Slightly off topic.
Interleukin-4 Pivotal in Development of Transplant Arteriosclerosis
--------------------------------------------------------------------------------
WESTPORT, CT (Reuters Health) Aug 10 - Interleukin-4 plays a critical role in the development of transplant arteriosclerosis in the absence of CD40-CD154 costimulation, UK researchers have determined.
Although blockade of the CD40-CD154 costimulatory pathway (important in the primary activation of T cells) inhibits autoimmune disease, the researchers explain, hindering CD154, even in the absence of CD8+ T cells, does not prevent transplant arteriosclerosis, a significant cause of allograft rejection.
Dr. Kathryn J. Wood, from the University of Oxford, and colleagues sought to determine what was responsible for the development of transplant arteriosclerosis when CD40-CD154 costimulation was absent, using CD40 knockout mice in an abdominal aortic allograft model.
Transplant arteriosclerosis developed regardless of whether CD40 was present on recipient antigen-presenting cells (APCs) and in the presence of anti-CD8 monoclonal antibody, the authors report in the Journal of Immunology for July 1. This suggests, they infer, that APCs play no role in transplant arteriosclerosis in this model.
"This was somewhat surprising," the investigators say, "because three of the major effector mechanisms implicated in the development of this disease were either reduced or impaired in CD40(-/-) mice."
CD40 knockout mouse allograft recipients showed significantly increased infiltration of eosinophils (52 eosinophils/grid) compared with heterozygous littermates (8 eosinophils/grid) (p < 0.05), the results indicated, as well as markedly increased IL-4 production (+181%).
Knockout mice treated with anti-IL-4 antibody showed significantly less transplant arteriosclerosis (18% intimal proliferation) than did untreated mice (46% proliferation) (p < 0.01), the researchers note, and such treatment abolished the eosinophil infiltrate.
Expression of eotaxin, a strong eosinophil chemoattractant, was also increased in knockout mouse allograft recipients and was reduced after anti-IL-4 treatment.
"IL-4 plays a pivotal role in the development of transplant arteriosclerosis in CD40(-/-) recipients in the absence of CD8+ T cells," the authors conclude. "Moreover, IL-4 [is] responsible for the strong intragraft eosinophil infiltration and eotaxin mRNA expression of aortic grafts implanted in CD40(-/-) recipients."
"IL-4-mediated transplant arteriosclerosis is an obstacle that has to be overcome if CD40-CD154 costimulatory blockade is to be developed into a successful strategy in clinical transplantation," the researchers suggest.
J Immunol 2001;167:532-541 |
