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The response of intestinal stem cells and epithelium after alemtuzumab administration

Cellular & Molecular Immunology volume 8, pages 325–332 (2011)Cite this article

Abstract

Intestinal stem cells may have important roles in the maintenance of epithelial integrity during tissue repair. Alemtuzumab is a humanized anti-CD52 lymphocytic antibody that is increasingly being used to induce immunosuppression; intestinal barrier function is impaired during treatment with alemtuzumab. We investigated the response of intestinal stem cells to epithelial damage resulting from alemtuzumab treatment. Intestinal epithelial cell loss and abnormal Paneth cell morphology were found following a single dose of alemtuzumab. The animals receiving alemtuzumab exhibited increased apoptosis in the villi 3 days after alemtuzumab treatment and in the crypt on day 9, but apoptosis was scarce on day 35. We assessed expression of Musashi-1- and Lgr5-positive stem cells following alemtuzumab treatment. Increased numbers of cells staining positive for both Musashi-1 and Lgr5 were found in the stem cell zone after alemtuzumab treatment for 3 and 9 days. These data indicated that the epithelial cells were injured following alemtuzumab treatment, with the associated expansion of intestinal stem cells. After alemtuzumab treatment for 35 days, the numbers of intestinal epithelial cells and intestinal stem cells returned to normal. This study suggests that alemtuzumab treatment induced the increase in stem cells, resulting in the availability of more enterocytes for repair.

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References

  1. Bjerknes M, Cheng H . Gastrointestinal stem cells. II. Intestinal stem cells. Am J Physiol Gastrointest Liver Physiol 2005; 289: G381–G387.

    Article  CAS  PubMed  Google Scholar 

  2. Gordon JI, Hermiston ML . Differentiation and self-renewal in the mouse gastrointestinal epithelium. Curr Opin Cell Biol 1994; 6: 795–803.

    Article  CAS  PubMed  Google Scholar 

  3. Potten CS, Booth C, Pritchard DM . The intestinal epithelial stem cell: the mucosal governor. Int J Exp Pathol 1997; 78: 219–243.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Okamoto R, Tsuchiya K, Nemoto Y, Akiyama J, Nakamura T, Kanai T et al. Requirement of Notch activation during regeneration of the intestinal epithelia. Am J Physiol Gastrointest Liver Physiol 2009; 296: G23–G35.

    Article  CAS  PubMed  Google Scholar 

  5. Okamoto R, Watanabe M . Molecular and clinical basis for the regeneration of human gastrointestinal epithelia. J Gastroenterol 2004; 39: 1–6.

    Article  PubMed  Google Scholar 

  6. Potten CS . A comprehensive study of the radiobiological response of the murine (BDF1) small intestine. Int J Radiat Biol 1990; 58: 925–973.

    Article  CAS  PubMed  Google Scholar 

  7. Kayahara T, Sawada M, Takaishi S, Fukui H, Seno H, Fukuzawa H et al. Candidate markers for stem and early progenitor cells, Msi-1 and Hes1, are expressed in crypt base columnar cells of mouse small intestine. FEBS Lett 2003; 535: 131–135.

    Article  CAS  PubMed  Google Scholar 

  8. Potten CS, Booth C, Tudor GL, Booth D, Brady G, Hurley P et al. Identification of a putative intestinal stem cell and early lineage marker; Msi-1. Differentiation 2003; 71: 28–41.

    Article  CAS  PubMed  Google Scholar 

  9. Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 2007; 449: 1003–1007.

    Article  CAS  PubMed  Google Scholar 

  10. Garcia M, Weppler D, Mittal N, Nishida S, Kato T, Tzakis A et al. Campath-1H immunosuppressive therapy reduces incidence and intensity of acute rejection in intestinal and multivisceral transplantation. Transplant Proc 2004; 36: 323–324.

    Article  CAS  PubMed  Google Scholar 

  11. Shapiro R, Ellis D, Tan HP, Moritz ML, Basu A, Vats AN et al. Alemtuzumab pre-conditioning with tacrolimus monotherapy in pediatric renal transplantation. Am J Transplant 2007; 7: 2736–2738.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Stanglmaier M, Reis S, Hallek M . Rituximab and alemtuzumab induce a nonclassic, caspase-independent apoptotic pathway in B-lymphoid cell lines and in chronic lymphocytic leukemia cells. Ann Hematol 2004; 83: 634–645.

    Article  CAS  PubMed  Google Scholar 

  13. Knechtle SJ, Pirsch JD, Fechner H, Becker BN, Friedl A, Colvin RB et al. Campath-1H induction plus rapamycin monotherapy for renal transplantation: results of a pilot study. Am J Transplant 2003; 3: 722–730.

