Abstract
We hypothesized that performing bone marrow transplant (BMT) using marrow extracted from the vertebral bodies (VB) of an unrelated deceased lung transplant (LTX) donor would be able to establish persistent hematopoiesis, generate immunity, and tolerance. A teenager with severe combined immunodeficiency with lung failure due to recurrent pneumonias underwent LTX in 2016 from a 1/8 HLA allele-matched unrelated donor, followed by BMT 4 months later using T-cell/B-cell-depleted, cryopreserved VB marrow. Rapid engraftment was followed by accelerating immune competence at 6 months, with independence from immunosuppression by 16 months. Donor T-cell (>95%) and myeloid chimerism (7-10%) have persisted for over nine years. At two years post-BMT, circulating T cells were hyporesponsive to host dendritic cells in vitro. T-cell receptor clonotyping revealed the disappearance of host-reactive clones, and T-cell RNA-sequencing exhibited downmodulated signaling pathways for cytotoxicity/rejection, paired with upregulated immunomodulatory pathways, suggesting active suppression. In parallel, host monocytes upregulated certain signaling pathways, indicating active interactions between post-thymic donor T cells and host monocytes. In summary, durable hematopoietic engraftment, immunity, and tolerance were demonstrable for the first time in a recipient of BMT obtained from VB graft.
Authors
Paul Szabolcs, Xiaohua Chen, Marian G. Michaels, Memphis Hill, Evelyn Garchar, Zarreen Amin, Heather M. Stanczak, Shawna McIntyre, Aleksandra Petrovic, Dhivyaa Rajasundaram, Ansuman Chattopadhyay, Jonathan E. Spahr, Peter D. Wearden, Geoffrey Kurland
