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Cytotherapy. 2019 Nov 26. pii: S1465-3249(19)30864-3. doi: 10.1016/j.jcyt.2019.10.003. [Epub ahead of print]

Ex vivo immunological evaluation of stable mixed chimeric patients after matched related donor allogeneic transplantation in sickle cell disease.

Author information

1
Cellular and Molecular Therapeutics Branch, National Heart Lung and Blood Institutes/National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
2
Cellular and Molecular Therapeutics Branch, National Heart Lung and Blood Institutes/National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA. Electronic address: johntis@mail.nih.gov.

Abstract

BACKGROUND AIMS:

Allogeneic hematopoietic stem cell transplantation is curative for sickle cell disease, and the use of matched related donors, non-myeloablative conditioning and sirolimus immunosuppression results in stable mixed chimerism without graft-versus-host disease (GVHD). However, the time to terminate sirolimus while maintaining mixed chimerism is unclear.

METHODS:

In this study, we developed a two-way mixed lymphocyte reaction (MLR) to evaluate ex vivo immunoreaction in mixed chimeric patients.

RESULTS:

In co-culture of peripheral blood mononuclear cells (PBMCs) from two healthy controls (without irradiation), we detected proliferation at various ratios of PBMC mixtures (1:9 to 9:1) as well as various concentrations of sirolimus, suggesting that two-way MLR is applicable to patients (having >10% chimerism) undergoing sirolimus treatment. In two-way MLR using PBMCs (including donor and recipient cells) from mixed chimeric patients (n = 28), greater ex vivo proliferation was observed <6 months compared with >6 months post-transplant and healthy control PBMC monoculture. Robust ex vivo proliferation was observed in a patient with acute GVHD, and persistent ex vivo proliferation (until 2 years) was observed in a patient with decreasing donor chimerism.

CONCLUSIONS:

In summary, we demonstrated that in two-way MLR, ex vivo immunoreaction decreases to low levels ~6 months post-transplant. These findings suggest a rationale to continue immunosuppression for 6 months.

KEYWORDS:

hematopoietic stem cell transplantation; matched related donor; mixed chimerism; mixed lymphocyte reaction; regulatory T cells; sickle cell disease; sirolimus

PMID:
31784240
DOI:
10.1016/j.jcyt.2019.10.003

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