Expression in transgenic mice of class I histocompatibility antigens controlled by the metallothionein promoter.

Abstract

To study the effects of increased expression of major histocompatibility complex class I molecules on the development of self-tolerance, transgenic mice were produced that expressed the H-2Kb gene under the control of the metallothionein promoter. Administration of zinc enhanced transgene expression in liver, kidney and exocrine pancreas. No evidence suggestive of an autoimmune response was found in transgene-expressing tissues in mice otherwise allogeneic to H-2K0. Despite this lack of responsiveness in vivo, T cells could be stimulated in vitro to lyse H-2Kb-bearing target cells. No infiltration was detected in transgenic mice after irradiation and reconstitution with bone marrow cells. When spleen cells were used for reconstitution, however, dense lymphocytic infiltration was seen, particularly in the portal tracts of the liver, and this was accompanied by piecemeal necrosis and apoptosis of periportal hepatocytes. This aggressive response progressively diminished with time, and by 12 weeks after reconstitution many of the portal tracts were free of infiltration while the others showed no accompanying necrosis. The picture at this stage was similar to that seen in chronic persistent hepatitis. These results suggest that, in addition to negative selection in the thymus, peripheral mechanisms not involving clonal deletion or permanent clonal anergy can prevent immune responses to self molecules.

T lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells

“…16,17 Support for a role of hepatocytes as APCs in vivo comes from studies performed using transgenic mouse models. When Alb-K b and Met-K b transgenic mice, expressing the allo-MHC H-2K b molecule on hepatocytes, 18,19 were adoptively transferred with TCR transgenic T cells specific for H-2K b , T cell primary activation occurred in the liver independently of lymphoid tissues, thus supporting the thesis that hepatocytes can interact with circulating T cells in vivo. 6,8 Such results suggest that hepatocytes can present antigen to both CD8 ϩ T lymphocytes and possibly also NKT lymphocytes, and thus play a major role in antigen-specific recruitment of these cells to the liver.…”

“…B10.BR and C57BL/6 mice were purchased from the Animal Resources Centre (Perth, Australia). Met-K b and Alb-K b transgenic mice expressing H-2K b on hepatocytes under the control of the sheep metallothionein 19 or the mouse albumin promoters, 18 respectively, were kindly provided by Drs Grant Morahan and Jacques Miller (WEHI, Australia) and Dr Bernd Arnold (DKZ, Germany). Des-TCR, which express an H-2K b -specific TCR, 25 were a gift of Dr. Bernd Arnold.…”

Antigen Nonspecific Suppression of T Cell Responses by Activated Stimulation-Refractory CD4+ T Cells

“…The more intense the stimulation, the greater the number of activated T cells and hence bystander suppression of the ongoing T cell response. Indeed in many in vivo models, continuous high-dose Ag results in a state of immune paralysis, in which T cells become unresponsive to stimulation (31)(32)(33)(34)(35). Bystander suppression by activated T cells may provide balance in immune responses so as to prevent immune exhaustion and thereby allow effective memory T cell development (36,37).…”

Molecular and cellular aspects of immunologic tolerance

“…Genes for a foreign antigen can be placed under the control of the insulin promoter [33, 341, thus targeting gene expression to the insulin-secreting cells of the pancreatic islets of Langerhans. Alternatively, targeting can be chiefly to the liver, through using the metallothionein promoter [35] or to the exocrine portion of the pancreas through use of the elastase promoter (361. If, as is usually the case in most founder lines, the transgene is expressed early in ontogeny, T cell tolerance to the antigen in question can develop (reviewed in [37,381).…”

“…Any specific B cells found to be present can then be placed singly into clonal microcultures with appropriately strong immunogens to ask whether the cell can develop into an antibody-forming clone. It turns out that, depending on the strength of the negative signal, both clonal abortion and clonal anergy can be induced [14,35,171 and indeed one and the same reagent can cause clonal abortion at high concentration and clonal anergy at low [17].…”