Cell Therapy for Severe Hemophilia: Study Has Come Full Circle

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We read with interest the study by Sokal et al1 on biodistribution and the effects of transfused allogeneic adult liver derived mesenchymal stem cells in a patient with severe hemophilia. The cells were infused in several aliquots, one of which used cells labeled with 111Indium oxine to demonstrate biodistribution in the lungs, liver, and the affected joint. The transfused cells showed adequate amount of immunoreactive factor VIII and factor VIII mRNA and requirement for factor concentrates in this patient was reduced over 15 weeks, but without changes in plasma levels of the deficient factor. The important question is thus: why did the plasma factor VIII levels not rise after the cellular therapy? Did the patient produce inhibitory antibody to factor VIII a titre sufficient to bind secreted factor VIII, but not be detected by screening coagulation and mixing tests? Were there inadequate cell numbers transfused despite the large number of cells infused over several installments, or were the cells not viable for long enough to produce the factor?
The authors explained the phenomenon by arguing that the factor VIII containing allogeneic cells could have had a more extensive biodistribution than that shown by the nuclear imaging1 and that bleeding was countered by locally secreted factor VIII from transplanted allogeneic cells which was sufficient to arrest bleeding but without increasing the level in plasma. However, there was no direct evidence provided to support this effect except the observation of temporary homing of these mesenchymal stem cells to the affected joints.
Could there be an alternative explanation for this clinical improvement? We have previously shown that in severe hemophilia patients coinheritance of natural anticoagulant (protein C, protein S, and antithrombin) deficiency modulates the severity of bleeding.2 In the present study, these analytes were not measured. Moreover, corticosteroid, which was used both to prevent rejection of the infused stem cells and the reaction of the infused cells to host tissues, could have produced a hypercoagulable state by upregulating tissue factor activity and activating endothelial cells through proinflammatory cytokines. In addition, other coagulation factors in the coagulation cascade including factor VIIa could also have been elevated explaining the amelioration of the disease.
Several investigators have used transfusion of spleen cells for hemophilia A3,4 and have shown amelioration of the condition with increase in factor levels in plasma 4 to 7 days after infusion and persistence of high factor VIII levels in plasma for as long as 58 weeks in a large subset of patients.4 Aronovich et al5 used fetal pig spleen cells in an attempt to correct hemophilia as a proof of concept for correction of monogenic disorders. These studies may, in fact unwittingly have included mesenchymal stem cells from the spleen; hence, cell therapy for hemophilia may now have come full circle round to providing alternatives to available therapy for hemophilia. We would be interested to know if the studied patient has developed antibody to factor VIII as a result of this procedure.
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