Reduced stem cell mobilization in mice receiving antibiotic modulation of the intestinal flora: involvement of endotoxins as cofactors in mobilization

Abstract

IntroductionTo reduce the risk of infections in neutropenic patients a combination of protective isolation and gut decontamination by oral administration of antibiotics is often used. [1][2][3][4] Since it has been shown that selective elimination of the major potentially pathogenic microorganisms from the digestive tract is as effective or even superior to total decontamination in preventing infections in neutropenic patients, 5-8 selective gut decontamination 9 or partial antibiotic decontamination 10 mainly directed against aerobic Gram-negative rods and fungi is usually applied. The various antibiotics used for selective decontamination can be divided into 2 main groups, those that are absorbed 11-13 after oral administration (eg, cotrimoxazole, quinolones) and those that are not absorbed 2-4 after oral administration (eg, polymyxin, colistin, aminoglycosides).Mobilized hematopoietic progenitor cells (HPCs) are increasingly used for hematopoietic recovery instead of bone marrow to allow rapid hematopoietic recovery after autologous and allogeneic transplantation. [14][15][16][17][18] An increasing number of different growth factors and chemokines such as granulocyte colony-stimulating factor (G-CSF), 19,20 granulocyte-macrophage colony-stimulating factor (GM-CSF), 19,21 stem cell factor (SCF), 22 flt3 ligand (FL), 23 interleukin-1 (IL-1), 24 26 and thrombopoietin 27 when either administered alone or in combination 28 are capable of mobilizing peripheral blood progenitor cells. In the clinical setting, the growth factor G-CSF has become the standard for autologous as well as allogeneic peripheral blood stem cell transplantation. [29][30][31] Although patients receiving selective gut decontamination or systemic antibiotic treatment while concurrently being treated with G-CSF are able to mobilize peripheral blood progenitor cells, little is known of the effect of antibiotics on the efficacy of mobilization.Endotoxins are ubiquitously present and constitute an important component of the normal intestinal flora and are known to induce HPC mobilization. [32][33][34] We therefore hypothesized that low levels of endotoxins passing through the intestinal mucosa into the blood may contribute to the levels of circulating HPCs. Here, we used a mouse model to study the effects of selective antibiotic decontamination on cytokine-induced stem cell mobilization. We found that the ability to mobilize in response to IL-8, G-CSF, or FL was significantly reduced in animals receiving endotoxin binding antibiotics or antibiotics that modulate the anaerobic flora. The mobilizing capacity was partially restored after adding endotoxins to the drinking water of decontaminated mice. These observations indicate that endotoxins are involved as cofactors in cytokineinduced hematopoietic stem cell mobilization. Supported by a grant from the Fund for Scientific Research FWO-Vlaanderen, the "Geconcerteerde Onderzoeks Acties" (GAO), and by the Dutch Cancer Society (NKB-RUL 99-2029).Reprints: Willem E. Fibbe, Department of Hematology, Lei...

Steady-state neutrophil homeostasis is dependent on TLR4/TRIF signaling

“…The importance of exogenous versus endogenous TLR-ligands as well as cell-type dependent mechanisms are still to be determined, but the fact that antibiotic treatment reduces the efficiency of stem-cell mobilization by G-CSF in humans 50 underscores the potential clinical importance of our findings.…”

Mouse models of human AML accurately predict chemotherapy response

“…Recipient mice were maintained on Ciprofloxacinsupplemented drinking water (Ciprofloxacin 125 mg/L, sucrose 20 g/L; both Sigma) until 2 wk after the end of chemotherapy. This antibiotic regimen has been shown to efficiently decontaminate aerobic Gram-negative pathogens without major effects on hematopoiesis (Velders et al 2004). Mice were monitored by bioluminescent imaging every 4 d, starting 10 d after transplantation.…”

Innate immunity as orchestrator of stem cell mobilization

“…92 This result is based on the observation that when mice are depleted of lipopolysaccharide-producing bacteria, they become poor mobilizers. 92 Thus, TLRs, which regulate several aspects of innate immunity and were recently also found on the surface of HSPCs (in addition to the surface of leukocytes), become important players in modulating the mobilization process. In support of this notion, TLR2 binds zymosan and TLR4 binds lipopolysaccharide.…”