Cytokine Detection and Modulation in Acute Graftvs. Host Disease in Mice

[摘要] A murine model for acute lethal graftvs. host disease (GVHD) wasused to study the role that a number of cytokines play in the development of lethal GVHD. In this study we focused on the role of IL-1, IL-2, IL-4, IL-6, IFN-γand TNF-α. Lethally irradiated (C57BL × CBA)F1 mice were reconstituted either with 107allogeneic BALB/c spleen cells or with a similar number of syngeneic cells, as a control. A significant rise in serum levels of IL-6, TNF-αand IFN-γlevels was found in allogeneically reconstituted mice. This is in contrast to thesyngeneic control group in which no rise was seen. Serum IL-2 and IL-4 levels were below the detection limit. In the supernatant of Con A stimulated spleen cells from allogeneically reconstituted miceIL-6, IFN-γand TNF-αconcentrations were increased. Theexpression of mRNA for cytokines as detected by reversetranscription PCR was studied in spleen cells. In the allogeneicreconstituted mice the mRNA expression of IL-1α, IL-2, IL-6,IFN-γand TNF-αdisplayed faster kinetics compared withthat in syngeneic reconstituted mice. The effect of treatment withrecombinant cytokines, antibodies to cytokines and to cytokinereceptors on the development of GVHD was investigated.Administration of recombinant IL-2 to allogeneically reconstitutedmice strongly increased the morbidity and mortality whereasinjection of IL-1αand TNF-αdid not influence survival.Administration of antibodies against IL-2 or the IL-2 receptordecreased the morbidity and mortality. Anti-IL-6, anti-IFN-γ,and anti-TNF-αmAB, on the other hand, did not affect themorbidity and mortality of GVHD. The results of this study suggestsuccessive waves of cytokine-secreting cell populations consistentwith the induction of an inflammatory response in the development ofacute GVH disease.

[学科分类] 生理学与病理学