Abstract
The efficacy of allogeneic, haemopoietic stem cell transplantation (HSCT) is limited by concomitant toxicity. This has led to the development of less toxic, reduced intensity conditioning (RIC) protocols, whose therapeutic benefit is largely related to an associated, immunity-mediated graft-versus-malignancy effect rather than by the cytotoxic treatment itself. Murine HSCT models suggests that acute graft-versus-host disease (GVHD) increases with the intensification of the conditioning regimen mediated by loss of integrity of the gut mucosa barrier. The present study was undertaken to investigate gastro-intestinal (GI) permeability during allogeneic HSCT with RIC. In 17 patients (myeloablative conditioning in nine, RIC in eight), intestinal permeability was assessed by a 51Cr-EDTA absorption test before the start of cytotoxic treatment the day before stem cell infusion (day −1) and 4, 7 and 14 days after stem cell infusion. Patients receiving RIC did not develop any significant increase in intestinal permeability during the transplantation course but in myeloablatively conditioned patients there was a significant increase in intestinal permeability the day before the stem cell infusion (P < 0.005), on day 4 (P < 0.005), on day 7 (P < 0.01) and on day 14 (P < 0.005) after stem cell infusion, compared with the baseline. Myeloablative conditioning also revealed increased intestinal permeability on day 7 compared with the RIC (P < 0.05). The finding of preserved intestinal-barrier function during allogeneic HSCT with RIC is discussed, with reference to the hypothesis that GI tract damage may be an important initiating event of GVHD. Bone Marrow Transplantation (2001) 28, 737–742.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Fegan C, Poynton CH, Whittaker JA . The gut mucosal barrier in bone marrow transplantation Bone Marrow Transplant 1990 5: 373–377
Johansson JE, Ekman T . Gastro-intestinal toxicity related to bone marrow transplantation: disruption of the intestinal barrier precedes clinical findings Bone Marrow Transplant 1997 19: 921–925
Berg R . Bacterial translocation from the gastrointestinal tract of mice receiving immunosuppressive chemotherapeutic agents Curr Microbiol 1983 8: 285–292
Antin JH, Weinstein HJ, Guinan EC et al. Recombinant human interleukin-1 receptor antagonist in the treatment of steroid-resistant graft-versus-host disease Blood 1994 84: 1342–1348
Ramadan AA, Yousif WB, Ali AM . The effect of methotrexate (MTX) on the small intestine of the mouse. IV. The Golgi apparatus, phosphatases and esterases Funct Dev Morphol 1992 2: 111–119
Holler E, Kolb HJ, Mittermuller J et al. Modulation of acute graft-versus-host-disease after allogeneic bone marrow transplantation by tumor necrosis factor alpha (TNF alpha) release in the course of pretransplant conditioning: role of conditioning regimens and prophylactic application of a monoclonal antibody neutralizing human TNF alpha (MAK 195F) Blood 1995 86: 890–899
Xun CQ, Thompson JS, Jennings CD et al. Effect of total body irradiation, busulfan-cyclophosphamide, or cyclophosphamide conditioning on inflammatory cytokine release and development of acute and chronic graft-versus-host disease in H-2-incompatible transplanted SCID mice Blood 1994 83: 2360–2367
Hill GR, Crawford JM, Cooke KR et al. Total body irradiation and acute graft-versus-host disease: the role of gastrointestinal damage and inflammatory cytokines Blood 1997 90: 3204–3213
Hill GR, Teshima T, Gerbitz A et al. Differential roles of IL-1 and TNF-alpha on graft-versus-host disease and graft versus leukemia J Clin Invest 1999 104: 459–467
Panoskaltsis-Mortari A, Lacey DL, Vallera DA, Blazar BR . Keratinocyte growth factor administered before conditioning ameliorates graft-versus-host disease after allogeneic bone marrow transplantation in mice Blood 1998 92: 3960–3967
Hill GR, Cooke KR, Teshima T et al. Interleukin-11 promotes T cell polarization and prevents acute graft-versus-host disease after allogeneic bone marrow transplantation J Clin Invest 1998 102: 115–123
Slavin S, Nagler A, Naparstek E et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases Blood 1998 91: 756–763
Adkins D, Brown R, Khoury H et al. Low-intensity conditioning regimen for related donor allogeneic peripheral blood stem cell (PBSC) transplant using low-dose (550 cGy) high dose rate (30 cGy/min) single-exposure total body irradiation (TBI) Blood 1998 92: 138a
Khouri IF, Keating M, Korbling M et al. Transplant-lite: induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies J Clin Oncol 1998 16: 2817–2824
Childs RW, Clave E, Tisdale J et al. Successful treatment of metastatic renal cell carcinoma with a nonmyeloablative allogeneic peripheral-blood progenitor-cell transplant: evidence for a graft-versus-tumor effect J Clin Oncol 1999 17: 2044–2049
Bjarnason I, Peters TJ, Veall N . A persistent defect in intestinal permeability in coeliac disease demonstrated by a 51Cr-labelled EDTA absorption test Lancet 1983 1: 323–325
Miller AB, Hoogstraten B, Staquet M, Winkler A . Reporting results of cancer treatment Cancer 1981 47: 207–214
Przepiorka D, Weisdorf D, Martin P et al. 1994 Consensus Conference on Acute GVHD Grading Bone Marrow Transplant 1995 15: 825–828
Pledger JV, Pearson AD, Craft AW et al. Intestinal permeability during chemotherapy for childhood tumours Eur J Pediatr 1988 147: 123–127
Sundstrom GM, Wahlin A, Nordin-Andersson I, Suhr OB . Intestinal permeability in patients with acute myeloid leukemia Eur J Haematol 1998 61: 250–254
