Cytokine and Chemokine Patterns Across 100 Days after Hematopoietic Stem Cell Transplantation in Children

Abstract

We mapped the cytokine response to hematopoietic stem cell transplantation (HSCT) by assaying 51 cytokines and chemokines each week for 100 days in 51 children receiving allogeneic (n = 44) or autologous HSCT (n = 7). Assay values were reported as mean fluorescence intensity (MFI). Log transformation converted MFI to clinically relevant measures (ie, pg/mL). We searched for potential markers of transplant complications by using mixed treatment by subject analysis of variance. Global cytokine secretion in HSCT recipients was significantly lower than in concurrent control patients (n = 11). Coincident with the nadir in WBC count, the concentration of many cytokines declined further by the second and third week. All analytes (except monokine induced by gamma interferon [MIG]) subsequently rebounded by week 4 (coincident with engraftment and recovery of WBC count) but often still remained well below control levels. Concurrent with the collective nadir of multiple cytokines, monocyte chemoattractant protein 1 (MCP-1), growth-regulated oncogene alpha (GRO-a), and leptin surged during weeks 2 to 4. High levels of leptin persisted throughout the 100 post-transplant days. Also during weeks 2 to 4, hepatocyte growth factor (HGF) and IL-6 surged in children with complications but not in those without complications. The peak in HGF was more pronounced in veno-occlusive disease (VOD). HGF and IL-6 secretion rose at least 2 weeks before the clinical diagnosis of VOD or graft-versus-host disease (GVHD). From week 4 onward in all groups, the MFI of the cytokine resistin increased to 5 to 15 times above concurrent control. HGF has now emerged in 3 or more biomarker discovery efforts for GVHD (and in our population for VOD as well). HGF (with or without IL-6) should be investigated as a potential predictive biomarker of VOD or GVHD. Alternatively, the hyperinflammatory “signature” provided by a multicytokine assay may be predictive.

Plasma biomarkers of acute GVHD and nonrelapse mortality: predictive value of measurements before GVHD onset and treatment

“…We speculate that virtually all allograft recipients experience graft-vs-host reactions as the cause of systemic inflammation, but not all will develop clinically significant disease. 25 In summary, we have identified plasma levels of TIM3, IL6, sTNFR1, and ST2 as informative analytes in predicting the development of more severe GVHD and NRM among patients with gastrointestinal GVHD. Our study has several limitations.…”

Cytokines in Graft-versus-Host Disease

“…The Journal of Immunologyproduction by flow cytometry have allowed identification of, and will continue to define, the key cytokines in aGVHD (45,79), as well as facilitate clinical translation of findings. However, a number of factors must be considered when extrapolating laboratory observations into clinical cohorts.…”

How do I manage hyperglycemia/post-transplant diabetes mellitus after allogeneic HSCT

“…After allo-HSCT, various inflammatory cytokine levels are significantly increased 25,26 and seem to be associated with complications, such as sinusoidal obstructive syndrome and GVHD. In addition to lymphocyte-secreted cytokines, adipocytederived cytokines may have a role in the development of insulin resistance and subsequent type 2 DM.…”