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High Interleukin-10 Serum Levels Are Associated with Fatal Outcome in Patients After Bone Marrow Transplantation

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Bone Marrow Transplantation, (1997) 20, 365–368 1997 Stockton Press All rights reserved 0268–3369/97 $12.00 High interleukin-10 serum levels are associated with fatal outcome in patients after bone marrow transplantation L Hempel1,DKo¨rholz2, P Nußbaum3,HBo¨nig2, S Burdach2,4 and F Zintl1 1Department of Pediatric Hematology and Oncology, Friedrich-Schiller University Medical Center, Jena; 2Department of Pediatric Hematology and Oncology, Heinrich-Heine University Medical Center, Du¨sseldorf; 3Institute of Clinical Pathology, Osnabru¨ck; and 4Biomedical Research Center, Heinrich-Heine University, Du¨sseldorf, Germany Summary: production.1–3 Experiences with IL-10 knock-out mice show that IL-10 may contribute to the control of inflamma- IL-10 plays an important role in the control of immune tory reactions because these animals showed severe gastro- reactions during systemic infection. Here, IL-10 serum intestinal inflammation.4 In mouse models, elevation of IL- levels were investigated in patients after BMT. The IL- 10 during systemic infection protected the animals from 10 levels correlated with the clinical course of the an overwhelming immune reaction. Furthermore, mice with patients and with serum levels of C-reactive protein high endogenous or exogenous IL-10 levels survived sys- (CRP) and neopterin (NP). A total of 26 patients with temic shock syndromes, while application of anti-IL-10 led AML (7), ALL (12), CML (2), NHL (3) and multifocal to a fatal reaction.5–7 In contrast, in humans elevated IL-10 Ewing’s sarcoma (2) had received autologous (10) or levels during systemic shock correlated with an increased allogeneic (16) BMT from related (9) or unrelated TNF-a production, increased severity of septic shock and donors (7). Routine serum samples were obtained prior a high risk of disseminated intravascular coagulation.8–10 to BMT and at days 46 and 100 after BMT. However, The association between high IL-10 levels and fatality of in patients with severe complications additional samples septic shock was explained by the fact that IL-10 might not were drawn at individual points in time. Prior to BMT, be able to inhibit production of proinflammatory cytokines, IL-10 serum levels were not detectable in 24/24 patients. while suppressing T cell reactions which might otherwise Post-BMT, 11 patients developed elevated IL-10 levels, have supported pathogen elimination. In this study the role of these eight died of complications (DOC), whereas of IL-10 in patients after BMT was investigated under the only one of 15 patients with undetectable IL-10 died of hypothesis that in post-BMT patients, as in sepsis, complications, indicating that high IL-10 levels were sig- increased IL-10 might be correlated to poor outcome. IL- nificantly correlated with severe life-threatening compli- 10 serum levels correlated with the clinical course of the cations (x2, P , 0.01). To determine the pathomechan- disease, the severity of acute phase reactions and macro- ism and role of the increased IL-10 levels, they were phage activation. correlated to the respective NP and CRP serum concen- trations. CRP and NP concentrations were found sig- nificantly elevated in patients with detectable IL-10, Patients and methods indicating a severe acute phase reaction associated with Patients macrophage activation. In conclusion, high IL-10 serum levels in patients after BMT were significantly associa- Twenty-six children and adolescents were enrolled into this ted with fatal outcome. Since IL-10 is a strong sup- study. Patients’ ages ranged from 4.0 to 22.4 years (median: pressor of T cell immunity, high IL-10 production in 13.4 years). The male to female ratio was 18 to 8. Patients patients with severe complications such as septic shock had previously been treated for ALL (12), AML (7), CML or GVHD .grade II after BMT might lead to functional (2), NHL (3) and Ewing’s sarcoma (2). Five patients had immunodeficiency contributing to the poor prognosis of received an allogeneic transplant from a matched-related these patients. donor, four patients had been transplanted with bone mar- Keywords: sepsis; bone marrow transplantation; inter- row from an haploidentical related donor and seven patients leukin 10; neopterin had had unrelated donors. In addition, 10 patients had received autologous bone marrow or peripheral blood stem cell transplants. Blood was drawn from patients prior to BMT and at days 46 and 100 after BMT. However, in IL-10 is a potent macrophage and T cell-deactivating patients with multi-organ failure (MOF) additional blood cytokine, leading to a significant suppression of cytokine samples were taken during these complications. At the time of study, all patients with allogeneic transplants received immunosuppressive treatment. Acute GVHD was seen in Correspondence: L Hempel, Department of Pediatric Hematology and Oncology, Friedrich-Schiller University Medical Center, Kochstr 2, D- only six of 16 patients (Table 1). However, six of 10 07740 Jena, Germany patients without acute GVHD died in the early post-trans- Received 21 March 1997; accepted 15 May 1997 plant period. Interleukin-10 and bone marrow transplantation L Hempel et al 366 Table 1 Patients characteristics No. Initials Sex Age Diagnosis Status at BMT Type of transplant Acute GVHD Status 1 DH F 17.2 ALL CR matched related GVHD II CCR 2 AK M 14.6 CML PR matched related none CCR 3 DS M 14.7 ALL CR matched related none DOC, day +67 4 KS M 4.0 ALL CR matched related none CCR 5 FT M 11.5 AML CR matched related none relapse day +126, died day +183 6 CK M 14.6 CML PR matched unrelated none DOC, day +34 7 RK M 8.7 AML relapse matched unrelated none DOC, day +20 8 CK M 10.4 NHL PR matched unrelated none DOC, day +26 9 SM F 7.1 ALL CR matched unrelated GVHD I–II CCR 10 KR F 22.4 ALL relapse matched unrelated none DOC, day +27 11 SR M 18.1 AML CR matched unrelated GVHD III DOC, day +103 12 FZ M 17.4 AML relapse matched unrelated none DOC, day +21 13 TB F 11.2 ALL CR mismatched related GVHD II CCR 14 CL F 10.8 ALL CR mismatched related GVHD II CCR 15 NS M 13.7 ALL relapse mismatched related GVHD II–III DOC, day +83 16 CS F 14.3 ALL relapse mismatched related none DOC, day +19 17 RB M 12.8 AML CR autologous none relapse day +293, alive 18 RF M 19.9 ALL CR autologous none relapse day +192, died day +220 19 EG M 17.7 AML CR autologous none CCR 20 MG M 17.9 NHL CR autologous none CCR 21 BH F 7.5 ALL CR autologous none CCR 22 HH M 17.5 AML CR autologous none CCR 23 DS M 15.4 EWS PR autologous none relapse day +161, alive 24 JS F 11.0 EWS PR autologous none CCR 25 NS M 7.3 NHL CR autologous none CCR 26 PW M 12.8 ALL CR autologous none CCR The study was performed in accordance with the ethical Statistical analysis of data standards laid down in the 1964 Declaration of Helsinki. 2 Patients or their parents gave their consent. The study was The Wilcoxon and x tests were used for statistical analysis. authorized by the local ethics committee. Results Cytokine analysis Concentrations of IL-10 were assessed by commercially To determine the role of IL-10 in patients after BMT, IL- available ultrasensitive ELISA kits (BioSource, Camarillo, 10 serum levels were correlated with the clinical course of CA, USA) as described previously.3 The lowest concen- the patients. Prior to BMT (‘day 0’) serum levels of IL- tration detected by this assay was 200 fg/ml. 10 were undetectable in all patients. Post-BMT 11 patients developed detectable IL-10 at various points in time. Of these, eight patients died of complications within 1–14 Neopterin (NP) determination (median 4) days after an elevated IL-10 had been found. The three surviving patients with elevated IL-10 serum lev- Serum neopterin levels were measured by HPLC. Briefly, els presented with acute GVHD grade II or severe CMV 200 ml samples or standards were added to a mobile phase infection. One patient received systemic IL-2 treatment at containing 0.1 m KH2PO4, (Merck, Darmstadt, Germany), the time of IL-10 determination. In 15/26 patients IL-10 0.005 m octansulfonic acid (Fluka, Bux, Switzerland; pH remained undetectable throughout the observation period. was adjusted to 3.0 with 1 N HCl) and 50 ml of 3.4 m Of these, only one succumbed to complications. The last HClO4. After vortexing the mixtures for 30 s, samples were IL-10 measurement in this patient had been done 21 days centrifuged at 11 500 r.p.m. for 5 min. Supernatants (50 ml) prior to his death so that an increased IL-10 may have been were applied to a HPLC (Li-Chros-Pher 100 RP 8E; missed. Thus, we found detectable IL-10 levels to be sig- Merck). Neopterin concentrations were determined at Ex nificantly correlated with DOC (Figure 1; Table 2; x2, wavelength of 360 nm compared with Em wavelength of P , 0.01). 430 nm. Next, the mechanism of in vivo IL-10 production was investigated. It was found that in patients with detectable CRP determination IL-10, CRP levels (median: 8.57 mg/dl) were significantly elevated as compared to patients with undetectable IL-10 CRP values were determined by particle-enhanced immu- (median: 0 mg/l; Figure 2, Wilcoxon test, P , 0.001). nonephelometry. 40 ml serum were applied to a fully auto- Thus, in our patient population the IL-10 serum levels were matic nephelometer (Behringwerke, Marburg, Germany).
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  • Abstract Background: Tuberculosis (TB) Is a Deadly Transmissible Disease That Can Infect Almost Any Body-Part of the Host but Is Mostly Infect the Lungs

