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Engrafted human cells generate adaptive immune responses to Mycobacterium bovis BCG infection in humanized mice

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اقرأ أكثر حفظ في قائمتي
  • معلومة اضافية
    • Contributors:
      Program in Molecular Medicine; Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine
    • الموضوع:
      2022
    • Collection:
      University of Massachusetts, Medical School: eScholarship@UMMS
    • نبذة مختصرة :
      BACKGROUND: Currently used mouse models fail to fully reflect human immunity to tuberculosis (TB), which hampers progress in research and vaccine development. Bone marrow-liver-thymus (BLT) mice, generated by engrafting human fetal liver, thymus, and hematopoietic stem cells in severely immunodeficient NOD/SCID/IL-2Rgamma(-/-) (NSG) mice, have shown potential to model human immunity to infection. We engrafted HLA-A2-positive fetal tissues into NSG mice transgenically expressing human leukocyte antigen (HLA)-A2.1 (NSG-A2) to generate NSG-A2-BLT mice and characterized their human immune response to Mycobacterium bovis bacillus Calmette-Guerin (BCG) infection to assess the utility of this model for investigating human TB. RESULTS: NSG-A2-BLT mice were infected intravenously with BCG and the immune response of engrafted human immune cells was characterized. After ex vivo antigenic stimulation of splenocytes, interferon (IFN)-gamma-producing cells were detected by ELISPOT from infected, but not uninfected NSG-A2-BLT mice. However, the levels of secreted IFN-gamma, determined by ELISA, were not significantly elevated by antigenic stimulation. NSG-A2-BLT mice were susceptible to BCG infection as determined by higher lung bacillary load than the non-engrafted control NSG-A2 mice. BCG-infected NSG-A2-BLT mice developed lung lesions composed mostly of human macrophages and few human CD4+ or CD8+ T cells. The lesions did not resemble granulomas typical of human TB. CONCLUSIONS: Engrafted human immune cells in NSG-A2-BLT mice showed partial function of innate and adaptive immune systems culminating in antigen-specific T cell responses to mycobacterial infection. The lack of protection was associated with low IFN-gamma levels and limited numbers of T cells recruited to the lesions. The NSG-A2-BLT mouse is capable of mounting a human immune response to M. tuberculosis in vivo but a quantitatively and possibly qualitatively enhanced effector response will be needed to improve the utility of this model for TB research.
    • Relation:
      Link to Article in PubMed; Lee J, Brehm MA, Greiner D, Shultz LD, Kornfeld H. Engrafted human cells generate adaptive immune responses to Mycobacterium bovis BCG infection in humanized mice. BMC Immunol. 2013 Dec 7;14:53. doi:10.1186/1471-2172-14-53. Link to article on publisher's site; 1471-2172 (Linking); http://hdl.handle.net/20.500.14038/30087; https://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1322&context=faculty_pubs&unstamped=1; https://escholarship.umassmed.edu/faculty_pubs/323; 5319138; faculty_pubs/323
    • الرقم المعرف:
      10.1186/1471-2172-14-53
    • الدخول الالكتروني :
      https://doi.org/10.1186/1471-2172-14-53
      https://hdl.handle.net/20.500.14038/30087
      https://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1322&context=faculty_pubs&unstamped=1
      https://escholarship.umassmed.edu/faculty_pubs/323
    • Rights:
      Copyright 2013 Lee et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
    • الرقم المعرف:
      edsbas.87D8A304