Editor's Note: Some of the articles described below are not yet available at the PNAS site, but they are scheduled to be posted some time this week.
In a paper set to appear in the Proceedings of the National Academy of Sciences this week, researchers from Harvard Medical School, the University of Groningen, and Dana-Farber Cancer Institute describe regulatory T cell immune system interactions that appear to dial down the risk of heart transplant rejection in mouse models. Through a series of flow cytometry, cell staining, and other experiments aimed at understanding immune responses in heart allograft recipient mice, the team found that the production of anti-allograft antibodies appeared to be staved off by a set of regulatory CD8+ T cells that interact with a major histocompatibility molecule called Qa-1 in mice or HLA-E in humans. "Since the production of anti-donor antibodies is currently a major barrier to successful transplantation, identification of this Qa-1/HLA-E-dependent pathway may pave the way to approaches to this pressing clinical problem," the authors note.
A University of Pennsylvania-led team presents a strategy for assessing gene regulation and insertion sites used by the lentiviral vectors used to deliver chimeric antigen receptor (CAR) sequences to T lymphocyte cells for CAR-T immunotherapy. The assay, known as EpiVIA, relies on the same transposase enzyme used in ATAC-seq to sequence lentiviral insertion sites and chromatin accessibility in individual or bulk cells, the researchers say — an approach they applied to cell lines, healthy donor cells, and cells from a CAR-T-treated chronic lymphocytic leukemia patient. "We report the development of an assay for the joint profiling of the epigenome and lentiviral integration site analysis at population and single-cell resolutions," they write. "We anticipate that our method should enable discovering cellular fates associated with durable CAR-T treatment."
Finally, members of an international team led by investigators at St. Jude Children's Research Hospital take a look at NUDT15 gene variants involved in thiopurine toxicity in patients receiving the purine antimetabolite treatment. Following from prior studies pointing to ties between NUDT15 polymorphisms and hematopoietic thiopurine toxicity, the team used a massively parallel variant function assay to uncover NUDT15 missense variants that impact the stability or activity of the enzyme encoded by it. They further note that the functional analyses of such NUDT15 variants "accurately predicted toxicity risk alleles in patients treated with thiopurines with far superior sensitivity and specificity compared to bioinformatic prediction algorithms."