Induction of donor-specific T-cell hyporesponsiveness using dexamethasone-treated dendritic cells in two fully mismatched rat kidney transplantation models.
BACKGROUND
Dendritic cells (DC) can exert powerful immune stimulatory as well as regulatory functions and are therefore important tools for therapeutic strategies. Dexamethasone (Dex) was previously shown to inhibit DC maturation and to induce regulatory properties both in vitro and in vivo. Here, we investigated the immunoregulatory role of DexDC in two different rat acute rejection models of kidney transplantation.


METHODS
Rat DC were generated from BN and DA bone marrow in the presence of the corticosteroid, Dex. The function of Dex-modulated DC was analyzed in vitro and in vivo, using a BN to LEW and a DA to LEW renal transplantation model in the absence of other forms of immunosuppression. T cells of transplanted rats were isolated and restimulated with donor mature DC (lipopolysaccharide [LPS] or CD40L activated). T-cell responsiveness was analyzed by proliferative capacity and IFN-gamma production.


RESULTS
Stimulation of Dex-modulated rat DC with LPS resulted in normal IL-10 production, whereas synthesis of IL-12 was impaired. In accordance, the capacity of LPS-DexDC to stimulate T-cell activation was decreased. In both renal transplantation models, treatment with donor-derived LPS-DexDC induced a significant donor-specific T-cell hyporesponse. However, pretreatment did not result in a prolonged graft survival.


CONCLUSIONS
In two fully mismatched kidney transplantation models, donor-derived LPS-DexDC induce a donor-specific T-cell hyporesponse. However, in this setting allograft survival was not improved, suggesting an important role for T cells with indirect alloreactivity. Understanding the underlying mechanism involved in the rejection process will improve the development of a cell-based immunotherapy.
Stax
Annelein M
AM
Department Nephrology, Leiden University Medical Center, Leiden, The Netherlands.
Gelderman
Kyra A
KA
Schlagwein
Nicole
N
Essers
Maria C
MC
Kamerling
Sylvia W A
SW
Woltman
Andrea M
AM
van Kooten
Cees
C
D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D000818:Animals; D002450:Cell Communication / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D006084:Graft Rejection / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D016030:Kidney Transplantation / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D023421:Models, Animal; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation*
D000305:Adrenal Cortex Hormones; D008070:Lipopolysaccharides; D016753:Interleukin-10; D003907:Dexamethasone; D007371:Interferon-gamma