CD8α-Deficient Mice Are Highly Susceptible to 5-Fluorouracil-Induced Lethality

Itoh, Naoto; Nishimura, Hitoshi; Matsuguchi, Tetsuya; Yajima, Toshiki; Mokuno, Yasuji; Hiromatsu, Takashi; Nimura, Yuji; Yoshikai, Yasunobu

doi:10.1128/cdli.9.3.550-557.2002

Cited by 8 publications

(8 citation statements)

References 39 publications

(38 reference statements)

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“…We speculate that IgA production could be negatively affected by a decrease in the number of CD21+ B cells in ileal PP and colon LGC, which are the main reservoirs of B cells in the intestine. This impairment in the immunological barriers of the intestine may lead to lethal translocation of bacteria from the intestinal lumen to the bloodstream and distant organs [7,8] .…”

Section: Discussionmentioning

confidence: 99%

“…The damage includes perturbed brush-border hydrolase activity [5] , reduced mucosal DNA, RNA and protein contents [1] , blunted villus height and crypt depth, and decreased proliferation and increased apoptosis of crypt cells [6] . Additionally, 5-FU impairs immunocompetent cells leading to lethal translocation of bacteria from the intestinal lumen to the bloodstream and distant organs [7,8] . These cellular changes ultimately result in a clinical syndrome of diarrhea, intestinal blood loss, dehydration, impaired nutrition, disseminated infections and weight loss.…”

Section: Introductionmentioning

confidence: 99%

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Intestinal Toxicity Induced by 5-Fluorouracil in Pigs: A New Preclinical Model

Manzano¹,

Bueno²,

Rueda³

et al. 2007

Chemotherapy

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Background: The goal of this study was to develop an animal model of intestinal injury induced by 5-fluorouracil (5-FU) in pigs. Methods: Six domestic pigs were used as control (healthy group) and another 6 malnourished pigs orally received 5-FU (treated group). After 4 weeks of treatment, pigs were sacrificed and jejunum, ileum and colon were isolated for histological, immunological and biochemical analyses. Results: 5-FU caused a decrease in the intestinal mass. Disaccharidase, and phosphate alkaline activities, and glutathione redox cycle were disrupted by 5-FU. Histopathological alterations in the crypts and villous were greater in the small intestine than in the colon. 5-FU decreased the number of peripheral and intestinal leukocytes, promoting an increase in T-cytotoxic cells and a decrease in T-helper and B cells. Conclusion: This pig model of intestinal dysfunction closely mimics the common side effects of cancer chemotherapy in humans, and provides a useful tool for evaluating novel antimucotoxic agents.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Intestinal Toxicity Induced by 5-Fluorouracil in Pigs: A New Preclinical Model

Manzano¹,

Bueno²,

Rueda³

et al. 2007

Chemotherapy

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“…They speculated that the direct stimulation of i-ECs by intestinal microflorae via MyD88-dependnet TLR signaling induces cytoprotective cytokines and proteins, including IL-6 and heat shock protein, which result in steady state intestinal epithelial homeostasis. We previously reported that CD8␣ Ϫ/Ϫ mice showed high susceptibility to 5-fluorouracil-induced intestinal injury (40), suggesting that CD8␣␣ i-IELs are important for intestinal homeostasis. Therefore, we suggest that impairment of development, differentiation, and maintenance of CD8␣␣ and TCR␥␦ i-IELs in MyD88…”

Section: Discussionmentioning

confidence: 99%

MyD88-Dependent Signaling for IL-15 Production Plays an Important Role in Maintenance of CD8αα TCRαβ and TCRγδ Intestinal Intraepithelial Lymphocytes

