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FRIMED2-FRIPRO forskerprosjekt, medisin og helse

Innate lymphocyte-based strategies to predict and prevent acute graft-versus-host disease after HSCT.

Alternative title: Strategier basert på innate lymfoide celler for å predikere og forhindre akutt graft-versus-host reaksjon etter HSCT.

Awarded: NOK 7.6 mill.

Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for many blood cancers, such as leukemia and lymphoma. With this treatment, a patient is transplanted with stem cells from a donor that will give rise to new immune cells that may target the cancer. The treatment is associated with serious complications. Among these, graft-verus-host reactions may arise when the donor immune cells attack the patient's tissues, particularly intestines, lung, and skin. We have studied how a newly defined group of lymphocytes, termed "innate lymphoid cells" (ILC), respond to the disease, in order to evaluate their usefulness for future cellular therapies. For this purpose we have utilize a rat model for GvHD in order to study the ILCs before and during disease in different tissues and organs. As part of this study we performed an in-depth characterization of rat ILCs, and confirmed that rat ILCs are remarkably similar to human ILCs with respect to phenotype and tissue localization. We also linked intestinal ILC abundance with particular microbiotic taxa indicative of close crosstalk. This work has been published. We have further found that two sub-groups of ILCs are dysregulated in affected tissues during GvHD. One of the groups are NK cells, and we have found that there is an accumulation of immature NK cells in affected tissues, and that the fraction of mature NK cells are functionally exhausted. This indicates a developmental block in NK cell maturation that could possibly impact their ability to control the pathologic T cells. This work is currently in manuscript form. Further, we found tissue-specific changes in ILC3s, and have characterized changes in microRNA expression during GvHD. MicroRNAs have an important immune regulatory activity. This work is also currently in manuscript form. We initially aimed to test therapeutic utility of ILCs to ameliorate GvHD, but was unable to conduct these studies due to technical limitations.

Vi har med prosjektet ekspandert vår viten om hvordan medfødte lymfocytter som NK-celler og ILC blir påvirket under utvikling av sykdommen akutt GvHD. Dette er viktig informasjon for å kunne nå i etterkant utvikle nye terapier basert på å reversere de negative virkningen sykdommen har på cellene, og å re-etablere cellenes beskyttende funksjon under kroppens barrierevev som tarm, lunge og hud. Dette vil forhåpentligvis til slutt komme pasientene til gode, da det er et stort behov for nye innovative terapeutiske løsninger for pasienter med GvHD. Vi håper at dataene kan danne grunnlag for utvikling av biologiske legemidler rettet mot NK-celler og ILC, gjennom et kommersielt løp med utspring fra forskningsgruppen.

Hematopoietic stem cell transplantation (HSCT) is used to treat a number of haematological cancers (e.g. leukemia and lymphomas) and other haematological and autoimmune diseases. More than 50.000 HSCT are performed annually worldwide, with the numbers increasing each year. Success of the treatment is still hampered by frequent occurrence of acute graft-versus-host disease (aGvHD), which is life-threatening and that significantly decrease the quality of life for the patients. While there has been progress in approaches to prevent aGvHD, there has been little advancement in the treatment of patients with aGvHD, which rely predominantly on systemic corticosteroids that is associated with substantial side effects. With this project we aim to increase the success of allo-HSCT (where patients are transplanted with hematopoietic stem cells from another person) by focusing on a relatively novel group of immune cells; the innate lymphoid cells (ILCs). We believe that certain groups of ILCs may be used therapeutically to prevent or reduce the severity of aGvHD. We will test cellular therapies in a previously established rat model of aGvHD, focusing on treatment of intestinal aGvHD. To select optimal groups of ILCs for therapy, we will extensively characterize ILCs from rat intestines at steady-state and during aGvHD. Data from the rat will be compared to immunophenotyping of ILCs in human gut biopsies from patients suffering from aGvHD. Due to general difficulties in obtaining gut biopsies for research, little is known about ILCs in human intestines during aGvHD. Our approach is multidisciplinary, and includes collaborations with world-leading international and national experts on HSCT/GvHD and innate immune cells.

Funding scheme:

FRIMED2-FRIPRO forskerprosjekt, medisin og helse

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