Thymus transplantation for complete DiGeorge syndrome: European experience

Background: Thymus transplantation is a promising strategy for the treatment of athymic complete DiGeorge syndrome (cDGS). Methods: Twelve patients with cDGS were transplanted with allogeneic cultured thymus. Objective: To confirm and extend the results previously obtained in a single centre. Results: Two patients died of pre-existing viral infections without developing thymopoeisis and one late death occurred from autoimmune thrombocytopaenia. One infant suffered septic shock shortly after transplant resulting in graft loss and the need for a second transplant. Evidence of thymopoeisis developed from 5-6 months after transplantation in ten patients. The median (range) of circulating naïve CD4 counts (x10663 /L) were 44(11-440) and 200(5-310) at twelve and twenty-four months post-transplant and T-cell receptor excision circles were 2238 (320-8807) and 4184 (1582 -24596) per106 65 T-cells. Counts did not usually reach normal levels for age but patients were able to clear pre-existing and later acquired infections. At a median of 49 months (22-80), eight have ceased prophylactic antimicrobials and five immunoglobulin replacement. Histological confirmation of thymopoeisis was seen in seven of eleven patients undergoing biopsy of transplanted tissue including five showing full maturation through to the terminal stage of Hassall body formation. Autoimmune regulator (AIRE) expression was also demonstrated. Autoimmune complications were seen in 7/12 patients. In two, early transient autoimmune haemolysis settled after treatment and did not recur. The other five suffered ongoing autoimmune problems including: thyroiditis (3); haemolysis (1), thrombocytopaenia (4) and neutropenia (1). Conclusions: This study confirms the previous reports that thymus transplantation can reconstitute T cells in cDGS but with frequent autoimmune complications in survivors

Nuclear lamin stiffness is a barrier to 3D migration, but softness can limit survival

Lamin-A provides stiff resistance to cell migration Harada et al. describe how nuclear lamins affect the ability of migrating cells to squeeze through tissues and survive the resulting stress. Migrating cells must maneuver their large and chromatin-packed nuclei through tiny gaps in the surrounding tissue. A- and B-type lamins assemble in the nuclear periphery and help determine the organelle’s mechanical properties, but whether these proteins affect cell migration is unclear. Harada et al. tested the role of lamin-A in several different cell types. Partially reducing lamin-A levels enhanced the ability of cells to move through extracellular matrix containing small, 3-μm pores, whereas overexpressing the protein inhibited cell migration. Cells that expressed stoichiometrically high amounts of lamin-B were particularly sensitive to changes in lamin-A levels. The researchers found that nuclei containing low amounts of lamin-A were softer, allowing them to squeeze through tiny pores and—due to the spring-like properties of lamin-B—return to their normal shape on the other side. In contrast, high lamin-A levels made nuclei stiff and harder to maneuver, a property that could help keep mesenchymal stem cells, which express large amounts of lamin-A, anchored in their niche. Nuclei can be too soft for their own good, however. Cells experience stress as they migrate through tissues, occasionally resulting in apoptosis. Cells lacking lamin-A were less resistant to stress and more prone to death, possibly because the