PMID- 24313934
OWN - NLM
STAT- MEDLINE
DCOM- 20140620
LR  - 20211021
IS  - 1471-2172 (Electronic)
IS  - 1471-2172 (Linking)
VI  - 14
DP  - 2013 Dec 7
TI  - Engrafted human cells generate adaptive immune responses to Mycobacterium bovis 
      BCG infection in humanized mice.
PG  - 53
LID - 10.1186/1471-2172-14-53 [doi]
AB  - 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.
FAU - Lee, Jinhee
AU  - Lee J
AD  - Department of Medicine, University of Massachusetts Medical School, Worcester, 
      MA, USA. jinhee.lee@umassmed.edu.
FAU - Brehm, Michael A
AU  - Brehm MA
FAU - Greiner, Dale
AU  - Greiner D
FAU - Shultz, Leonard D
AU  - Shultz LD
FAU - Kornfeld, Hardy
AU  - Kornfeld H
LA  - eng
GR  - P01 AI046629/AI/NIAID NIH HHS/United States
GR  - R01 HL081149/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20131207
PL  - England
TA  - BMC Immunol
JT  - BMC immunology
JID - 100966980
RN  - 0 (Il2rg protein, mouse)
RN  - 0 (Interleukin Receptor Common gamma Subunit)
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
MH  - Adaptive Immunity/*immunology
MH  - Animals
MH  - CD4-Positive T-Lymphocytes/immunology/metabolism
MH  - CD8-Positive T-Lymphocytes/immunology/metabolism
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Heterografts/cytology/*immunology/microbiology
MH  - Host-Pathogen Interactions/immunology
MH  - Humans
MH  - Interferon-gamma/immunology/metabolism
MH  - Interleukin Receptor Common gamma Subunit/deficiency/genetics
MH  - Lung/immunology/metabolism/microbiology
MH  - Macrophages/immunology/metabolism
MH  - Mice
MH  - Mice, Inbred NOD
MH  - Mice, Knockout
MH  - Mice, SCID
MH  - Mice, Transgenic
MH  - Mycobacterium bovis/*immunology/physiology
MH  - Tuberculosis/*immunology/microbiology/veterinary
PMC - PMC3924189
EDAT- 2013/12/10 06:00
MHDA- 2014/06/21 06:00
PMCR- 2013/12/07
CRDT- 2013/12/10 06:00
PHST- 2013/08/07 00:00 [received]
PHST- 2013/12/02 00:00 [accepted]
PHST- 2013/12/10 06:00 [entrez]
PHST- 2013/12/10 06:00 [pubmed]
PHST- 2014/06/21 06:00 [medline]
PHST- 2013/12/07 00:00 [pmc-release]
AID - 1471-2172-14-53 [pii]
AID - 10.1186/1471-2172-14-53 [doi]
PST - epublish
SO  - BMC Immunol. 2013 Dec 7;14:53. doi: 10.1186/1471-2172-14-53.