Donor chimerism and immune reconstitution following haploidentical transplantation in sickle cell disease. Front Immunol 2022;13:1055497
Date
12/27/2022Pubmed ID
36569951Pubmed Central ID
PMC9780682DOI
10.3389/fimmu.2022.1055497Scopus ID
2-s2.0-85144637382 (requires institutional sign-in at Scopus site)Abstract
INTRODUCTION: We previously reported the initial results of a phase II multicenter transplant trial using haploidentical parental donors for children and aolescents with high-risk sickle cell disease achieving excellent survival with exceptionally low rates of graft-versus-host disease and resolution of sickle cell disease symptoms. To investigate human leukocyte antigen (HLA) sensitization, graft characteristics, donor chimerism, and immune reconstitution in these recipients.
METHODS: CD34 cells were enriched using the CliniMACS® system with a target dose of 10 x 106 CD34+ cells/kg with a peripheral blood mononuclear cell (PBMNC) addback dose of 2x105 CD3/kg in the final product. Pre-transplant HLA antibodies were characterized. Donor chimerism was monitored 1-24 months post-transplant. Comprehensive assessment of immune reconstitution included lymphocyte subsets, plasma cytokines, complement levels, anti-viral T-cell responses, activation markers, and cytokine production. Infections were monitored.
RESULTS: HLA antibodies were detected in 7 of 11 (64%) evaluable patients but rarely were against donor antigens. Myeloid engraftment was rapid (100%) at a median of 9 days. At 30 days, donor chimerism was 93-99% and natural killer cell levels were restored. By 60 days, CD19 B cells were normal. CD8 and CD4 T-cells levels were normal by 279 and 365 days, respectively. Activated CD4 and CD8 T-cells were elevated at 100-365 days post-transplant while naïve cells remained below baseline. Tregs were elevated at 100-270 days post-transplant, returning to baseline levels at one year. At one year, C3 and C4 levels were above baseline and CH50 levels were near baseline. At one year, cytokine levels were not significantly different from baseline.
DISCUSSION: These results suggest that haploidentical transplantation with CD34-enriched cells and peripheral blood mononuclear cell addback results in rapid engraftment, sustained donor chimerism and broad-based immune reconstitution.
Author List
Chu Y, Talano JA, Baxter-Lowe LA, Verbsky JW, Morris E, Mahanti H, Ayello J, Keever-Taylor C, Johnson B, Weinberg RS, Shi Q, Moore TB, Fabricatore S, Grossman B, van de Ven C, Shenoy S, Cairo MSAuthors
Bryon D. Johnson PhD Adjunct Professor in the Medicine department at Medical College of WisconsinJulie-An M. Talano MD Professor in the Pediatrics department at Medical College of Wisconsin
James Verbsky MD, PhD Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Anemia, Sickle CellChild
Chimerism
Cytokines
Hematopoietic Stem Cell Transplantation
Humans
Immune Reconstitution
Leukocytes, Mononuclear
Transplantation, Haploidentical
