TITLE

1008. Characterization of Peripheral Regulatory T Cell Phenotype Generated in Molecular Chimeras by Gene Therapy

AUTHOR(S)
Paez-Cortez, Jesus R.; Tian, Chaorui; Iacomini, John
PUB. DATE
June 2006
SOURCE
Molecular Therapy;Jun2006, Vol. 13, pS388
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Introduction. Donor-specific tolerance to MHC class I antigens can be achieved following reconstitution of mice with genetically modified autologous bone marrow cells expressing allogeneic MHC class I genes. The mechanisms by which CD4 T cells that recognize allogeneic antigens through the indirect pathway are rendered tolerant involve incomplete central thymic deletion and the generation of regulatory T cells. Here we assess the peripheral regulatory T cell phenotype generated in molecular chimeras by gene therapy.Methods. Bone marrow cells harvested from B10.AKM mice were transduced using a VSV G pseudotyped retrovirus carrying the gene encoding H-2Kb (Kb). B10.AKM recipients were reconstituted with mock or Kb transduced bone marrow and bone marrow cells from transgenic Tg361 TRC transgenic mice after lethal irradiation and T cell depletion. Tg361 cells recognize specific Kb peptides presented by I-Ak. At week 20, CD25+, CD25- and Foxp3+ expression were determined in host CD4+ T cells as well in donor alloreactive Tg361 derived cells.Results. There was no difference in the frequency of the total CD4+CD25+ T cell population between animal receiving mock or Kb transduced bone marrow over 20 weeks period after reconstitution. However, the frequency of CD4+Foxp3+ T cells was increased in animals receiving Kb transduced bone marrow (18-24%) compared with controls (8-12%). The majorities of the cells expressing the alloreactive Tg361 TCR were CD25- and up to 18% of them expressed Foxp3. The total frequency of CD4+Foxp3+ T cell population was higher in animals receiving Kb transduced bone marrow (18-25%) compared to controls (5-8 %).Conclusions. In Kb molecular chimeras the generated CD4 T cell regulatory population has predominantly a CD4+CD25-Foxp3+ rather than CD4+CD25+Foxp3+ phenotype. The CD4 regulatory T cell subpopulation is increased in animals expressing Kb on bone marrow derived cells and 18% of the allogeneic Tg361 cells that persist in the host express Foxp3. The generation and high frequency of donor specific CD4+Foxp3+ T cells in transduced animals might be responsible for prevention of alloreactive CD4 T cells responses that lead to rejection.Molecular Therapy (2006) 13, S388–S389; doi: 10.1016/j.ymthe.2006.08.1102
ACCESSION #
25974621

 

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