Muhammad Saif

Hematopoietic stem cell transplantation improves the high incidence of neutralizing allo-antibodies observed in Hurler's syndrome after pharmacological enzyme replacement therapy.

Background Mucopolysaccharidosis type I is caused by deficiency of α-L-iduronidase. Currently available treatment options include an allogeneic hematopoietic stem cell transplant and enzyme replacement therapy. Exogenous enzyme therapy appears promising but the benefits may be attenuated, at least in some patients, by the development of an immune response to the delivered enzyme. The incidence and impact of alloimmune responses in these patients remain unknown. Design and Methods We developed an immunoglobulin G enzyme-linked immunosorbent assay as well as in vitro catalytic enzyme inhibition and cellular uptake inhibition assays and quantified enzyme inhibition by allo-antibodies. We determined the impact of these antibodies in eight patients who received enzyme therapy before and during hematopoietic stem cell transplantation. In addition, 20 patients who had previously received an allogeneic stem cell transplant were tested to evaluate this treatment as an immune tolerance induction mechanism. Results High titer immune responses were seen in 87.5% (7/8) patients following exposure to α-L-iduronidase. These patients exhibited catalytic enzyme inhibition (5/8), uptake inhibition of catalytically active enzyme (6/8) or both (4/8). High antibody titers generally preceded elevation of previously described biomarkers of disease progression. The median time to development of immune tolerance was 101 days (range, 26–137) after transplantation. All 20 patients, including those with mixed chimerism (22%), tested 1 year after transplantation were tolerized despite normal enzyme levels. Conclusions We found a high incidence of neutralizing antibodies in patients with mucopolysaccharidosis type I treated with enzyme replacement therapy. We also found that allogeneic hematopoietic stem cell transplantation was an effective and rapid immune tolerance induction strategy.

The role of antibodies in enzyme treatments and therapeutic strategies

Substitution of the defective lysosomal enzyme in lysosomal storage disorders (LSDs) often elicits antibody formation towards the infused protein. Aside from Gaucher disease, antibodies often lead to infusion associated reactions and a reduced biochemical response. In Pompe disease, antibody titer is predictive of clinical outcome, but this is less apparent in other LSDs and warrants further study. Few laboratories are capable of enzyme-antibody determination: often physicians need to rely on the enzyme manufacturer for analysis. Currently, laboratories employ different antibody assays which hamper comparisons between cohorts or treatment regimens. Assay standardisation, including measurement of antibody-related enzyme inhibition, is therefore urgently needed. Successful immunomodulation has been reported in Pompe and in Gaucher disease, with variable success. Immunomodulation regimens that contain temporary depletion of B-cells (anti-CD20) are most used. Bone marrow transplantation in MPS-I results in disappearance of antibodies. No other clinical studies have been conducted in humans with immunomodulation in other LSDs.

Is it congenital or acquired von Willebrands disease

essential aspect of the study. The BAT used is not validated for evaluating bleeding tendency among haemophilia carriers, which may be a limitation of the study. The BAT has, however, been used in several publications to rate and compare the severity and frequency of bleeding symptoms among individuals with a certain diagnosis [10]. Another limitation of the study may be the lack of use of CTI. However, there are reports suggesting that CTI addition is only beneficial for thrombin generation triggered with TF concentrations below 0.5 pM [5,11]. We speculate that carriers might lack the ability to mobilize FVIII from depots in situations that challenge the haemostatic system, such as trauma and surgery. In this study, blood was not sampled during such situations, which might have contributed to the outcome. Inter-individual variations in other clotting factor levels, platelet function, fibrinolytic activity or endothelial vessel wall components might also contribute to variation in clinical phenotype among carriers and explain the difficulty in demonstrating that TGA is a useful tool in this setting. In conclusion, the TGA results did not differ between carriers of haemophilia A with and without bleeding tendency. Our results suggest that TGA may not be a suitable test to predict bleeding risk among carriers of moderate and severe haemophilia A.

How necessary is it to revaccinate hemopoietic transplant recipients

The loss of specific immunity against vacci nation-preventable diseases after hemopoietic stem cell transplantation (HSCT) was repeatedly reported in the literature during the 1980s and 1990s. Those observations, mainly based on quantitative antibody assays, led to the gener ation of various schemes for the revaccination of HSCT recipients [1,101]. Although based on a low level of evidence and differing in the recommended timing to start the revaccination program, all recommendations followed common patterns (e.g., administering live vaccines only after the first year post-HSCT and delaying immunizations in the event of graft-versus-host disease). Following these revaccination guidelines seems to reassure clinicians and appears to satisfy transplant physicians. Also, from a public health perspective, revaccinating the increasing population of long-term HSCT survivors may reduce the impact that these patients may have in the protection of the overall population. Conversely, reimmunizing HSCT recipients may protect them against the risks derived from the growing tendency to disregard the advice to vaccinate children against certain diseases [2,3]. It would therefore appear that “all is well”, as the scientific community has accepted that the low post-HSCT antibody titers translate into a loss of protection, and the implementation of revaccination schedules appears to correct this deficiency [4,5]. However, from a transplantation immunology point of view, a key question remains unanswered: have the post-HSCT antibody titers for these diseases ever been compared with those of age-paired healthy volunteers? Or, in other words, have we investigated whether it is really necessary to revaccinate these patients in the first place?