Engrafted human cells generate adaptive immune responses to Mycobacterium bovis BCG infection in humanized mice
dc.contributor.author | Lee, Jinhee | |
dc.contributor.author | Brehm, Michael A. | |
dc.contributor.author | Greiner, Dale L. | |
dc.contributor.author | Shultz, Leonard D. | |
dc.contributor.author | Kornfeld, Hardy | |
dc.date | 2022-08-11T08:08:29.000 | |
dc.date.accessioned | 2022-08-23T15:56:58Z | |
dc.date.available | 2022-08-23T15:56:58Z | |
dc.date.issued | 2013-12-07 | |
dc.date.submitted | 2014-03-11 | |
dc.identifier.citation | 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. <a href="http://dx.doi.org/10.1186/1471-2172-14-53">Link to article on publisher's site</a> | |
dc.identifier.issn | 1471-2172 (Linking) | |
dc.identifier.doi | 10.1186/1471-2172-14-53 | |
dc.identifier.pmid | 24313934 | |
dc.identifier.uri | http://hdl.handle.net/20.500.14038/30087 | |
dc.description.abstract | 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. | |
dc.language.iso | en_US | |
dc.relation | <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=24313934&dopt=Abstract">Link to Article in PubMed</a> | |
dc.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 (<a href="http://creativecommons.org/licenses/by/2.0">http://creativecommons.org/licenses/by/2.0</a>), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. | |
dc.subject | Animal model | |
dc.subject | BCG | |
dc.subject | Tuberculosis | |
dc.subject | BLT mice | |
dc.subject | NSG mice | |
dc.subject | Bacterial Infections and Mycoses | |
dc.subject | Immunity | |
dc.subject | Immunology of Infectious Disease | |
dc.title | Engrafted human cells generate adaptive immune responses to Mycobacterium bovis BCG infection in humanized mice | |
dc.type | Journal Article | |
dc.source.journaltitle | BMC immunology | |
dc.source.volume | 14 | |
dc.identifier.legacyfulltext | https://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1322&context=faculty_pubs&unstamped=1 | |
dc.identifier.legacycoverpage | https://escholarship.umassmed.edu/faculty_pubs/323 | |
dc.identifier.contextkey | 5319138 | |
refterms.dateFOA | 2022-08-23T15:56:58Z | |
html.description.abstract | <p>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.</p> <p>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.</p> <p>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.</p> | |
dc.identifier.submissionpath | faculty_pubs/323 | |
dc.contributor.department | Program in Molecular Medicine | |
dc.contributor.department | Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine | |
dc.source.pages | 53 |