NYMC Faculty Publications

Donor Chimerism and Immune Reconstitution Following Haploidentical Transplantation in Sickle Cell Disease

Authors

Yaya Chu, Department of Pediatrics, New York Medical College, Valhalla, NY, United States.Follow
Julie-An Talano, Department of Pediatrics, Hematology/Oncology and BMT, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI, United States.
Lee Ann Baxter-Lowe, Department of Pathology, Children's Hospital of Los Angeles, University of Southern California, Los Angeles, CA, United States.
James W. Verbsky, Department of Pediatrics, Hematology/Oncology and BMT, Children's Hospital of Wisconsin, Medical College of Wisconsin, Milwaukee, WI, United States.
Erin Morris, Department of Pediatrics, New York Medical College, Valhalla, NY, United States.
Harshini Mahanti, Department of Pediatrics, New York Medical College, Valhalla, NY, United States.
Janet Ayello, Department of Pediatrics, New York Medical College, Valhalla, NY, United States.Follow
Carolyn Keever-Taylor, Department of Medicine, Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, United States.
Bryon Johnson, Department of Medicine, Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, United States.
Rona S. Weinberg, New York Blood Center, New York, NY, United States.
Qiuhu Shi, Department of Epidemiology and Community Health, New York Medical College, Valhalla, NY, United States.
Theodore B. Moore, Department of Pediatrics, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, United States.
Sandra Fabricatore, Department of Pediatrics, New York Medical College, Valhalla, NY, United States.
Brenda Grossman, Department of Pathology and Immunology, Washington University, St Louis, MO, United States.
Carmella van de Ven, Department of Pediatrics, New York Medical College, Valhalla, NY, United States.
Shalini Shenoy, Department of Pediatrics and Transfusion Medicine, Washington University, St Louis, MO, United States.
Mitchell S. Cairo, Department of Pediatrics, New York Medical College, Valhalla, NY, United States.Follow

Author Type(s)

Faculty

DOI

10.3389/fimmu.2022.1055497

Journal Title

Frontiers in Immunology

First Page

1055497

Document Type

Article

Publication Date

1-1-2022

Department

Pediatrics

Second Department

Public Health

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 10 CD34 cells/kg with a peripheral blood mononuclear cell (PBMNC) addback dose of 2x10 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.

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