Interleukin-7 Permits Th1/Tc1 Maturation and PromotesEx vivoExpansion of Cord Blood T Cells: A Critical Step toward Adoptive Immunotherapy after Cord Blood Transplantation

Abstract

Donor leukocyte infusions (DLI) in the allogeneic hematopoietic transplant setting can provide a clinically relevant boost of immunity to reduce opportunistic infections and to increase graft-versus-leukemia activity. Despite significant advances in applicability, DLI has not been available for single-unit recipients of unrelated cord blood transplant. Ex vivo expansion of cord blood T cells can be achieved with interleukin (IL)-2 and CD3/CD28 costimulatory beads. However, significant apoptosis occurs in proliferating T cells, diminishing the yield and skewing the CD4/CD8 ratio in the T-cell population, jeopardizing the potential efficacy of DLI. In this study, we show that interleukin (IL)-7 not only reduces apoptosis of activated T lymphocytes and enhances their proliferation but also promotes functional maturation, leading to secretion of IFN-γ and other key cytokines. Recognizing that infused T lymphocytes will need to meet microbial antigens in secondary lymphoid organs to generate effectors, we also show that expansion with IL-7 promotes the preservation of a polyclonal broad T-cell receptor repertoire and a surface phenotype that favors lymph node homing. Expanded lymphocytes lack alloreactivity against recipient and other allogeneic cells, indicating a favorable safety profile from graft-versus-host disease. Nevertheless, expanded T cells can be primed subsequently against lymphoid and myeloid leukemia cells to generate tumor-specific cytotoxic T cells. Taken together, our findings offer a major step in fulfilling critical numerical and biological requirements to quickly generate a DLI product ex vivo using a negligible fraction of a cord blood graft that provides a flexible adoptive immunotherapy platform for both children and adults. Cancer Res; 70(13); 5249-58. ©2010 AACR.

CMV reactivation drives posttransplant T-cell reconstitution and results in defects in the underlying TCRβ repertoire

“…Indeed, several of the traditional hallmarks of T-cell reconstitution, often attributed to post-HSCT immune reconstitution per se, [44][45][46][47][48][49][50][51] occurred exclusively in those patients that reactivated CMV. These included the inversion of the CD4:CD8 T-cell ratio, as well as the enhanced expression of the terminal differentiation marker CD57 52-55 on CD8 1 T cells in the 1CMV cohort.…”

PAX5 interacts with RIP2 to promote NF-κB activation and drug-resistance in B-lymphoproliferative disorders

“…Moreover, a large proportion of B-LPDs show a limited response to chemotherapy. To explore the relevance of PAX5 for drug resistance in B-LPDs, the PAX5-positive IM9 cell line was used as a representative PAX5-positive malignant B-cell line (Brien et al, 2007;Chu et al, 2014;Davis et al, 2010;Min et al, 2009;Shimizu et al, 2006). U266 and RPMI8226 cell lines were employed as PAX5-null multiple myeloma cell lines, and the Daudi cell line was used as a PAX5-positive Burkitt's-lymphomaderived B-lymphoblast representative (Fig.…”

Umbilical Cord Blood Immunology—Relevance to Stem Cell Transplantation

“…Strategies to improve UCB transplantation outcomes may include the administration of cytokines like IL-7 [75,76] and IL-15 [77] to enhance T cell reconstitution. The adoptive transfer of CD3/CD28-stimulated T cells may facilitate engraftment in UCB transplantation [78].…”