Cellular immunotherapy with ex vivo expanded cord blood T cells in a humanized mouse model of EBV-associated lymphoproliferative disease

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From: Immunotherapy(Vol. 7, Issue 4)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 3,548 words
Lexile Measure: 1930L

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Author(s): Go Matsuda aff1 , Ken-Ichi Imadome aff1 , Fuyuko Kawano aff1 , Masashi Mochizuki aff1 , Nakaba Ochiai aff2 aff3 , Tomohiro Morio aff2 aff4 , Norio Shimizu aff5 , Shigeyoshi Fujiwara [*] aff1 aff6

Keywords:

cord blood transplantation; donor lymphocyte infusion; Epstein-Barr virus; humanized mouse; lymphoproliferative disease

Background

Donor lymphocyte infusion (DLI) is an established therapy for recurrence of malignancy, opportunistic infections and mixed chimerism following treatment of various hematologic malignancies with bone marrow transplantation [ 1 ]. In DLI, a large number ([greater than]108 cells) of lymphocytes collected from a donor are infused to the corresponding recipient. Allospecific and/or virus-specific T-cell immune responses are supposed to play a role in eliminating the outgrowth of malignant cells and suppressing the spread of viral infection [1 ]. DLI is not feasible, however, for recipients of cord blood transplantation because the donors are mostly infants and cannot provide a large number of lymphocytes required for this therapy. The unavailability of DLI is thus a serious disadvantage of cord blood transplantation that is performed in increasing number of not only pediatric patients but also adult patients. To overcome this problem, we intended to use ex vivo expanded cord blood T cells as the material for DLI in recipients of cord blood transplantation. A procedure to expand cord blood T cells was developed [2,3 ] by modifying the previously established protocol for expanding peripheral blood T cells for use in adoptive immunotherapy of cancers and severe infections [4-7 ]. Pilot clinical studies revealed that infusion of ex vivo expanded cord blood-derived T cells was effective in repairing mixed chimerism following treatment of Omenn syndrome with cord blood transplantation [2 ]. Preparations of expanded cord blood-derived T cells were also effective in the treatment of ganciclovir-resistant cytomegalovirus infection and coxsackievirus colitis following cord blood transplantation [Morio et al ., Unpublished Data]. However, thorough preclinical studies of this novel therapy (tentatively called cord blood DLI) to prepare for a large-scale clinical trial were hampered by the absence of suitable animal models. Recently, we have developed a humanized mouse model of Epstein-Barr virus (EBV) infection that reproduced EBV-associated lymphoproliferative disease (LPD), a representative opportunistic infection following cord blood transplantation supposed as a target of cord blood DLI [8 ]. Human immune system components including T cells, B cells, NK cells, dendritic cells and macrophages were reconstituted in mice of the immunodeficient strain NOD/shi-scid /IL-2R[gamma]null following transplantation with hematopoietic stem cells derived from cord blood. Inoculation of these humanized mice with EBV resulted in the development of LPD remarkably similar to EBV-associated LPD in recipients of hematopoietic stem cell transplantation, with respect to histology, marker expression, and EBV gene expression [8 ]. In the present study, this mouse model was used as an in vivo system to evaluate the effect of cord blood DLI and the results indicated that it is effective in prolonging the survival of EBV-infected mice.

Materials & methods

Cord blood

Cord blood was supplied by the Tokyo Cord Blood Bank. Stocks that were not appropriate for transplantation due to low...

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Gale Document Number: GALE|A411322524