Immune mechanisms of Concanavalin A model of autoimmune hepatitis

Abstract

As a chronic inflammatory disease of the liver, the pathogenic mechanisms of autoimmune hepatitis (AIH) have not yet been elucidated, with prognosis and diagnosis remaining unsatisfied. Currently the only viable treatments of AIH are immunosuppressant application and liver transplantation. It is considered that lack of good animal AIH models is the main reason for the shortage of a simple and efficient cure. The Concanavalin A (Con A) model is a typical and well established model for investigating T-cell and macrophage dependent liver injury in mice, which closely mimics the pathogenesis mechanisms and pathological changes of patients, and is regarded as the best experimental model for AIH research so far. In this paper we elucidated the pathogenic mechanisms of AIH and the evolution of relative animal models. We go on to further focus on Con A-induced liver injury from the point of immunological mechanisms and the change of cytokine levels. Finally, we manifested the clinical significance of the AIH animal models and the challenges they would meet during their future development.

Betulin from Hedyotis hedyotidea ameliorates concanavalin A-induced and T cell-mediated autoimmune hepatitis in mice

“…Accumulating evidence suggests that CD4 + T cells [18,31] and NKT cells [25,28] are both critical in Con A-induced liver damage. After Con A challenge, polyclonal T cells are directly activated independently of TCR-mediated recognition; this activation is followed by the secretion of a large amount of Th1-type cytokines.…”

“…Although IL-4, IL-2, and IL-17 have been reported to promote inflammation in Con A-induced hepatitis, we did not observe elevation of these cytokines after Con A injection. Each cytokine is secreted with specific kinetics in response to Con A [31] . For example, after Con A challenge, circulating TNF-α levels reached the peak first and rapidly decrease; IL-2 and IL-4 reach a peak after approximately 2-4 h and then rapidly decrease; IFN-γ rises slowly, but this peak is long lasting; IL-6 reaches a peak after approximately 3 h and then decreases to a lower level after 6 h [18,31] .…”

“…Each cytokine is secreted with specific kinetics in response to Con A [31] . For example, after Con A challenge, circulating TNF-α levels reached the peak first and rapidly decrease; IL-2 and IL-4 reach a peak after approximately 2-4 h and then rapidly decrease; IFN-γ rises slowly, but this peak is long lasting; IL-6 reaches a peak after approximately 3 h and then decreases to a lower level after 6 h [18,31] . Ten hours after Con A injection, we found that Con A challenge resulted in a burst of IFN-γ, TNF-α, and IL-6 secretion ( Figure 3A-3C), results consistent with those from previous reports [32] .…”

Morphological Changes in Mice Liver in Dynamics of Concanavalin a - Induced Hepatitis

“…Найважливішим ланцюгом при Кон А-гепатиті є активація Т-клітин, в тому числі печінкових лімфоцитів-кіллерів, а також взаємодія Т-хелперів і макрофагів [1,4,5]. Однак серед чисельних літературних даних патоморфологічні особливості дії лек-тину на печінку описані поверхнево [6][7][8].…”

“…Суттєве збільшення дифузної інфільтрації печінки (вже через 6 год після введення КонА), ймовірно, пов'язано зі збільшенням синтезу хемокінів і молекул міжклітинної адгезії. ІФН-γ, що виділяється при активації Т-клітин Кон А, стимулює синусоїдальні ендотеліальні клітини, ЗР і гепатоцити до продукції численних хемокінів та адгезивних молекул, відповідальних за розвиток інфільтрації в печінку лейкоцитів, що, зрештою, призводить до розвитку гепа-титу [5,13,14]. Вогнищева інфільтрація, що спостерігалася периваскулярно та у стромі органа, на тлі локального геморагічного про-сякання паренхіми посилювалася пізніше.…”