Effect of neonatal thymectomy on experimental autoimmune hepatitis in mice.

Abstract

Using an autoimmune hepatitis model of A/J mice which was prepared with immunization by syngeneic crude liver proteins, various influences of neonatal thymectomy were studied by observations of histological liver changes, autoantibody to liver-specific membrane lipoprotein (LSP), delayed-type hypersensitivity (DTH) to LSP, and purified protein derivative (PPD), and suppressor activity to LSP. The liver changes in the thymectomized mice were more intense than those in the non-thymectomized controls. Production of the anti-LSP autoantibodies and positive DTH to syngeneic LSP could be recognized in both groups of the thymectomized mice and the non-thymectomized controls, but the levels of those were higher in the former. In the level of DTH to PPD the thymectomized mice were lower than the non-thymectomized controls. Adoptive transfer experiments showed that suppressor activity to LSP was reduced in the spleen cells of neonatally thymectomized mice. This experiment suggests that neonatal thymectomy is apt to abolish tolerance to LSP on account of depressed suppressor activity to autoantigen, and accordingly liver damage is increased Keywords experimental hepatitis liver-specific membrane lipoprotein neonatal thymectomy suppressor cells

Animal models of autoimmune hepatitis

“…The transient liver damage produced in these models was characterized by perivascular infiltrates, mononuclear portal infiltrates and lobular hepatitis [98]. Antibodies to liver-specific proteins were produced; liver-specific T-cell responses were demonstrated; and counter-regulation of the autoreactive response by the thymus was recognized (TaBle 1) [99].…”

“…Mononuclear portal infiltrates Lobular hepatitis and perivascular infiltrates Antibodies to liver-specific protein T-cell vaccination experiments [97] Neonatal thymectomy Delayed hypersensitivity to liver-specific protein Decreased T regulatory cells [99] Cytokine induction IFN-g or TNF-a produce hepatocyte apoptosis TGF-b suppresses cytotoxic T cells [66,101,105] Concanavalin A T-cell induction…”

Mouse Models for Experimental Autoimmune Hepatitis: Limits and Chances

“…Retrospectively, these are very interesting because it has been shown by Asano et al [22] that neonatal thymectomy prevents the proper development of T reg . Therefore, their data suggest that liver-specific T cell-mediated autoimmune responses are controlled by the T reg population [21] . It is supposed that spontaneously developed autoimmune diseases are caused by a lack of functional regulatory activity by these cells.…”

“…A new aspect in EAH was brought in by Watanabe et al [21] when they found that histological hepatitis, the production of autoantibodies to LSP and delayed-type hypersensitivity to LSP were pronounced in mice after a neonatal thymectomy. The same was true for the disease after adoptively transferring the splenocytes.…”

Immunopathogenic Mechanisms of Autoimmune Hepatitis: How Much Do We Know from Animal Models?

“…The presence of liver autoantigen-specific T cells was demonstrated later by Lohse et al, who induced EAH by immunization of C57BL/6 mice with a crude 100,000 g supernatant of syngeneic liver homogenate (S-100) emulsified in complete Freund’s adjuvant [79]. Many follow-up studies used the S-100 injection model in various inbred mouse strains giving rise to valuable information on effector cells and regulatory phenomena in liver-specific immune reactions [80,81,82]. In addition, it has also become evident that an external trigger is required to induce acute and/or chronic hepatitis.…”