Post-Transplantation B Cell Function in Different Molecular Types of SCID

Abstract

Purpose Severe combined immunodeficiency (SCID) is a syndrome of diverse genetic cause characterized by profound deficiencies of T, B and sometimes NK cell function. Non-ablative HLA-identical or rigorously T cell-depleted haploidentical parental bone marrow transplantation (BMT) results in thymus-dependent genetically donor T cell development in the recipients, leading to a high rate of long-term survival. However, the development of B cell function has been more problematic. We report here results of analyses of B cell function in 125 SCID recipients prior to and long-term after non-ablative BMT, according to their molecular type. Methods Studies included blood immunoglobulin measurements; antibody titers to standard vaccines, blood group antigens and bacteriophage Φ × 174; flow cytometry to examine for markers of immaturity, memory, switched memory B cells and BAFF receptor expression; B cell chimerism; B cell spectratyping; and B cell proliferation. Results The results showed that B cell chimerism was not required for normal B cell function in IL7Rα-Def, ADA-Def and CD3-Def SCIDs. In X-linked-SCID, Jak3-Def SCID and those with V-D-J recombination defects, donor B cell chimerism was necessary for B cell function to develop. Conclusion The most important factor determining whether B cell function develops in SCID T cell chimeras is the underlying molecular defect. In some types, host B cells function normally. In those molecular types where host B cell function did not develop, donor B cell chimerism was necessary to achieve B cell function. 236 words

Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency

“…Following GT, all patients reported infection AEs, including severe, opportunistic, and urinary tract infections. Infections of the respiratory and gastrointestinal tracts were the most frequently reported AEs; these organ systems are targets for infections in both ADA-SCID 42 and normal pediatric populations. 36 Following GT, the majority of infectious AEs were not serious, and all infectious AEs resolved.…”

Long-term outcome of hematopoietic stem cell transplantation for IL2RG/JAK3 SCID: a cohort report

“…11 One study suggested that donor B-lymphocyte chimerism is required for establishment of functioning B lymphocytes in IL2RG, JAK3, and VDJ-recombinant defect SCID genotypes. 12 Sustained thymopoiesis and donor Blymphocyte chimerism may require administration of myeloablative preparative regimens 7,13,14 and modified T-lymphocyte depletion techniques. 15 Long-term immune function may impact on subsequent health-related quality of life (QoL) and presence or absence of ongoing medical issues, which may be dependent on prior use of a preparative regimen.…”

Mini Review: Screening and Management of Late Effects in Patients with Severe Combined Immunodeficiency after Allogeneic Hematopoietic Cell Transplantation

“…Overall, poor B cell reconstitution defined by continued need for IVIG replacement is common (15% to 58%) on long-term follow-up 11,13,23 . Patients with IL7Rα, CD3, and ADA SCID are more likely to recover B cell immunity, as host B cells may function normally with competent donor T-cell help 23 . Conversely, IL2RG and JAK3 SCID patients have intrinsically dysfunctional B cells and require donor B cell engraftment for normal B cell function post-HCT 23 .…”

“…Patients with IL7Rα, CD3, and ADA SCID are more likely to recover B cell immunity, as host B cells may function normally with competent donor T-cell help 23 . Conversely, IL2RG and JAK3 SCID patients have intrinsically dysfunctional B cells and require donor B cell engraftment for normal B cell function post-HCT 23 . The use of either myeloablative or reducedintensity conditioning, particularly busulfan-containing regimens, is associated with improved ability to achieve B cell engraftment and immunoglobulin independence in all forms of SCID.…”

“…Immunoglobulin levels (IgA, IgG, and IgM) and isohemagglutinin titers should also be followed as indices of normal B cell function. The presence of switched memory B cells (CD19+/CD27+/IgD-) to demonstrate normal B cell maturation may also be useful 23 .…”