A minimal dose of unmanipulated bone marrow infusion without conditioning for T-B+NK- severe combined immunodeficiency

Hematopoietic stem cell transplantation (HSCT) is the standard method of reconstituting immune function in severe combined immunodeficiency (SCID); however, there is no consensus about optimal cell doses. In this study, we investigated HSCT outcomes and immune reconstitution, following minimal dose (MD) HSCT in T cell-negative (T-), B cell-positive (B+), natural killer cell-negative (NK-) SCID patients. We retrospectively reviewed patients with SCID who received HSCT between 2002–2018. Standard dose (SD) and MD were classified based on a total nucleated cell count (TNC) of 1.0 × 108/kg or more and less. Total seven patients with SCID received HSCT. MD group (n = 4) were administered 5 mL or less of bone marrow without conditioning, with median TNC and CD34+ cell counts of 0.49 × 108/kg and 0.62 × 106/kg, respectively. T cells recovered within a year, and immunoglobulin supplementation was discontinued at median 3.5 months after HSCT in all MD recipients. All MD recipients were alive without disease recurrence at a median of 126.9 months after HSCT, exhibiting donor chimerism in the range of 10.1–100%. In patients with T-B + NK- SCID, sufficient therapeutic effects were safely obtained with minimal dose of bone marrow infusion without conditioning.

A minimal dose of unmanipulated bone marrow infusion without conditioning for T-B+NK- severe combined immunodeficiency

Purpose Hematopoietic stem cell transplantation (HSCT) is the standard method of reconstituting immune function in severe combined immunodeficiency (SCID); however, current conditioning recommendations and optimal cell doses lack consensus. In this study, we investigated HSCT outcomes and immune reconstitution, following minimal dose (MD) HSCT in T cell-negative (T-), B cell-positive (B+), natural killer-cell negative (NK-) SCID patients. Methods We retrospectively reviewed patients with SCID who received HSCT between 2002–2018. Standard dose (SD) and MD were classified based on a total nucleated cell count (TNC) of 1.0 × 10 8 /kg or more and less. Results Seven patients with SCID received HSCT, of which four belonged to the MD group. Patients in the MD group were administered 5 mL or less of bone marrow without conditioning, with median TNC and CD34+ cell counts of 0.49 × 10 8 /kg and 0.62 × 10 6 /kg, respectively. T cells recovered within a year after HSCT, and immunoglobulin supplementation was discontinued at a median of 3.5 months after HSCT in all MD recipients. All MD recipients were alive without disease recurrence at a median of 126.9 months after HSCT, exhibiting donor chimerism in the range of 10.1%–100%. Although grade II–III graft-versus-host diseases occurred, these were manageable in all patients. One of the three patients in the SD group died of cytomegalovirus infection, while another was dependent on intravenous immunoglobulin until 41 months after HSCT. Conclusion In patients with T-B+NK- SCID, sufficient therapeutic effects were safely obtained with minimal dose of bone marrow infusion without conditioning.

Endothelial cell fitness dictates the source of regenerating liver vasculature

Neoangiogenesis plays a key role in diverse pathophysiological conditions, including liver regeneration. Yet, the source of new endothelial cells (ECs) remains elusive. By analyzing the regeneration of the liver vasculature in irradiation-based myeloablative and nonmyeloablative bone marrow transplantation mouse models, we discovered that neoangiogenesis in livers with intact endothelium was solely mediated by proliferation of resident ECs. However, following irradiation-induced EC damage, bone marrow–derived mononuclear cells were recruited and incorporated into the vasculature. Further experiments with direct bone marrow infusion or granulocyte colony–stimulating factor (G-CSF)–mediated progenitor cell mobilization, which resembles clinically relevant stem cell therapy, demonstrated that bone marrow–derived cells did not contribute to the regeneration of liver vasculature after two-thirds partial hepatectomy (PHx). Taken together, the data reconcile many of the discrepancies in the literature and highlight that the cellular source of regenerating endothelium depends on the fitness of the residual vasculature.

From Auto- to Allotransplantation: Immunomodulatory Protocol for Hand and Arm Transplantation

Aim To achieve a favorable risk–benefit balance for hand transplantation, an immunomodulatory protocol was developed in the laboratory and translated to clinical application. Methods Following donor bone marrow infusion into transplant recipients, hand and arm allografts have been maintained on low-dose tacrolimus monotherapy. Results Good-to-excellent functional recovery has been achieved in patients compliant with medication and therapy, thus restoring autonomous and productive lives. Conclusion The risk-benefit balance can be tilted in favor of the hand transplant recipients by using an immunomodulatory protocol with minimum immunosuppression.