    Abstract Background: Tuberculosis (TB) Is a Deadly Transmissible Disease That Can Infect Almost Any Body-Part of the Host but Is Mostly Infect the Lungs

    bioRxiv preprint doi: https://doi.org/10.1101/414110; this version posted September 14, 2018. The copyright holder for this preprint (which was Stagenot certified specific by peer classification review) is the author/funder. of DEGs All rights via reserved. statistical No reuse profiling allowed without and permission. network analysis reveals potential biomarker associated with various stages of TB Aftab Alam1. Nikhat Imam2, Mohd Murshad Ahmed1, Safiya Tazyeen1, Anam Farooqui1, Shahnawaz Ali1, Md. Zubbair Malik1 and Romana Ishrat*1 1Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi-110025 (India) 2Institute of Computer Science & Information Technology, Department of Mathematics, Magadh University, Bodh Gaya-824234 (Bihar, India) Abstract Background: Tuberculosis (TB) is a deadly transmissible disease that can infect almost any body-part of the host but is mostly infect the lungs. It is one of the top 10 causes of death worldwide. In the 30 high TB burden countries, 87% of new TB cases occurred in 2016. Seven countries: India, Indonesia, China, Philippines, Pakistan, Nigeria, and South Africa accounted for 64% of the new TB cases. To stop the infection and progression of the disease, early detection of TB is important. In our study, we used microarray data set and compared the gene expression profiles obtained from blood samples of patients with different datasets of Healthy control, Latent infection, Active TB and performed network-based analysis of DEGs to identify potential biomarker. We want to observe the transition of genes from normal condition to different stages of the TB and identify, annotate those genes/pathways/processes that play key role in the progression of TB disease during its cyclic interventions in human body.