bims-actimu 2024-09-08 papers

Issue of 2024–09–08
two papers selected by
Elodie Busch, University of Strasbourg

J Allergy Clin Immunol. 2024 Sep 02. pii: S0091-6749(24)00904-7. [Epub ahead of print]

Hematopoietic Cell Transplantation for DOCK8 Deficiency: Results from a Prospective Clinical Trial.

BACKGROUND: Dedicator of cytokinesis 8 (DOCK8) deficiency is a primary immunodeficiency in which allogeneic hematopoietic cell transplantation (HCT) represents the only known cure. We tested the ability of a busulfan-based regimen to achieve reliable engraftment and high levels of donor chimerism with acceptable toxicity in a prospective clinical trial in DOCK8 deficiency.
OBJECTIVE: To both evaluate the ability of HCT to reverse the clinical phenotype and to correct the immunologic abnormalities by 1-year post-HCT.
METHODS: We conducted a prospective HCT trial for recipients with DOCK8 deficiency. Subjects were recruited from October 5th, 2010, to December 30th, 2022. Donor sources included fully matched related (MRD) and unrelated (MUD) and haploidentical (Haplo) donors. The reduced toxicity, myeloablative conditioning regimen contained no serotherapy. Graft-versus-host disease (GVHD) prophylaxis included either a calcineurin inhibitor (CNI) with methotrexate (MTX) or post-HCT cyclophosphamide (PT/Cy) followed by tacrolimus and mycophenolate mofetil (MMF). The trial was later amended to study PT/Cy in all patients. (ClinicalTrials.gov NCT01176006).
RESULTS: Thirty-six subjects, children, and adults (median age 16.4 years) underwent HCT for DOCK8 deficiency. Most patients, 33 of 36 (92%), achieved full (≥98%) donor chimerism in whole blood as early as day +30. With a median potential follow-up of 7.4 years, 29 (80.6%) were alive with no evidence of new DOCK8 deficiency-related complications. PT/Cy was effective in reducing the risk of acute GVHD in patients who had received MUDs and Haplo transplants, but it was associated with transient delays in immune-reconstitution and hemorrhagic cystitis (HC).
CONCLUSION: A busulfan-based HCT regimen using PT/Cy for GVHD prophylaxis and a broad range of donor types and hematopoietic cell sources were well-tolerated, leading to the reversal of the clinical immunophenotype.

Keywords: DOCK8 Deficiency; Immunophenotype reversal; hematopoietic cell transplantation

DOI: https://doi.org/10.1016/j.jaci.2024.08.021

Eur J Immunol. 2024 Sep 05. e2451004

Tviblindi algorithm identifies branching developmental trajectories of human B-cell development and describes abnormalities in RAG-1 and WAS patients.

Marina Bakardjieva, Ondřej Pelák, Marjolein Wentink, Hana Glier, David Novák, Jitka Stančíková, Daniela Kužílková, Ester Mejstříková, Iga Janowska, Marta Rizzi, Mirjam van der Burg, Jan Stuchlý, Tomáš Kalina.

Detailed knowledge of human B-cell development is crucial for the proper interpretation of inborn errors of immunity and malignant diseases. It is of interest to understand the kinetics of protein expression changes during development, but also to properly interpret the major and possibly alternative developmental trajectories. We have investigated human samples from healthy individuals with the aim of describing all B-cell developmental trajectories. We validated a 30-parameter mass cytometry panel and demonstrated the utility of "vaevictis" visualization of B-cell developmental stages. We used the trajectory inference tool "tviblindi" to exhaustively describe all trajectories leading to all developmental ends discovered in the data. Focusing on Natural Effector B cells, we demonstrated the dynamics of expression of nuclear factors (PAX-5, TdT, Ki-67, Bcl-2), cytokine and chemokine receptors (CD127, CXCR4, CXCR5) in relation to the canonical B-cell developmental stage markers. We observed branching of the memory development, where follicular memory formation was marked by CD73 expression. Lastly, we performed an analysis of two example cases of abnormal B-cell development caused by mutations in RAG-1 and Wiskott-Aldrich syndrome gene in patients with primary immunodeficiency. In conclusion, we developed, validated, and presented a comprehensive set of tools for the investigation of B-cell development in the bone marrow compartment.

Keywords: B‐cell development; CD73; Mass cytometry; RAG‐1; Trajectory inference; WAS

DOI: https://doi.org/10.1002/eji.202451004