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S. Schlickeiser, U. Pleyer, T. Ritter, X. Li, C. Appelt, H.-D. Volk, B. Sawitzki; Application of Gene-Engineered Dendritic Cells Secreting CTLA4-Ig and vIL-10 Leads to Prolongation of Corneal Allograft Survival. Invest. Ophthalmol. Vis. Sci. 2007;48(13):184.
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Recent approaches in transplantation medicine to induce donor-specific tolerance focus on the application of tolerogenic dendritic cells (DCs). It has been previously shown that adenoviral CTLA4-Ig or vIL-10 gene therapy successfully prevented allograft rejection in experimental keratoplasty. Since systemic administration of adenoviral particles is associated with undesired effects, this study focuses on the adoptive transfer of ex vivo gene-modified DCs.
DCs were generated from murine bone marrow of BALB/c mice. Cells were transduced with an adenovirus encoding vIL-10, CTLA4-Ig or EGFP as control. Allostimulatory capacity of DCs was determined by analyzing the proliferation of co-cultured allogeneic T cells. 7 days prior to experimental keratoplasty 2x106 transduced BALB/c donor DCs wereinjected i.v. into C57BL/6 mice receiving corneal allografts. Transplants weredaily graded by a rejection score based on cornea clarity and edema. Recipient alloantibody production and presence of Foxp3+ CD25+ CD4+ regulatory T cells in lymphoid organs were analyzed by flow cytometry.
In vitro, transgene-expression dramatically diminished the allo-stimulatory capacity after LPS stimulation of CTLA4-Ig transduced DCs and to a lesser extent of vIL-10 secreting cells. In contrast, adoptive transfer of CTLA4-Ig transduced DCs resulted in a moderate reduction of the rejection rate (p=0.455), whereas vIL-10 expressing DCs significantly prolonged allograft survival (p=0.0049). This was confirmed by increased frequencies of Foxp3+ CD25+ CD4+ regulatory T cells in spleen of animals receiving CTLA4-Ig (p=0.275) and vIL-10 (p=0.0495) transduced DCs, respectively.
Tolerogenic dendritic cells could successfully be generated by CTLA4-Ig and vIL-10 adenoviral gene transfer. Adoptive transfer of gene-engineered DCs is a promising approach for the prevention of corneal allograft rejection. (Supported in part by DFG Pl 150/14-1 and Ri 764/10-1)
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