T-cell receptor αß+ and CD19+ cell-depleted haploidentical and mismatched hematopoietic stem cell transplantation in primary immune deficiency.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) is used as a therapeutic approach for primary immunodeficiencies (PIDs). The best outcomes have been achieved with HLA-matched donors, but when a matched donor is not available, a haploidentical or mismatched unrelated donor (mMUD) can be useful. Various strategies are used to mitigate the risk of graft-versus-host disease (GvHD) and rejection associated with such transplants. OBJECTIVE: We sought to evaluate the outcomes of haploidentical or mMUD HSCT after depleting GvHD-causing T-cell receptor (TCR) αß CD3+ cells from the graft. METHODS: CD3+TCRαß+/CD19+ depleted grafts were given in conditioned (except 3) children with PIDs. Treosulfan (busulfan in 1 patient), fludarabine, thiotepa, and anti-thymocyte globulin or alemtuzumab conditioning were used in 77% of cases, and all but 4 received GvHD prophylaxis. RESULTS: Twenty-five patients with 12 types of PIDs received 26 HSCTs. Three underwent transplantation for refractory GvHD that developed after the first cord transplantation. At a median follow-up of 20.8 months (range, 5 month-3.3 years), 21 of 25 patients survived and were cured of underlying immunodeficiency. Overall and event-free survival at 3 years were 83.9% and 80.4%, respectively. Cumulative incidence of grade II to IV acute GvHD was 22% ± 8.7%. No case of visceral or chronic GvHD was seen. Cumulative incidences of graft failure, cytomegalovirus, and/or adenoviral infections and transplant-related mortality at 1 year were 4.2% ± 4.1%, 58.8% ± 9.8%, and 16.1% ± 7.4%, respectively. Patients undergoing transplantation with systemic viral infections had poor survival in comparison with those with absent or resolved infections (33.3% vs 100%). CONCLUSION: CD3+TCRαß+ and CD19+ cell-depleted haploidentical or mMUD HSCT is a practical and viable alternative for children with a range of PIDs.

Cytostatic conditioning in experimental allogeneic bone marrow transplantation: Busulfan causes less early gastrointestinal toxicity but Treosulfan results in improved immune reconstitution.

BACKGROUND: Acute graft versus host disease (aGVHD) after allogeneic bone marrow transplantation (allo-BMT) is associated with significant morbidity and mortality. We evaluated the impact of the conditioning regimen on aGVHD comparing Treosulfan (Treo) and Busulfan (Bu) with total body irradiation (TBI). METHODS: Using a haploidentical murine model, B6D2F1 mice conditioned with Bu (100 mg/kg)/Fludarabine (Flu, 500 mg/kg) or Treo (6000 mg/kg)/Flu (500 mg/kg) or TBI with 14 Gy received bone marrow cells and splenocytes (20 × 10(6)) from either syngeneic (B6D2F1) or allogeneic (C57BL/6N) donors in order to analyze aGVHD outcome. RESULTS: Conditioning with Bu/Flu or Treo/Flu resulted in significantly reduced aGVHD severity and improved survival (p < 0.05) after allo-BMT compared to TBI. On day 5 after allo-BMT, the organ damages of Bu/Flu conditioned animals were significantly reduced in association with diminished expression of tumor necrosis factor in serum compared to Treo/Flu. Interestingly, the early toxicity of Treo/Flu did not result in significantly higher aGVHD severity; furthermore, a significantly improved immune reconstitution of B220-positive B cells was observed at day 42 after Treo/Flu conditioning compared to Bu/Flu. CONCLUSION: Conditioning with Treo/Flu or Bu/Flu results in decreased aGVHD severity compared to TBI. Moreover, Treo/Flu was associated with improved immune reconstitution despite the early toxicity.

[A medical-pharmaceutical partnership model as a contributor to the success in conditioning regimen for allogenic hematopoietic stem cell transplantation in adults: a cross-reflection on our organizations]. / Modèle de coopération médico-pharmaceutique comme contributeur au succès du conditionnement de la greffe allogénique de cellules souches hématopoïétiques chez l'adulte : un regard croisé sur nos organisations.

Allogeneic hematopoietic stem-cell transplant (allo-SCT) remains the only cure for many hematological malignancies and some benign and congenital diseases. Busulfan, proposed in its injectable form, has quickly become a mainstay of pharmacological and myeloablative (or non-myeloablative) conditioning. This is following the outbreak in 2010 of a multicenter international clinical phase II trial, we tested the robustness and reliability of our organization in a complex model of organization and multifactorial partnership. In this type "BuCy2" protocol based on a classical treatment duration of 4 consecutive days, the administration of IV busulfan is given in one single daily infusion instead of the conventional 16 infusions, while keeping the same total dose. Under these conditions, the treatment is totally secured using a therapeutic drug monitoring of busulfan, applied in real-time. The process is technically complex and requires the very close cooperation of the teams involved. A strength, weakness, opportunity and threat (SWOT) analysis has been constructed; it fully supports continuous quality improvement to the triple benefit of the nursing chain, the patients and their environment. Several critical points were identified and corrected. The experiment strongly contributes to the safety and security of the medication circuit at the hospital and, improves the performance of allo-SCT. It also contributes to the protection of all actors in the health field and their working environment via a well-functioning quality management system.

The role of platelets in leukocyte recruitment in chronic contact hypersensitivity induced by repeated elicitation.

Platelets have been shown to be important in inflammation, but their role in chronic allergic dermatitis remains unclear. To investigate the role of platelets in a mouse model of chronic contact hypersensitivity induced by repeated elicitation, mice were sensitized and repeatedly elicited in ears with hapten, with or without platelet depletion, by administering antiplatelet antibody or busulfan. Ear thickness, leukocyte infiltration, serum IgE, and scratching behavior significantly decreased in thrombocytopenic mice. cDNA microarray of ear tissue showed reduced gene expression associated with Th2 lymphocytes. Flow cytometry showed increased P-selectin expression on platelets and an increased number of platelet-leukocyte aggregates in blood of repeatedly elicited mice, compared with sham-sensitized mice. In thrombocytopenic mice, inflammation was restored by platelet infusion, which was blocked by platelets from P-selectin-deficient mice or by pretreating platelets with anti-P-selectin antibody. Moreover, injection of activated platelet supernatant into ears led to increased leukocyte infiltration, which was blocked by pretreating platelets with antiplatelet compounds or neutralizing several chemokines in the platelet supernatant. These results suggest that platelets induce leukocyte recruitment into skin by forming platelet-leukocyte aggregates via P-selectin in blood and secreting chemokines at inflamed sites. Therefore, controlling platelet activity may be useful for treatment of chronic allergic dermatitis.