CMV-, EBV- and ADV-Specific T Cell Immunity: Screening and Monitoring of Potential Third-Party Donors to Improve Post-Transplantation Outcome

Abstract

Adoptive immunotherapy with virus-specific T lymphocytes can efficiently reconstitute antiviral immunity against cytomegalovirus (CMV), Epstein-Barr virus (EBV), and adenovirus (ADV) without causing acute toxicity or increasing the risk of graft-versus-host disease. To gain insight into antiviral T cell repertoires and to identify the most efficient antigens for immunotherapy, the frequencies of CMV-, EBV- and ADV-specific T cells in 204 HLA-typed healthy donors were assessed using viral peptides and peptide pools. Confirmatory testing for CMV serology by Western blot technique revealed 19 of 143 (13%) false-positive results. We observed highly significant individual and overall differences in T cell frequencies against CMV, EBV, and ADV antigens, whereas antigen-specific T cells were detected in 100% of CMV- seropositive donors, 73% of EBV- seropositive donors, and 73% of ADV-seropositive donors. At least 124 (61%) potential T cell donors were identified for each virus. Among the tested antigens, frequencies for CMVpp65 and EBVBZLF1 peptide pools were highest. Short-term in vitro peptide stimulation revealed that a donor response to a certain ADV- and EBV-derived peptide may not be determined without prior stimulation. A modified granzyme B ELISpot was used to detect T cell specificity and alloreactivity. Treatment with allogeneic virus-specific cytotoxic T lymphocytes from seropositive third-party donors may be a feasible therapeutic option for infections following cord-blood stem cell transplantation or hematopoietic stem cell transplantation from virus-seronegative donors.

T-bet:Eomes Balance, Effector Function, and Proliferation of Cytomegalovirus-Specific CD8+ T Cells during Primary Infection Differentiates the Capacity for Durable Immune Control

“…Previous studies have shown adoptive T-cell therapy can be effective in controlling active CMV infection (17). Successful ex vivo expansion of CMV- specific cells from autologous patient PBMCs could provide broad HLA-restricted specificities to a major antigen such as pp65 compared to single HLA-restricted, matched donor-derived cells.…”

Fungal and viral infections after allogeneic hematopoietic transplantation from unrelated donors in adults: improving outcomes over time

“…[36][37][38][39] Further improvements in IRM, however, will probably require the use of adjuvant pharmacological or cellular-based therapies, which improve the long-term cellular and humoral immunities. [40][41] The main limitations of the present study are linked to the multicenter and retrospective design, although the conditioning regimens were quite homogeneous for myeloablative and reduced-intensity conditioning recipients, while CB recipients all followed the same national protocol. 17 However, as far as we know there are no previous studies analyzing the infectious morbidity and mortality over such a long period of time (12 years) and comparing the results of different UD sources.…”

Adenovirus Infections in Immunocompetent and Immunocompromised Patients

“…However, clinical implementation of this approach requires the availability of a large pool of HLA-typed healthy donors, and the use of incompletely HLA-matched T cells bears the risk of complications resulting from alloreactive side effects (264). Despite the existing concerns, this approach appears to be feasible, and current clinical results are encouraging (265). Another recently presented methodology is the generation of VST cell lines from healthy donors with common HLA polymorphisms (266).…”