Abstract
Induction of immune tolerance for solid organ and vascular composite allografts is the Holy Grail for transplantation medicine. This would obviate the need for life-long immunosuppression which is associated with serious adverse outcomes, such as infections, cancers, and renal failure. Currently the most promising means of tolerance induction is through establishing a mixed chimeric state by transplantation of donor hematopoietic stem cells; however, with the exception of living donor renal transplantation, the mixed chimerism approach has not achieved durable immune tolerance on a large scale in preclinical or clinical trials with other solid organs or vascular composite allotransplants (VCA). Ossium Health has established a bank of cryopreserved bone marrow (BM), termed “hematopoietic progenitor cell (HPC), Marrow,” recovered from deceased organ donor vertebral bodies. This new source for hematopoietic cell transplant will be a valuable resource for treating hematological malignancies as well as for inducing transplant tolerance. In addition, we have discovered and developed a large source of mesenchymal stem (stromal) cells (MSC) tightly associated with the vertebral body bone fragment byproduct of the HPC, Marrow recovery process. Thus, these vertebral bone adherent MSC (vBA-MSC) are matched to the banked BM obtained from each donor, as opposed to third-party MSC, which enhances safety and potentially efficacy. Isolation and characterization of vBA-MSC from over 30 donors has demonstrated that the cells are no different than traditional BM-MSC; however, their abundance is >1,000-fold higher than obtainable from living donor BM aspirates. Based on our own unpublished data as well as reports published by others, MSC facilitate chimerism, especially at limiting hematopoietic stem and progenitor cell (HSPC) numbers and increase safety by controlling and/or preventing graft-vs.-host-disease (GvHD). Thus, vBA-MSC have the potential to facilitate mixed chimerism, promote complementary peripheral immunomodulatory functions and increase safety of BM infusions. Both HPC, Marrow and vBA-MSC have potential use in current VCA and solid organ transplant (SOT) tolerance clinical protocols that are amenable to “delayed tolerance.” Current trials with HPC, Marrow are planned with subsequent phases to include vBA-MSC for tolerance of both VCA and SOT.
Highlights
SOT has become standard of care over the last half century, resulting in a significant life extension and an enhancement of quality of life (QOL) for end-stage organ failure patients [1, 2]
While chronic allograft failure is associated with more frequent hospitalization, higher morbidity and increased health care costs, chronic immunosuppression (IS) is linked to side effects that range from malignancy, infection, toxicities to cardiovascular and metabolic diseases [5,6,7,8,9,10,11,12,13,14,15]
Providing the protocol is amenable to a delayed tolerance approach, deceased donor HPC, Marrow could offer a distinct advantage for manufacture of facilitating cells (FC) given the high abundance of BM cells available and the enhanced time provided for manufacture and testing
Summary
SOT has become standard of care over the last half century, resulting in a significant life extension and an enhancement of quality of life (QOL) for end-stage organ failure patients [1, 2]. Of particular note is the increasing number of exploratory cell-based immunoregulatory and tolerizing therapies [29,30,31,32,33,34,35,36,37] One such immunomodulatory protocol that is already in clinical use utilizes unmodified deceased donor-derived BM cell infusion following HLA-mismatched VCA using a Campathbased induction regimen [38]. Superficially similar in that both approaches administer hematopoietic cells, there are fundamental differences with respect to safety and mechanisms between the mixed chimerism-based approaches that are currently used in clinical trials to promote tolerance in SOT and the immunomodulatory approach in clinical use for VCA. Current successes in clinical trials using these protocols to induce tolerance of SOT through mixed chimerism have been achieved exclusively in the setting of living donor kidney transplantation [39]. The full complement of mechanisms involved in augmentation is not known but at least partially involves supplementation with regulatory cell types and may additively involve alloreactive clonal T cell exhaustion and deletion [55]
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