Kinetics of Serum Macrophage Migration Inhibitory Factor (MIF) and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) in Allogeneic Stem Cell Transplantation.
Authors: Toubai Tomomi , Tanaka Junji , Ota Shuichi , Sugita Junichi , Kato Naoko , Kondo Keiichi , Iwao Noriaki , Asaka Masahiro , Imamura Masahiro 
Published: April 2020

Buckgrand. Graft-versus host disease (GVHD) is a major complication after hematopoietic stem cell transplantation (HSCT). Macrophage migration inhibitory factor (MIF) plays a pivotal role in systemic as well as local inflammatory and immune responses. Recent reports that MIF expression is up-regulated in the allo-immune reaction during renal transplantation. Otherwise, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a type II transmembrane protein belong to the TNF family. The level of TRAIL expression in T cells as well as NK cells can be markedly up-regulated after cell activations. In this study we report that kinetics of serum level of MIF and TRAIL in GVHD patients before and after HSCT.

Patients and Methods. Date randomly obtained from 16 patients (10 males and 6 females) who underwent allo-SCT for treatment of hematological malignancies at Hokkaido University Hospital during the period May 2001 to January 2005. All patients were informed consent of peripheral blood smpling. Eight patients were received conventional transplantation and the others were reduced intensity stem cell transplantation (RIST). Seven patients have HLA identical sibling donor, but the others were received unrelated donor. Twelve of the 16 patients was achieved acute GVHD (aGVHD), gradeIto IIin 8 patients. Twelve patients survived day 100 after allo-SCT, 9 of those 12 patients developed chronic GVHD(cGVHD). Serum MIF and TRAIL concentration were measured at various time points using enzyme-linked immunosorbent assays (ELISAs).

Results. Serum MIF concentration analysis by ELISA showed that only patients who developed aGVHD significantly increased (two folds) before and after allo-SCT (avelage, from 7.34 ng/ml before allo-SCT to 14.7 ng/ml after allo-SCT, p=0.018). However, we could not detect any correlation of MIF levels and aGVHD severity, donor sources. On the other hand, serum TRAIL concentration analysis by ELISA showed that patients who developed aGVHD were not associated (avelage, from 458.6 pg/ml before allo-SCT to 484.12 pg/ml after allo-SCT, p=0.632). We could not detect association aGVHD severity, donor sources. However, peak titer in aGVHD patients tends to decrease in unrelated transplantation (related 580.86pg/ml, unrelated 415.59pg/ml, p=0.22). Interestingly, we showed that average serum TRAIL concentration before allo-SCT associated with aGVHD and cGVHD. Serum TRAIL concentration with aGVHD patients (n=12, 458.85pg/ml) was tended to increase than without aGVHD (n=4, 330.45pg/ml, P=0.063) and with cGVHD patients (n=9, 535.21pg/ml) was significantly increase without cGVHD patients (n=3, 282.0 ng/ml, P=0.007).

Discussion. The present study demonstrated the kinetics of MIF and TRAIL. Systemic up-regulation of MIF expression is associated with the occurrence of aGVHD. This data suggested that MIF after allo-SCT might play a pathogenetic role in aGVHD. On the other hand, we suggested that high level of TRAIL before allo-SCT associated acute and cGVHD. Maybe we might be to estimate acute and cGVHD in examining TRAIL level before allo-SCT. In conclusion our data are the first to establish an association TRAIL and GVHD in allogeneic stem cell transplantation.