Play it, Jen

Every good movie has a piano player somewhere in the background--
sometimes seen, usually unseen.
Seldom really noticed.
The feeling, the very soul of a scene, is created by that person tinkering at the keys.
It has been said, "All the world's a stage."
Well then...Play it, Jen.

My Photo
Location: Over Yonder, Missouri

I'm a California Native transplanted to the Missouri Ozarks. I've learned how to chase cows in high heels and load hay faster than you can say "Coco Chanel." These are some of our pictures and stories of living in a land with breath-taking beauty and adventure around every bend.

Thursday, July 13, 2006

Ideas on Biliary Atresia

Biliary Atresia -- Mechanism and Outcome
Biliary atresia is the most common indication for liver transplantation in children, yet its cause is elusive. One theory implicates a virus-initiated process that culminates in autoimmune-mediated destruction of bile ducts. New insight has been provided by the rhesus rotavirus (RRV)-induced murine model of biliary atresia that resembles the human disease. In this model, immune-mediated inflammation of bile ducts progresses to biliary obstruction and death by 3 weeks of age.

During the plenary session at this year's AASLD meeting, Mack and colleagues[1] reported the results of a study to test the theory that autoreactive T cells are present in the RRV-model, and thus that transfer of these cells should elicit an autoimmune attack on the bile ducts of a recipient mouse. Liver lymphocytes from RRV-diseased animals were adoptively transferred into immunodeficient mice; this transfer resulted in marked cellular infiltration surrounding the bile ducts of all mice. The infiltrates were composed, in part, of the adoptively transferred CD3+ T cells. This periductular inflammation was not found in the control group and was organ-specific. The T cells migrated to bile duct epithelium in an antigen-specific fashion, suggesting autoreactive T-cell-mediated bile duct injury. Future studies are needed that include T-cell proliferation assays aimed at investigating bile duct epithelium as the target antigen.

Narayanaswamy and colleagues[2] characterized the nature of the inflammatory process in biliary atresia in 21 affected infants. They noted a persistent inflammatory process that involved both a nonpolarized T-helper cell (Th1 and Th2) response, as well as macrophages. The intensity of the inflammatory process correlated directly with outcome. A Th1 commitment also occurs in the murine model. The livers of mice with induced biliary atresia demonstrate increased numbers of T lymphocytes along with high-level expression of Th1-type cytokines (interleukin [IL]-2 and interferon [IFN]-alpha). By 2 weeks post infection, the disease is marked by elevated numbers of macrophages concurrent with high expression of the proinflammatory cytokine TNF-alpha. In mouse models of other inflammatory diseases, TNF- blockade results in rapid recovery or prevention of disease. In view of the similar increase in expression of TNF-alpha at time of diagnosis in infants with biliary atresia, Hendrickson and colleagues[3] hypothesized that elimination of a functional TNF pathway in RRV-infected mice would result in enhanced recovery. Although RRV-infected mice had elevated expression of TNF-alpha, depletion of this cytokine was not sufficient to affect the progression of bile duct inflammation and obstruction. In related murine studies, it has been noted that the absence of IFN-gamma improves cholestasis by decreasing the tropism of lymphocytes to bile ducts. On the basis of previous findings of high levels of expression of the Th1 cytokine IL-12 at the time of duct obstruction, Mohanty and colleagues[4] hypothesized that loss of IL-12 would prevent bile duct obstruction. They found that loss of functional IL-12 did not prevent bile duct obstruction, attenuated -- but did not abolish -- the Th1 response, and induced high expression of type-1 IFNs and infiltration of bile ducts by neutrophils.

Cumulatively, these studies strongly support a role for type-1 IFNs and neutrophils in the pathogenesis of biliary atresia. Additional elucidation of this process may enable specific immunomodulatory therapy for this condition.


Post a Comment

<< Home