Recovery of the immune system and resistance against infections in paediatric patients undergoing chemotherapy

The overall vision with our research is to provide an optimal life quality – in terms of resistance to infections – for children that have undergone or are undergoing treatment against cancers.

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To this end, our in vivo and in vitro projects examine in detail how cell cytotoxic treatments influence children’s immune responses to infectious agents. Both during an acute state, while the treatment is ongoing, as well as during long-term, after cessation of chemotherapy. Through further collaborations, we investigate how the recovery of the immune system and its functions, as well as chemotherapy efficacy itself, are influenced by the gut microbiome. In addition, in order to broaden and update our knowledge about infections among the paediatric population in Sweden, our ongoing clinical research projects assess vaccination coverage, and the prevalence and type of infections, in healthy children and children with underling comorbidities.

Research projects

Recovery of B-lymphocytes and antibody-mediated immune memory to vaccines after acute lymphoblastic leukaemia treatment – does the plasma cell niche matter?

The central benefit of vaccination is that it prevents disease by stimulating the formation of immune memory against administered immunogens. A robust immunity following vaccination is correlated with high levels of pathogen-specific protective antibodies produced by plasma cells, which originate from B-lymphocytes. Loss of protective antibodies against vaccine-preventable diseases is one of the usual side effects after chemotherapy treatment, and as a rule more common among paediatric compared to adult patients.

However, not all patients regain protective antibody titres despite revaccination. This may put them at risk of infection, that in turn aggravates the risk of late complications following cancer treatment. Here we aim to examine the cellular and molecular mediators behind defective antibody-mediated immune memory (humoral immunity) after paediatric cancer treatment by using lymphoblastic leukaemia (ALL) as our disease model. Cell lines and primary bone-marrow stromal cells are used to study factors important for plasma cell homing and survival in vitro, following Doxorubicin treatment. In addition to this experimental setup, we use in vivo animal models, and clinical material from patients under chemotherapy treatment to gain further insights to why defective humoral immunity emerges after ALL treatment.

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Anna Nilsson

Principal investigator

Contributing investigator:
Shanie Saghafian-Hedengren, PhD, Assistant Professor

PhD students and collaborators:
Gintare Lasaviciute, PhD student
Rayan Chikhi, PhD, CNRS Researcher
Staffan Eksborg, PhD, Adjunct Professor
Mikael Sundin, MD, PhD, Associate Professor
Francesca Chiodi, PhD, Professor
Eva Sverremark-Ekström, PhD, Professor

The short and long-term effects of conventional and metronomic chemotherapy regimens on the cell-mediated immune system of children

Despite the contribution of vaccines to global health, our immune system has the capacity to control the majority of infections by itself. Human herpesviruses belong to the latter category of infections, which are tightly controlled by our immune system after the initial encounter usually occurring in childhood. Through their long co-evolution with humans, following primary infection herpesviruses have managed to find mechanisms to hide from the immune system and persist in a clinically silent state for life. Despite this, some findings suggest that these viruses can influence the antibody-mediated immune response to vaccines and environmental antigens. In the otherwise healthy host, herpesvirus latency is a rule since T- and to some degree NK-cells, which can kill virus-infected cells, keep herpesviruses under control by constantly patrolling the body. In immunocompromised patients on the other hand, herpesviruses can become reactivated and cause serious health complications.

Through this project we want to understand how the capacity of T- and NK-cells to combat infectious agents is affected by current chemotherapy protocols and immunosuppressive drugs. After stimulation with Doxorubicin or Methotrexate, we monitor cell-mediated immune responses against two common herpesviruses, Epstein-Barr virus and cytomegalovirus. Within this context, the association between gut microbiota and priming of antiviral responses is investigated. The ongoing experiments are in vitro, with cells derived from healthy blood donors, paediatric cancer patients or patients with chronic disorders.

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Shanie Saghafian-Hedengren

Principal investigator:

Students and collaborators:
Gintare Lasaviciute, PhD Student
Anna Höbinger, PhD Student
Rayan Chikhi, PhD, CNRS Researcher
Mats Bemark, PhD, Scientist
Anna Nilsson, MD, PhD, Chief physician, Associate Professor
Eva Sverremark-Ekström, PhD, Professor

Serious complications following infectious diseases in healthy children and paediatric patients with underlying comorbidities

Infections are still one of the leading worldwide cause of death among children under 5 years. Despite a low mortality rate in Sweden, infectious diseases are among most common reasons behind health care contact, and hospitalization of children with or without underlying comorbidities. The pattern and type of childhood infections have changed along with changes in the national childhood vaccination programs. For instance, a marked reduction of children with pneumococcal meningitis was noted following introduction of the pneumococcal immunization in to the Swedish national vaccination program. Likewise, reported cases of measles infections from Swedish hospitals are very rare due to our high national measles vaccine coverage.

The clinical and epidemiological studies conducted here are together with paediatric infectious disease specialists, who assess the changes in infection type and patterns over time, during childhood. For instance, we monitor the coverage of the national childhood vaccination program in term and pre-term children. Our other study cohorts consist of both healthy children and those needing extra health care due to their underlying comorbidities, such as cancer and autoimmunity. Indeed, there are individual variations among paediatric cancer patients concerning episodes and severity of infections during and after chemotherapy treatment. We aim to understand the reason behind this observation by examining the connection between genetic polymorphisms in the innate immune system and infection type and frequency.

Principal investigator:
Anna Nilsson, MD, PhD, Chief physician, Associate Professor

Students and collaborators:
Joachim Luthander, MD, PhD Student
Cecilia Chrapkowska, MD, PhD Student
Johan Hamrin, MD, PhD student
Martina Söderman, MD, PhD Student
Joseph Mathew, MD, PhD
Anna Berggren, MD, PhD
Shanie Saghafian-Hedengren, PhD, Assistant Professor
Susanna Ranta, MD, Associate Professor
Eva Sverremark-Ekström, PhD, Professor