PMID- 21611197
OWN - NLM
STAT- MEDLINE
DCOM- 20110912
LR  - 20211020
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 6
IP  - 5
DP  - 2011
TI  - Expression of HLA class II molecules in humanized NOD.Rag1KO.IL2RgcKO mice is 
      critical for development and function of human T and B cells.
PG  - e19826
LID - 10.1371/journal.pone.0019826 [doi]
LID - e19826
AB  - BACKGROUND: Humanized mice able to reconstitute a surrogate human immune system 
      (HIS) can be used for studies on human immunology and may provide a predictive 
      preclinical model for human vaccines prior to clinical trials. However, current 
      humanized mouse models show sub-optimal human T cell reconstitution and limited 
      ability to support immunoglobulin class switching by human B cells. This 
      limitation has been attributed to the lack of expression of Human Leukocyte 
      Antigens (HLA) molecules in mouse lymphoid organs. Recently, humanized mice 
      expressing HLA class I molecules have been generated but showed little 
      improvement in human T cell reconstitution and function of T and B cells. 
      METHODS: We have generated NOD.Rag1KO.IL2RgammacKO mice expressing HLA class II 
      (HLA-DR4) molecules under the I-E(d) promoter that were infused as adults with 
      HLA-DR-matched human hematopoietic stem cells (HSC). Littermates lacking 
      expression of HLA-DR4 molecules were used as control. RESULTS: HSC-infused 
      HLA-DR4.NOD.Rag1KO.IL-2RgammacKO mice developed a very high reconstitution rate 
      (>90%) with long-lived and functional human T and B cells. Unlike previous 
      humanized mouse models reported in the literature and our control mice, the 
      HLA-DR4 expressing mice reconstituted serum levels (natural antibodies) of human 
      IgM, IgG (all four subclasses), IgA, and IgE comparable to humans, and elicited 
      high titers of specific human IgG antibodies upon tetanus toxoid vaccination. 
      CONCLUSIONS: Our study demonstrates the critical role of HLA class II molecules 
      for development of functional human T cells able to support immunoglobulin class 
      switching and efficiently respond to vaccination.
FAU - Danner, Rebecca
AU  - Danner R
AD  - US Military Malaria Vaccine Program, Naval Medical Research Center/Walter Reed 
      Army Institute of Research, Silver Spring, Maryland, United States of America.
FAU - Chaudhari, Snehal N
AU  - Chaudhari SN
FAU - Rosenberger, John
AU  - Rosenberger J
FAU - Surls, Jacqueline
AU  - Surls J
FAU - Richie, Thomas L
AU  - Richie TL
FAU - Brumeanu, Teodor-Doru
AU  - Brumeanu TD
FAU - Casares, Sofia
AU  - Casares S
LA  - eng
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20110517
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Histocompatibility Antigens Class II)
RN  - 0 (Homeodomain Proteins)
RN  - 0 (Il2rg protein, mouse)
RN  - 0 (Immunoglobulins)
RN  - 0 (Interleukin Receptor Common gamma Subunit)
RN  - 0 (Tetanus Toxin)
RN  - 128559-51-3 (RAG-1 protein)
SB  - IM
MH  - Animals
MH  - B-Lymphocytes/cytology/*immunology
MH  - CD8-Positive T-Lymphocytes/cytology/immunology
MH  - Hematopoietic Stem Cells/cytology/metabolism
MH  - Histocompatibility Antigens Class II/*immunology
MH  - Homeodomain Proteins/*metabolism
MH  - Humans
MH  - Immunization
MH  - Immunoglobulin Class Switching
MH  - Immunoglobulins/blood
MH  - Interleukin Receptor Common gamma Subunit/*deficiency/metabolism
MH  - Killer Cells, Natural/cytology/immunology
MH  - Kinetics
MH  - Lymphoid Tissue/immunology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Inbred NOD
MH  - Mice, Knockout
MH  - T-Lymphocytes/cytology/*immunology
MH  - T-Lymphocytes, Regulatory/cytology/immunology
MH  - Tetanus Toxin/immunology
PMC - PMC3096643
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2011/05/26 06:00
MHDA- 2011/09/13 06:00
PMCR- 2011/05/17
CRDT- 2011/05/26 06:00
PHST- 2010/12/08 00:00 [received]
PHST- 2011/04/18 00:00 [accepted]
PHST- 2011/05/26 06:00 [entrez]
PHST- 2011/05/26 06:00 [pubmed]
PHST- 2011/09/13 06:00 [medline]
PHST- 2011/05/17 00:00 [pmc-release]
AID - PONE-D-10-06080 [pii]
AID - 10.1371/journal.pone.0019826 [doi]
PST - ppublish
SO  - PLoS One. 2011;6(5):e19826. doi: 10.1371/journal.pone.0019826. Epub 2011 May 17.