Abstract
Infection with and reactivation of human cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus (ADV) are frequent and severe complications in immunocompromised recipients after hematopoietic stem cell transplantation (HSCT) or solid organ transplantation (SOT). These serious adverse events are associated with significant morbidity and mortality. Donor lymphocyte infusions (DLIs) are often used to treat both viral infections and leukemia relapses after transplantation but are associated with potentially life-threatening graft-versus-host disease (GvHD). Adoptive immunotherapy with virus-specific cytotoxic effector T cells (CTLs) derived from seropositive donors can rapidly reconstitute antiviral immunity after HSCT and organ transplantation. Therefore, it can effectively prevent the clinical manifestation of these viruses with no significant acute toxicity or increased risk of GvHD. In conditions, where patients receiving an allogeneic cord blood (CB) transplant or a transplant from a virus-seronegative donor and since donor blood is generally not available for solid organ recipients, allogeneic third party T-cell donors would offer an alternative option. Recent studies showed that during granulocyte colony-stimulating factor (G-CSF) mobilization, the functional activity of antiviral memory T cells is impaired for a long period. This finding suggests that even stem cell donors may not be the best source of T cells. Under these circumstances, partially human leukocyte antigen (HLA)-matched virus-specific CTLs from healthy seropositive individuals may be a promising option. Therefore, frequency assessments of virus-specific memory T cells in HLA-typed healthy donors as well as in HSCT/SOT donors using a high throughput T-cell assay were performed over a period of 4 years at Hannover Medical School. This chapter will address the relevance and potential of a third-party T-cell donor registry and will discuss its clinical implication for adoptive T-cell immunotherapy.
Highlights
Hematopoietic stem cell transplantation (HSCT) is used to cure many malignant, benign and genetic disorders of the bone marrow, solid tumors, immunodeficiencies, metabolic, and autoimmune disorders (Ljungman et al, 2010)
We identified at least 61% potential CTL donors with highly significant differences in frequencies of T cells against each of the six viral antigens tested: pp65 and immediate early (IE)-1 (CMV), BZLF1, latent membrane protein 2A (LMP2A), and EBNA1 (EBV), and hexon (ADV)
The alloTCDR database will document the donors’ human leukocyte antigen (HLA)-type, virus serology (ADV, CMV, and Epstein-Barr virus (EBV)), virus-specific T-cell frequencies, best T-cell detection method, and results of functional and alloreactivity assays. This registry of HLA-typed allogeneic T-cell donors profiled for virus-specific T cells will ensure the rapid availability of T cells for adoptive immunotherapy of virusassociated diseases in transplant recipients without an adequate T-cell donor
Summary
Hematopoietic stem cell transplantation (HSCT) is used to cure many malignant, benign and genetic disorders of the bone marrow, solid tumors, immunodeficiencies, metabolic, and autoimmune disorders (Ljungman et al, 2010). Adoptive immunotherapy with virus-specific cytotoxic effector T cells (CTLs) derived from seropositive donors can rapidly reconstitute antiviral immunity after HSCT and organ transplantation.
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