Increased serum levels of tumor necrosis factor alpha precede major complications of bone marrow transplantation [see comments]

Abstract

Acute graft-versus-host disease, interstitial pneumonitis, endothelial leakage syndrome, and veno-occlusive disease are major complications of bone marrow transplantation. Though several new regimens for prophylaxis and treatment of these syndromes have been introduced, the overall incidence has been only slightly reduced over the last few years. We retrospectively analyzed tumor necrosis factor alpha (TNF alpha) serum levels between day -8 and day 100 after bone marrow transplantation in 56 patients transplanted in our unit for a variety of hematological diseases. In 34 patients with uneventful courses, mean TNF alpha levels rose to a maximum of 76 +/- 29 pg/mL. In contrast, 22 patients with major transplant related complications showed mean increases of TNF alpha of 492 +/- 235 pg/mL (P less than .0001). Increases of TNF alpha occurred before interstitial pneumonitis and severe acute graft-versus-host disease with a latency of 25 to 54 days. Early complications such as endothelial leakage syndrome and veno- occlusive disease were closely associated with increases of TNF alpha serum levels. Our study suggests two pathways of TNF alpha release: activation of host macrophages and stimulation of donor cells in the course of acute graft-versus-host disease. Cytokine monitoring should be helpful for prediction and earlier treatment of major transplant related complications.

An Official American Thoracic Society Research Statement: Noninfectious Lung Injury after Hematopoietic Stem Cell Transplantation: Idiopathic Pneumonia Syndrome

“…Any process that ultimately results in large amounts of endotoxin and/or TNF-a in the pulmonary circulation may contribute to the development of lung injury in this setting. This hypothesis is consistent with the observation that serum and BAL fluid TNF-a levels are increased in patients with IPS (106,107). A clinical linkage of hepatic dysfunction to lung injury after HSCT is also suggested by associations between veno-occlusive disease (VOD) and IPS and between hepatic failure and death from IPS (3,14).…”

Interferon (IFN)-gamma is a main mediator of keratinocyte (HaCaT) apoptosis and contributes to autocrine IFN-gamma and tumour necrosis factor-alpha production.

“…TNF-a has also been shown to be an important mediator during acute GvHD. 19,27 TNF-a alone did not induce HaCaT apoptosis significantly but acted synergistically with IFN-c. Therefore, as TNF-a is also present in MLC-SN this may explain why even 1 : 10 diluted MLC-SN containing only 350 pg mL )1 IFN-c is as effective as 200 U mL )1 rIFN-c alone, corresponding to 10 ng mL )1 [compare Fig.…”

Toxic Epidermal Necrolysis Possibly Linked to Hyperacute Graft‐versus‐Host Disease after Allogeneic Bone Marrow Transplantation

“…GVHD is one of the major complications in allogeneic BMT and is an inflammatory disorder mounted by the donor cells against specific host organs such as skin, liver, and gastrointestinal tract. T-cells, NK-cells, and cytokines play important roles in the pathogenesis of GVHD (16)(17)(18)(19)(20). This disease can be divided into three clinical phases.…”

“…In acute GVHD, the donor cells have already engrafted; engrafted cells such as Tcells and NK-cells attack the host organs. Cytokines such as IFN-y, TNF-a, and IL-6 also participate in the assault (16)(17)(18)(19)(20). In hyperacute GVHD, however, the timing of onset seems to be too early for the donor cells to have engrafted.…”