Downregulation of Interleukin-13 by PUVA Treatment in a Human Model of Graft-Versus-Host Disease May Highlight the Importance of This Cytokine in the Mechanism of Extracorporeal Phototherapy Treatment.

Graft-versus-Host disease (GvHD) remains the most serious complication following haemopoietic stem cell transplantation, with an incidence of 40–60% and can be fatal in up to 50% of cases. Extracorporeal phototherapy (ECP) is a novel treatment of both acute and chronic GvHD involving psoralen and UVA (PUVA) treatment of peripheral blood cells with high reported success even in those resistant to conventional immunosuppressive treatments. ECP appears to induce selective immune suppression without increased rates of infection or disease relapse. It is well tolerated by patients with minimal side effects and therefore is emerging as a highly desirable therapy. However, its mechanism of action remains poorly understood. An in vitro human skin explant model for GvHD has been used to study the role of cytokine changes induced by ECP. The model involves sensitising donor lymphocytes with recipient lymphocytes in vitro in a primary mixed lymphocyte reaction and then evaluating the secondary response on recipient skin biopsies by grading the graft-versus-host reactivity (grades I-IV) histopathologically using the Lerner grading system for GvHD. The assay has been proved to be superior to other assays used to predict clinical GvHD and has been used to investigate the pathophysiology of GvHD. Skin explant supernatants were collected and stored at −80 C and measured in batches using a multiplex Th1/Th2 cytokine assay. In 20 experiments where PUVA treatment of responder cells caused down regulation of GvHR in the skin explant model, statistically significant downregulation of IL-13, IL-5 and IFNgamma (p=<0.05) was demonstrated. No changes of IL-6, IL-1b, IL-10, IL-2, IL-4 or TNFalpha levels were demonstrated. Further evidence for the importance of IL-13 was highlighted in 3 skin explant assays where no downregulation of GvHR was seen with PUVA treatment and IL-13 levels remained high. Jordon et Al (Blood Jan2004) have documented the association between IL-13 production and the incidence of acute GvHD. Our data adds further evidence to challenge the notion that acute GvHD is purely a Th1-type cytokine response and that there may be a significant link between the Th2-type cytokine IL-13 with acute GvHD. Furthermore, downregulation of IL-13 and by PUVA may be important in the control of GvHD. More skin explant assays will be performed to consolidate these provisional findings.