protocols. There is no good evidence that immunosuppressive drug regimens are effective. [source]


The future of plasma-derived clotting factor concentrates

HAEMOPHILIA, Issue 2001
W.K. Hoots
In developed countries, preferred treatments for both haemophilia A and B have moved toward recombinant clotting factor concentrates, while plasma-derived replacement therapies are still required by many patients. Great improvements have been made in producing relatively pathogen-free clotting factor replacements from pooled plasma. The fluidity and complexity of the worldwide plasma product market are discussed in the context of the ,yin and yang' of plasma therapeutics, showing how multiple issues can influence the safety and availability of clotting factor concentrates. Use of plasma-derived products will likely continue for the next decade for patients with inhibitors, patients with von Willebrand disease, those requiring bypassing agents, in immune tolerance induction, and for treatment of rare inherited deficiencies of procoagulant or anticoagulant proteins. Furthermore, in developing countries many of the most advanced therapies are not available for the majority of haemophilia patients, and thus plasma-derived replacement concentrates will continue to be used even for noninhibitor patients. [source]


Oral immune tolerance induction to factor VIII via breast milk, a possibility?

HAEMOPHILIA, Issue 5 2000

[source]


Factor VIII gene (F8) mutations as predictors of outcome in immune tolerance induction of hemophilia A patients with high-responding inhibitors

JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 11 2009
A. COPPOLA
Summary.,Background:, Immune tolerance induction (ITI) is the only therapeutic approach that can eradicate factor VIII (FVIII) inhibitors in patients with hemophilia A. Predictors of ITI outcome are still debated, and the role of F8 gene mutations in this is not well established. Objectives: To investigate the relationship between F8 genotype and ITI outcome in patients with severe hemophilia A and high-responding inhibitors. Patients and Methods:F8 mutations were identified in 86 patients recruited as part of the Italian ITI registry (the PROFIT study). ITI outcome was centrally reviewed according to the following definitions: success (undetectable inhibitor and normal FVIII pharmacokinetics), partial success (inhibitor titer < 5 BU mL,1 and/or abnormal FVIII pharmacokinetics), and failure. Results:F8 mutations known to be associated with a high risk of inhibitor development (large deletions, inversions, nonsense mutations and splice site mutations) were found in 70 patients (81%); among these, the intron 22 inversion was present in 49 patients (57%). In 16 patients (19%) lower-risk F8 defects (small insertions/deletions and missense mutations) were identified. The latter group of patients showed a significantly higher ITI success rate than those carrying high-risk mutations [13/16 (81%) vs. 33/70 (47%); risk ratio 1.7, 95% confidence interval (CI) 1.1,2.1, P = 0.01]. On multivariate analysis, the mutation risk class remained a significant predictor of success [adjusted odds ratio (OR) 6.2, 95% CI 1.1,36.0, P = 0.04], as were inhibitor titer at ITI start (< 5 BU mL,1, OR 11.8, 95% CI 3.5,40.2, P < 0.001), and peak titer during ITI (< 100 BU mL,1, OR 11.4, 95% CI 3.2,40.8, P < 0.001). Conclusions: ITI success is influenced by F8 genotype. This knowledge should contribute to the stratification of prognosis, and to the clinical choices made for ITI in patients with high-responding inhibitors. [source]


Partial phenotypic correction and immune tolerance induction to enzyme replacement therapy after hematopoietic stem cell gene transfer of ,-glucosidase in Pompe disease

THE JOURNAL OF GENE MEDICINE, Issue 4 2009
Gaëlle Douillard-Guilloux
Abstract Background Glycogen storage disease type II (GSDII) or Pompe disease is an inherited disease of glycogen metabolism caused by a lack of functional lysosomal acid ,-glucosidase (GAA). Affected individuals store glycogen in lysosomes resulting in fatal hypertrophic cardiomyopathy and respiratory failure in the most severe form. Even if enzyme replacement therapy (ERT) has already proven some efficacy, its results remain heterogeneous in skeletal muscle, especially in cross reactive immunological material (CRIM)-negative patients. We investigated for the first time the use of hematopoietic stem cell (HSC) gene therapy in a murine model of GSDII. Methods Deficient HSC were transduced with a lentiviral vector expressing human GAA or enhanced green fluorescent protein (GFP) under the control of the retroviral MND promoter and transplanted into lethally irradiated GSDII mice. Animals were then subjected to an ERT protocol for 5 weeks and monitored for metabolic correction and GAA-induced immune reaction. Results GAA was expressed as a correctly processed protein, allowing a complete enzymatic correction in transduced deficient cells without toxicity. Seventeen weeks after transplantation, a partial restoration of the GAA enzymatic activity was observed in bone marrow and peripheral blood cells of GSDII mice, allowing a significant glycogen clearance in skeletal muscle. ERT induced a robust antibody response in GFP-transplanted mice, whereas no immune reaction could be detected in GAA-transplanted mice. Conclusions Lentiviral vector-mediated HSC gene therapy leads to a partial metabolic correction and induces a tolerance to ERT in GSDII mice. This strategy could enhance the efficacy of ERT in CRIM-negative Pompe patients. Copyright © 2009 John Wiley & Sons, Ltd. [source]


Feasibility of prophylaxis and immune tolerance induction regimens in haemophilic children using fully implantable central venous catheters

BRITISH JOURNAL OF HAEMATOLOGY, Issue 5 2008
Maria Elisa Mancuso
Summary Venous access represents the major barrier to the feasibility of prophylaxis and immune tolerance induction (ITI) in haemophilic children. Ports improve treatment feasibility, but their duration is limited by infectious complications. This study aimed at evaluating whether or not ports allow haemophilic children to maintain the treatment regimen in the long term. Children were prospectively followed-up and underwent port removal either for complications or transition to peripheral veins. Of 27 ports (17 used for prophylaxis and 10 for ITI), 25 were removed after a median of 3·3 years. Inhibitor children showed a younger age at port insertion (P = 0·02), an earlier occurrence of infections (P = 0·006) at a higher rate (P = 0·00001) and an earlier removal for infection (P = 0·05) than non-inhibitor patients. Daily port use was associated with earlier infections at a higher rate compared to less frequent use (P = 0·02). Port removal after a median of 0·8 years prevented ITI completion in 50% of children, while it hampered the maintenance of prophylaxis in 27% of patients. This study showed that ports improved the feasibility of prophylaxis in the majority of non-inhibitor children, while they were not suitable for inhibitor children who require a prolonged ITI regimen with daily infusions. [source]