Longitudinal Evaluation of Immune Reconstitution and B-cell Function After Hematopoietic Cell Transplantation for Primary Immunodeficiency

Abstract

Purpose Hematopoietic cell transplantation (HCT) provides a curative therapy for severe forms of primary immunodeficiencies (PID). While the timing and extent of Tcell reconstitution following transplant for PID has been studied in depth, less is known about the kinetics of B-cell development and long-term restoration of humoral functions, which been often reported to be suboptimal after HCT. Methods We studied longitudinally B-cell development and function in a cohort of 13 PID patients transplanted between 1997 and 2010, with a follow-up ranging from 0.7 to 15 years. Flow cytometric analysis of naïve and antigen-experienced Bcell subsets and in vitro functional responses to CpG were compared with data from healthy children and correlated with the degree of B-cell chimerism and in vivo antibody production.Results We found that total memory B-cells count remained below normal levels for the first 2 years of follow up and progressively normalized. Switched memory B-cells (CD19+ CD27+IgD-IgM-) were restored early and better than IgM memory B-cells (CD19+CD27+IgD+IgM+), which remained significantly reduced long-term. The recovery of memory Bcells correlated with good in vivo humoral function and normalization of CpG-response. A complete B-cell reconstitution was usually associated with donor B-cells chimerism and pretransplant conditioning. Donor source and the underlying genetic defect represented also important variables. Conclusion Monitoring of phenotypic and functional changes on B-cells following HCT may prove clinically relevant to tailor patients' care. In particular the analysis of IgM memory and switched memory B-cells in addition to in vitro B-cells stimulation are recommended before Ig replacement therapy (IgRT) discontinuation.

Hematopoietic stem cell transplantations for primary immune deficiencies associated with NFκB mutations: A review of the literature

“…Moreover, in some defects, engraftment and complete immune reconstitution might be more difficult to achieve, such as T-cells and B-cells in CBM and NFKBIA defects, respectively. Whether the persistently low number of switched-memory B-cells is also related to the developmental abnormalities of secondary lymphoid organs caused by the IκBα defect remains to be determined (Scarselli et al 2015). Hence, the optimal conditioning for patients with NFκB defects undergoing HSCT is still not clear, particularly when considering the multiple cells of the immune system that are dependent on NFκB pathway.…”

“…Between the years 2003 and 2015, reports of 7 patients with AD-EDA-ID who underwent HSCT were published (Courtois et al 2003;Janssen et al 2004;Dupuis-Girod et al 2006;Lopez-Granados et al 2008;Fish et al 2009;Wu et al 2010;Schimke et al 2013;Yoshioka et al 2013;Scarselli et al 2015). A summary of patient characteristics can be found in Table 3.…”

B Cell Reconstitution and Influencing Factors After Hematopoietic Stem Cell Transplantation in Children

“…To obtain more insight in the mechanism and dynamics of B cell regeneration, κ-deleting recombination excision circles (KRECs) might serve as a useful biomarker for replication history and to evaluate the onset of de novo B-cells, as KRECs have been reported to be positively correlated with B cell numbers after transplantation (11–15). At one year after HSCT, the B cell reconstitution stabilizes reaching age-corrected normal total B cell counts in peripheral blood in most patients (Figure 1B) (16–20). Looking further into the B cell populations, non-switched (CD27+IgM+IgD+/-) and switched (CD27+IgD-IgM-) memory B-cells appear slowly, taking up to two years or longer after HSCT to reach normal age matched levels (16, 17, 20, 21).…”

T cell regeneration after immunological injury

“…However, restoration of the B cell compartment is primarily mediated by de novo regeneration from bone marrow progenitors. B cell recovery following HCT is reminiscent of B cell ontogeny 264,265 . Transitional CD19 + CD21 low CD38 hi B cells are the first B cells to emerge following HCT.…”