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Pediatric Research Center

The Pediatric Research Center currently represents almost 30 research groups carrying out clinical, translational and basic research in pediatrics in the University of Helsinki, Finland. Our mission is to promote research, to communicate the latest research results to physicians, patients and the general public, and to serve as a reference guide for researchers and companies seeking academic collaboration.  We warmly invite students and young physician-scientists to join our growing team!

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.

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.

NEW INSIGHTS INTO RSV DISEASE

In developed countries respiratory syncytial virus (RSV) causes busy epidemics during winter seasons but fortunately with very low levels of mortality in children. However, in developing countries the situation is different. In a recent meta-analysis it was estimated that globally RSV causes more than 100 000 deaths in children <5 years of age every year (Shi et al. Lancet 2017) and RSV is considered the second most important pathogen causing mortality in children only after malaria (Lozano et al. 2012 Lancet). This is something that we pediatricians in Finland and other developing countries often forget when we worry about crowded emergency departments, overfilled wards and busy on call shifts every winter during RSV epidemics.

Despite decades of research efforts there are no vaccines against or effective antivirals available for RSV. Vaccine development has been challenging after unfortunate clinical trials with inactivated RSV vaccine in 1960s, which not only failed to protect children from RSV but also caused enhanced disease in RSV naïve children with two study participants dying due to severe disease. Furthermore, as natural infection with RSV fails to produce protective immune response leading to re-infections throughout lifetime, inducing protective immunity will be a challenge also for the vaccine development. We still lack complete understanding of the immunological mechanisms contributing to increased disease severity and poor immune responses in children with RSV.

During my post doctoral training I worked in Nationwide Children’s Hospital in Columbus, Ohio in Asuncion Mejias’ and Octavio Ramilo’s group focusing on immunological host responses in children with viral respiratory tract infections. We used systems analysis approach with an aim to combine flow cytometry derived cellular immunophenotype data and transcriptomic data from peripheral white blood cells with detailed clinical and microbiological data.

In Columbus, we used microarray based methods for the transcriptome analyses but in the past few years more powerful methods have been developed. Microarray based methods have been replaced by RNA sequencing (RNAseq) and advances in microfluidics and nanotechnology have enabled transcriptome analyses at single cell level. Earlier we analyzed pooled RNA from large number of cells but these novel methods allow us to simultaneously obtain thousands of single cell transcriptomes from each patient sample.

After returning from Columbus a few years ago, I first wanted to focus on clinical work in order to advance my pediatric residency but I soon found myself planning new research projects. During the past winter season we started enrolling infants with RSV bronchiolitis in our study where we aim to take advantage of novel methods and use single cell RNAseq to gain better understanding of the host immune responses during RSV infection. The study will be conducted in collaboration with Päivi Saavalainen’s group from the University of Helsinki. Now that the RSV epidemic is over for this year, we will continue to enroll healthy controls. What constantly keeps amazing me is the positive attitude of the parents towards our study and research in general. Even if our study has no potential to help their sick child, they are willing to participate in order to help other children in the future. None of the parents we’ve approached so far have declined to participate in our study and we are truly thankful to all participating families.

I feel privileged to be able to continue research activities in parallel with my pediatric residency. For this I’m grateful for the flexibility of my supervisors in the Children’s Hospital and our residency program in the University of Helsinki and for the support from the Pediatric Research Center.

A NOVEL THERAPY TRIAL FOR AGU DISEASE AT HUCH

We have recently started a novel investigator initiated therapy trial for AGU (aspartylglucosaminuria) with betaine in HUCH child neurology clinic. It is performed in collaboration with Prof. Ritva Tikkanen, University of Giessen. AGU is a progressive disease leading to mental retardation due to the accumulation of aspartylglucosamine in all tissues and also in the brain. It belongs to the Finnish disease heritage, and most of the patients are from Finland (about 160 alive patients). AGU disease is diagnosed by urine oligosaccharides at the average age of five, when global developmental delay is noticed. (Read more)

Monogenic primary immunodeficiencies reveal new concepts of immune regulation

Rapid development of next generation sequencing (NGS) technologies and decreased costs of the whole exome and genome sequencing coupled with modern biochemistry and cellular biology methodology, have made identification of novel disease-causing gene mutations routine. Primary immunodeficiency diseases (PIDDs) are a clinically heterogeneous group of clinical entities caused by mutations in the genes which control the immune responses. Most of the PIDDs are monogenic rare disorders that follow Mendelian inheritance. (Read more)

New treatment options for neuromuscular diseases

We really live in a changing world of medicine. Majority of research in medicine aims at seeking new and better treatment options. All neuromuscular diseases are rare diseases, and most of them without specific treatments. Now first medicines for the most common childhood-onset neuromuscular diseases, Duchenne muscular dystrophy and spinal muscular atrophy, have become available, and novel therapies have filled the community with hope, but at the same time new questions and concerns have raised – is it safe? Is it really effective? Is it cost-beneficial? Is it ethical? Is it equal? (Read more)