EARLY INCREASED CHEMOKINE EXPRESSION AND PRODUCTION IN MURINE ALLOGENEIC SKIN GRAFTS IS MEDIATED BY NATURAL KILLER CELLS1


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Abstract

Background.Increased expression of chemokine mRNA is observed in allogeneic but not syngeneic skin grafts 3–4 days after transplantation. The recipient cells mediating this early inflammatory response in allografts remain unidentified.Methods.Isogeneic and allogeneic skin grafts were transplanted to euthymic and athymic nude mice. mRNA expression and protein production of macrophage inflammatory protein-1α (MIP-1α), MIP-1β, and the murine homolog of Groα, i.e. KC, from graft homogenates retrieved 3–4 days posttransplantation was tested by Northern blot hybridization and ELISA. To deplete NK cells, recipients were treated with anti-asialo GM1 (ASGM1) antisera or with anti-NK1.1 mAb before transplantation.Results.Expression of KC, MIP-1α, and MIP-1β mRNA was equivalent in C57BL/6 allogeneic skin grafts and BALB/c isografts at day 2 posttransplant. At day 3 posttransplant, chemokine mRNA levels decreased in isografts but were maintained at high levels in the allografts. Increased early chemokine mRNA was also observed in C57BL/6, but not BALB/c+/+ grafts on BALB/c athymicnu/nu recipients. Treatment of allograft recipients with ASGM1 or with anti-NK1.1 antibody eliminated NK cells from the spleen and allograft infiltrating cell populations and decreased early chemokine mRNA levels in allografts 60–70%. Analyses of allograft homogenates indicated increased levels of KC, MIP-1α, and MIP-1β protein at day 4 posttransplant that were decreased in recipients depleted of NK cells. Early chemokine mRNA levels were equivalent in isogeneic and semiallogeneic F1 grafts.Conclusions.Early chemokine mRNA expression and protein production in allogeneic skin grafts is amplified by recipient natural killer (NK) cells. These results indicate a novel function for infiltrating NK cells in mediating early increased intra-allograft chemokine production and inflammation during the initiation of acute rejection.

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