Immune Regulation and Tolerogenic Mechanisms in Organ Transplantation

This research project is focused on mechanisms that regulate the immune system prior to and after solid organ transplantation. The primary function of the immune system is to combat viral and bacterial infections and eradicate malignant cells. After transplantation the immune system will be activated and mount an immune response against the transplant and reject it. Immunosuppressive medication is administered in order to avoid rejection, but these are associated with increased risk for infections and malignancies. In this project, we have studied the mechanisms that regulate the immune system in order to establish new therapeutic avenues for patients that receive kidney, pancreas and liver transplants. Our primary objective has been to map the mechanisms that a particular type of T cells called regulatory T cells utilize. These cells are suppressive, and manipulating the activity of these cells may inhibit rejection reactions. We have published our findings that in detail describe how these cells work at the molecular level and we have recently identified a substance that selectively modulate the functions av regulatory T cells. We are also conducting clinical studies of kidney, pancreas and liver recipients with the aim of exploiting our experimental studies in clinical practise. In pancreas recipients, we have shown that parts of the transplant have different risk for rejection. This have changed how we evaluate rejection reactions in these patients, and will be important for future surveillance of the grafts. From all transplant recipients, we have taken blood samples prior to and at intervals after transplantation, and it will be interesting to see whehter the same phenomenon is present in liver recipients that we evaluate in a parallell study. The patients that have experienced rejection reactions have been studied in detail. These studies are challenging because the ordinary immunosuppressive medication greatly influence the immune responses that we want to measure, however we want to investigate the combined effects of immune suppression with alloreactivity. The last year we have completed the analyses of samples from diabetic patients that receive pancreas transplants. These patients receive intense immunosuppressive treatment in order to avoid rejection, and our results indicate that changes in the first weeks after transplantation may be correlated to the risk for rejection later on. These results are important as they can be exploited to individualize the treatment to avoid rejection. The effects of the immunosuppressive medication is also important to determine as it likely inhibits all immune cells - including the regulatory T cells. This is not beneficially as ideally these cells should be preserved. Future treatment may be able to only suppress the cells involved in the rejection reactions. We hope and believe that the knowledge of these important mechanisms that regulate the immune system will be used in clinical practice in order to increase the graft survival, improve the life quality and increase the patient survival of transplant recipients.

Prosjektet har identifisert molekylære mekanismer som er aktive i en subgruppe av immunceller som kalles regulatoriske T celler. Mekanismene vi har kartlagt gir en generell forståelse av hvordan immunapparatet fungerer, og er egnet for fremtidig terapeutisk manipulering. Prosjektet har også ledet frem til pågående studier av en substans som kan benyttes selektivt til å manipulere funksjonen av de regulatoriske T cellene. Prosjektet har også bidratt til endrede prosedyrer for overvåking av pasienter som er transplantert med bukspyttkjertel (pancreas) for alvorlig diabetes type I. Vi har parallelle studier av andre pasientgrupper også (blant annet levertransplanterte), men for pancreastransplenterte pasienter har prosjektet ført til praktiske endringer i oppfølgingen. Det avgjørende er at ulike deler av transplantatet er ulikt utsatt for rejeksjon og for å optimalisere graftfunksjon og overlevelse har vi endret måten transplantatene blir vurdert på.

The group aims to elucidate molecular mechanisms of immune cells that are involved in human disease. Regulatory T (TR) cells represent a subset of CD4+ T helper cells with potent immunosuppressive properties that play a key physiologic role in maintaining immune tolerance and to prevent autoimmunity. TR cells also contribute to and are involved in various immune-related diseases including cancer, chronic infectious diseases and host-versus-graft rejection reactions after cell- and organ transplantation. T o avoid host-versus-graft immune responses after cell- and organ transplantation, therapeutically enhanced TR-cell function may be an important strategy to achieve graft immune tolerance. Therefore, TR cells represent an attractive target for future immun e therapy for various clinical conditions. Acute and chronic rejection after organ transplantation is the most important negative contributor to the short- and long-term prognosis of transplants recipients. In kidney transplants, acute rejection episode s lead to accumulated tissue destruction and fibrosis and reduced graft function, whereas chronic rejection leads to chronic allograft nephropathy (CAN) and reduced graft survival. Modern immunosuppressive treatment protocols are efficient in controlling acute rejections, whereas CAN remains a therapeutic challenge that severely affect the prognosis of kidney transplant recipients and often leads to re-transplantation. However, efficient immunosuppression comes at the expense of the ability of the immune system to combat infections and prevent tumor formation. In addition, calcineurin inhibitors, which are included in most immunosuppressive treatment protocols, are nephrotoxic. Novel treatment strategies aimed to induce allograft immune tolerance represen t the holy grail in organ transplantation, and therapeutic manipulation of TR cells in order to induce immune tolerance may be an effective strategy for organ transplant recipients.