Yu¹,

Tang²,

Sun³

et al. 2006

The Journal of Immunology

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Interaction between commensal bacteria and intestinal epithelial cells (i-ECs) via TLRs is important for intestinal homeostasis. In this study, we found that the numbers of CD8αα TCRαβ and TCRγδ intestinal intraepithelial lymphocytes (i-IELs) were significantly decreased in MyD88-deficient (−/−) mice. The expression of IL-15 by i-ECs was severely reduced in MyD88−/− mice. Introduction of IL-15 transgene into MyD88−/− mice (MyD88−/− IL-15 transgenic mice) partly restored the numbers of CD8αα TCRαβ and TCRγδ i-IELs. The i-IEL in irradiated wild-type (WT) mice transferred with MyD88−/− bone marrow (BM) cells had the same proportions of i-IEL as WT mice, whereas those in irradiated MyD88−/− mice transferred with WT BM cells showed significantly reduced proportions of CD8αα TCRαβ and TCRγδ i-IELs, as was similar to the proportions found in MyD88−/− mice. However, irradiated MyD88−/− IL-15 transgenic mice transferred with WT BM cells had increased numbers of CD8αα TCRαβ and TCRγδ subsets in the i-IEL. These results suggest that parenchymal cells such as i-ECs contribute to the maintenance of CD8αα TCRαβ and γδ i-IELs at least partly via MyD88-dependent IL-15 production.

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“…Hematopoietic cells and normal epithelial cells of the gastrointestinal tract are susceptible to 5-FU induced cytotoxicity producing severe leukopenia and intestinal toxicity leading to lethal translocation of intestinal microflora [21][22][23][24] . In general our findings are in line with previous studies that have reported that systemic 5-FU administration causes epithelial barrier dysfunction of the rat intestine [25] , and causes bacterial translocation [26] .…”

Section: Discussionmentioning

confidence: 99%

Effects of granulocyte-colony stimulating factor on peritoneal defense mechanisms and bacterial translocation after administration of systemic chemotherapy in rats

Çerçi¹

2007

WJG

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activity of peritoneal fluid and phagocytic activity of polymorphonuclear leucocytes in the peritoneal fluid. G-CSF increased both bactericidal activity of the peritoneal fluid and phagocytic activity of polymorphonuclear leucocytes in the peritoneal fluid, and prevented the bacterial translocation. We conclude that intraperitoneal GCSF administration protects the effects of systemic 5-FU on peritoneal defense mechanisms. INTRODUCTIONChemotherapy is one of the most important methods in the therapy of malignant diseases. It has been widely used and it is well known that systemic chemotherapy has immunosuppressive effects [1] . 5-Fluorouracil (5-FU) has side effects, including leucopoenia, stomatitis, appetite loss, diarrhea, and mild fever like other chemotherapy agents [2,3] . It has been reported that a high dose of 5-FU often induces cytotoxicity in intestinal tissue that results in ulceration, diarrhea, and bacterial translocation [4][5][6][7][8] .Bacterial translocation is one of the most important causes of sepsis and multiple organ failure. Intestinal mucosa has a barrier function that prevents the colonization of the bacteria and the passage of bacteria and their toxins from the intestinal system into the systemic circulation. It has been shown that bacterial translocation is also augmented by shock, mesenteric ischemia, thermal injury, malnutrition, obstructive jaundice, and intestinal obstruction [9][10][11][12][13][14] . Granulocyte-colony stimulating factor (G-CSF) is a cytokine that is used to reverse the neutropenia associated with cytotoxic chemotherapy bone marrow and haemopoietic stem cell transplantation [15] . Abstract AIM: To investigate the effects of granulocyte-colony stimulating factor (G-CSF) on peritoneal defense mechanisms and bacterial translocation after systemic 5-Fluorouracil (5-FU) administration.

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CD8α-Deficient Mice Are Highly Susceptible to 5-Fluorouracil-Induced Lethality

Abstract: Intestinal intraepithelial lymphocytes (i-IEL

Cited by 8 publications

References 39 publications

Intestinal Toxicity Induced by 5-Fluorouracil in Pigs: A New Preclinical Model

Intestinal Toxicity Induced by 5-Fluorouracil in Pigs: A New Preclinical Model

MyD88-Dependent Signaling for IL-15 Production Plays an Important Role in Maintenance of CD8αα TCRαβ and TCRγδ Intestinal Intraepithelial Lymphocytes

Effects of granulocyte-colony stimulating factor on peritoneal defense mechanisms and bacterial translocation after administration of systemic chemotherapy in rats

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