    Article  CAS  PubMed  Google Scholar 

  14. Walsh R, Ortiz J, Foster P, Palma-Vargas J, Rosenblatt S, Wright F . Fungal and mycobacterial infections after Campath (alemtuzumab) induction for renal transplantation. Transpl Infect Dis 2008; 10: 236–239.

    Article  CAS  PubMed  Google Scholar 

  15. Heider U, Fleissner C, Zavrski I, Jakob C, Dietzel T, Eucker J et al. Treatment of refractory chronic lymphocytic leukemia with Campath-1H in combination with lamivudine in chronic hepatitis B infection. Eur J Haematol 2004; 72: 64–66.

    Article  PubMed  Google Scholar 

  16. Li QR, Zhang Q, Wang CY, Li YX, Wu B, Liu XX et al. Alteration of tight junctions in intestinal transplantation with use of alemtuzumab (Campath-1H). Clin Immunol 2009; 132: 141–143.

    Article  CAS  PubMed  Google Scholar 

  17. Cadwell K, Liu JY, Brown SL, Miyoshi H, Loh J, Lennerz JK et al. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 2008; 456: 259–264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Qu LL, Li QR, Jiang HT, Gu LL, Zhang Q, Wang CY et al. Effect of anti-mouse CD52 monoclonal antibody on mouse intestinal intraepithelial lymphocytes. Transplantation 2009; 88: 766–772.

    Article  CAS  PubMed  Google Scholar 

  19. Loisel S, Ohresser M, Pallardy M, Dayde D, Berthou C, Cartron G et al. Relevance, advantages and limitations of animal models used in the development of monoclonal antibodies for cancer treatment. Crit Rev Oncol Hematol 2007; 62: 34–42.

    Article  PubMed  Google Scholar 

  20. Roberts SA, Hendry JH, Potten CS . Intestinal crypt clonogens: a new interpretation of radiation survival curve shape and clonogenic cell number. Cell Prolif 2003; 36: 215–231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Brittan M, Wright NA . Stem cell in gastrointestinal structure and neoplastic development. Gut 2004; 53: 899–910.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Barker N, van de Wetering M, Clevers H . The intestinal stem cell. Genes Dev 2008; 22: 1856–1864.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bloom DD, Hu HZ, Fechner JH, Knechtle SJ . T-lymphocyte alloresponses of campath-1H-treated kidney transplant patients. Transplantation 2006; 81: 81–87.

    Article  PubMed  Google Scholar 

  24. Cheng H, Bjerknes M . Whole population cell kinetics and postnatal development of the mouse intestinal epithelium. Anat Rec 1985; 211: 420–426.

    Article  CAS  PubMed  Google Scholar 

  25. Clarke RM . The effect of growth and of fasting on the number of villi and crypts in the small intestine of the albino rat. J Anat 1972; 112: 27–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Dekaney CM, Fong JJ, Rigby RJ, Lund PK, Henning SJ, Helmrath MA . Expansion of intestinal stem cells associated with long-term adaptation following ileocecal resection in mice. Am J Physiol Gastrointest Liver Physiol 2007; 293: G1013–G1022.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the National Basic Research Program (973 Program) in China (nos. 2009CB522405 and 2007CB513005), the Key Project of National Natural Science Foundation in China (30830098), the National Natural Science Foundation in China (81070375), the Scientific Research Fund in Jiangsu Province (BK2009317), the National Key Project of Scientific and Technical Supporting Programs Funded by the Ministry of Science and Technology of China (2008BAI60B06) and the Military Scientific Research Fund (0603AM117). We thank the Deutscher Akademischer Austauschdienst Researcher Fellowship (Bioscience Special Program, Germany) on behalf of Dr Qiurong Li.

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  1. Dr JS Li, Institute of General Surgery, Jinling Hospital, No. 305 East Zhongshan Road, Nanjing 210002, China. E-mail: liqiurong@yahoo.com

Authors and Affiliations

  1. Department of Surgery, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China

    Qiurong Li, Qiang Zhang, Chenyang Wang, Ning Li & Jieshou Li

  2. Department of Pathology, Jinling Hospital, Nanjing, China

    Shaojun Jiang

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Li, Q., Zhang, Q., Wang, C. et al. The response of intestinal stem cells and epithelium after alemtuzumab administration. Cell Mol Immunol 8, 325–332 (2011). https://doi.org/10.1038/cmi.2011.10

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