Single T cells under scrutiny
Hematological stem cell transplantation (HSCT) is a life-saving treatment of choice in many pediatric malignancies showing an inadequate response to standard chemotherapeutic approaches. In addition, HSCT is increasingly utilized as a curative option in non-malignant primary immunodeficiencies and hemoglobinopathies. (Read more)
One of the major limiting factors for the use of HSCT is the availability of suitable human leucocyte antigen (HLA) matched donors. Unfortunately, a fully matching HLA -transplant can be found for only 50-85% of pediatric patients in need. Furthermore, the search for a suitable registry donor may postpone the HSCT for up to two months; a possibly fatal delay in the case of critically ill patient.
Recently, haploidentical HSCT has enabled a successful transplantation from a donor sharing only 5/10 identical HLA profile. This approach has made it possible to quickly find a suitable donor to virtually all the patients in need. Especially in pediatric setting, where either one of the parents offers a reliable and readily available source of a haploidentical transplant, the proportion of haploidentical HSCT has been increasing rapidly.
In haploidentical transplantation, the mismatching HLA profile potentially elicits a strong immune response as these transplanted immune cells attack their new host. Unattended, this alloreactivity often results in graft failure and severe graft-versus-host disease (GvHD). In addition, similarly to traditional HSCTs, complete quantitative and qualitative restoration of acquired immunity may take years after HSCT predisposing patients to serious infections. Especially both primary diseases and reactivations of herpes viruses, are frequent and may cause significant complications.
To address these issues, the haploidentical HSCT grafts are processed by selectively enriching or depleting subtypes of immune cells, typically based on the specific cluster of differentiation (CD) molecules expressed on their surface. Indeed, besides stem cells to establish the new hematopoiesis, an optimal haploidentical HSCT graft would include functional T cells necessary to ward off infections but lack the immune cells responsible for GvHD.
Recent evidence suggests that the so-called naïve T cells seem to be responsible for much of the alloreactivity behind GvHD. On the contrary, the more matured memory T cells are unable to induce persistent GvHD. Furthermore, these memory T cells are capable of inducing a rapid immune response against viral infections. The better understanding of the molecular details regulating these processes would offer new insights both in the pathogenesis of GvHD and in the reconstitution of the immune system.
Interestingly, the rapid advances in high-throughput technologies are enabling the analysis of molecular processes on a level of individual cells. One of these new methods is single-cell RNA sequencing (mRNAseq) which offers us to analyse exact molecular processes, on a single T cell accuracy during the immune reconstitution post-HSCT.
In collaboration with University Hospital Frankfurt, a major center for pediatric haploidentical transplantation, we are setting up a study utilizing mRNAseq to analyse the T cell reconstitution in pediatric patients undergoing haploidentical HSCT. The data analysis is performed together with Eliisa Kekäläinen´s group here at HUCH. When successful, the project will reveal novel information on the restoration of immune system post-HSCT and offer new insights into the pathobiology of GvHD.
Being part of this project offers a great opportunity to get inspired by one of the leading pediatric HSCT centers in the world, to learn from the newest translational research methods available, and -what matters the most - to help our little patients.