Cytokine production in allogeneic haematopoietic stem-cell transplantation patients

Sammanfattning: Severe immunological complications may occur after haematopoietic stem-cell transplantation (HSCT). These include acute graft-versus-host disease (GVHD), veno-occlusive disease of the liver (VOD) and severe infections. Since cytokines control the behaviour of all cells involved in the immune system, it has been proposed that dysregulation of the cytokine network may be involved in these complications. We determined the serum levels of cytokines during pretransplant conditioning and during various complications. We found increased serum levels of TNF-[alpha] during conditioning in patients who later developed moderate to severe acute GVHD. Furthermore, high levels of TNF-[alpha] were associated with a lowered risk of relapse among patients with malignant disease. Diagnoses like CML and MDS were also associated with higher levels of TNF-[alpha] Another feared complication is VOID, with an incidence of 10% - 70% and a mortality rate of 30%-50%. The initiating factor appears to be endothelial injury caused by chemotherapy or chemo-radiotherapy. We found increased levels of soluble IL-2 receptors (slL-2R) during VOID. This indicates an activation of the immune system during such a complication since IL-6 and IFN-[gamma] had also increased. We likewise found extremely high levels of IL-8 during severe VOD. This is probably a marker of the extent of tissue damage. Such findings may be used as diagnostic tools and prognostic markers of VOID. A non-invasive diagnostic tool is valuable since biopsy may cause haemorrhage because the patients are often refractory to platelet transfusions during VOID. The highest levels of IL-10 occurred early during acute GVHD, with decreasing levels when GVHD persisted. Since IL-10 is an inhibitor of inflammatory reactions, this may represent an inadequate attempt by the immune system to reverse an inflammatory state. In an analysis of the serum levels of various cytokines in sibling HSCT recipients, we found a correlation between IVIG treatment and decreased serum levels of i) sIL-2R, IL-3, IL-4 and GM-CSF in patients with no complications, ii) IL-1ra in patients with acute GVHD and iii) IL-1 0 in those with CMV infection. Using an unrelated donor, anti-T-cell antibodies was added to the conditioning regimen to reduce the risk of rejection and GVHD. We compared the outcome using three antibodies. The highest incidence of acute GVHD II-IV occurred in patients treated with OKT-3. Marked increase in the release of inflammatory cytokines like IL-2, IFN-[gamma], TNF-[alpha] and GM-CSF were found after OKT-3 treatment. This may explain why the incidence of GVHD was increased in this group, since patients with high levels of TNF-[alpha] run a greater risk of developing GVHD. The lowest incidence of GVHD was found after treatment with Thymoglobuline. This antibody was also the most effective in depleting T-cells. In patients with CML relapses occurred only in those treated with Thymoglobuline. Conclusion: Dysregulation of cytokines is involved in the induction and effector phase of complications like acute GVHD and VOD after HSCT. This dysregulation is initiated during pre-transplant conditioning. Modulation of cytokines may be used for prevention or treatment of such complications. Cytokine analysis are also useful diagnostic tools.