Pearson AD, Craft AW, Pledger JV et al. Small bowel function in acute lymphoblastic leukaemia Arch Dis Child 1984 59: 460–465
Menzies IS, Laker MF, Pounder R et al. Abnormal intestinal permeability to sugars in villous atrophy Lancet 1979 2: 1107–1109
Sandhu JS, Fraser DR . Assessment of intestinal permeability in the experimental rat with [3H]cellobiotol and [14C]mannitol Clin Sci 1982 63: 311–316
Bjarnason I, O'Morain C, Levi AJ, Peters TJ . Absorption of 51chromium-labeled ethylenediaminetetraacetate in inflammatory bowel disease Gastroenterology 1983 85: 318–322
Hill GR, Ferrara JL . The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation Blood 2000 95: 2754–2759
Nestel FP, Price KS, Seemayer TA, Lapp WS . Macrophage priming and lipopolysaccharide-triggered release of tumor necrosis factor alpha during graft-versus-host disease J Exp Med 1992 175: 405–413
Holler E, Kolb HJ, Hintermeier-Knabe R et al. Role of tumor necrosis factor alpha in acute graft-versus-host disease and complications following allogeneic bone marrow transplantation Transplant Proc 1993 25: 1234–1236
Norton J, Sloane JP . ICAM-1 expression on epidermal keratinocytes in cutaneous graft-versus-host disease Transplantation 1991 51: 1203–1206
Cavender DE, Haskard DO, Joseph B, Ziff M . Interleukin 1 increases the binding of human B and T lymphocytes to endothelial cell monolayers J Immunol 1986 136: 203–207
Leeuwenberg JF, Van Damme J, Meager T et al. Effects of tumor necrosis factor on the interferon-gamma-induced major histocompatibility complex class II antigen expression by human endothelial cells Eur J Immunol 1988 18: 1469–1472
Sykes M, Szot GL, Swenson KA, Pearson DA . Induction of high levels of allogeneic hematopoietic reconstitution and donor-specific tolerance without myelosuppressive conditioning Nat Med 1997 3: 783–787
Hill RS, Petersen FB, Storb R et al. Mixed hematologic chimerism after allogeneic marrow transplantation for severe aplastic anemia is associated with a higher risk of graft rejection and a lessened incidence of acute graft-versus-host disease Blood 1986 67: 811–816
Petz LD, Yam P, Wallace RB et al. Mixed hematopoietic chimerism following bone marrow transplantation for hematologic malignancies Blood 1987 70: 1331–1337
Clift RA, Buckner CD, Thomas ED et al. Marrow transplantation for chronic myeloid leukemia: a randomized study comparing cyclophosphamide and total body irradiation withbusulfan and cyclophosphamide Blood 1994 84: 2036–2043
Deeg HJ, Spitzer TR, Cottler-Fox M et al. Conditioning-related toxicity and acute graft-versus-host disease in patients given methotrexate/cyclosporine prophylaxis Bone Marrow Transplant 1991 7: 193–198
Nash RA, Pepe MS, Storb R et al. Acute graft-versus-host disease: analysis of risk factors after allogeneic marrow transplantation and prophylaxis with cyclosporine and methotrexate (see comments) Blood 1992 80: 1838–1845
Farrell CL, Bready JV, Rex KL et al. Keratinocyte growth factor protects mice from chemotherapy and radiation-induced gastrointestinal injury and mortality Cancer Res 1998 58: 933–939
Housley RM, Morris CF, Boyle W et al. Keratinocyte growth factor induces proliferation of hepatocytes and epithelial cells throughout the rat gastrointestinal tract J Clin Invest 1994 94: 1764–1777
Khan WB, Shui C, Ning S, Knox SJ . Enhancement of murine intestinal stem cell survival after irradiation by keratinocyte growth factor Radiat Res 1997 148: 248–253
Du XX, Doerschuk CM, Orazi A, Williams DA . A bone marrow stromal-derived growth factor, interleukin-11, stimulates recovery of small intestinal mucosal cells after cytoablative therapy Blood 1994 83: 33–37
Acknowledgements
We are indebted to Hanna Karlsson and the nursing staff at the Department of Haematology, Sahlgrenska University Hospital, for clinical assistance. This work was financially supported by the Göteborg Medical Society, the funds of Jubileumskliniken at Sahlgrenska University Hospital and by the funds of Assar Gabrielsson.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Johansson, JE., Brune, M. & Ekman, T. The gut mucosa barrier is preserved during allogeneic, haemopoietic stem cell transplantation with reduced intensity conditioning. Bone Marrow Transplant 28, 737–742 (2001). https://doi.org/10.1038/sj.bmt.1703230
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.bmt.1703230
Keywords
This article is cited by
-
Application of big data analyses to compare the impact of oral and gastrointestinal mucositis on risks and outcomes of febrile neutropenia and septicemia among patients hospitalized for the treatment of leukemia or multiple myeloma
Supportive Care in Cancer (2023)
-
Challenges and opportunities targeting mechanisms of epithelial injury and recovery in acute intestinal graft-versus-host disease
Mucosal Immunology (2022)
-
G-CSF-primed haplo-identical HSCT with intensive immunosuppressive and myelosuppressive treatments does not increase the risk of pre-engraftment bloodstream infection: a multicenter case–control study
European Journal of Clinical Microbiology & Infectious Diseases (2019)
-
Initial fluconazole prophylaxis may not be required in adults with acute leukemia or myelodysplastic/myeloproliferative disorders after reduced intensity conditioning peripheral blood stem cell allogeneic transplantation
Annals of Hematology (2015)
-
Population pharmacokinetics analysis of cyclophosphamide with genetic effects in patients undergoing hematopoietic stem cell transplantation
European Journal of Clinical Pharmacology (2013)