Autoimmune liver diseases, such as autoimmune hepatitis (AIH) and primary biliary cirrhosis, often have severe consequences for the patient. Because of a lack of appropriate animal models, not much is known about their potential viral etiology. Infection by liver-tropic viruses is one possibility for the breakdown of self-tolerance. Therefore, we infected mice with adenovirus Ad5 expressing human cytochrome P450 2D6 (Ad-2D6). Ad-2D6–infected mice developed persistent autoimmune liver disease, apparent by cellular infiltration, hepatic fibrosis, “fused” liver lobules, and necrosis. Similar to type 2 AIH patients, Ad-2D6–infected mice generated type 1 liver kidney microsomal–like antibodies recognizing the immunodominant epitope WDPAQPPRD of cytochrome P450 2D6 (CYP2D6). Interestingly, Ad-2D6–infected wild-type FVB/N mice displayed exacerbated liver damage when compared with transgenic mice expressing the identical human CYP2D6 protein in the liver, indicating the presence of a stronger immunological tolerance in CYP2D6 mice. We demonstrate for the first time that infection with a virus expressing a natural human autoantigen breaks tolerance, resulting in a chronic form of severe, autoimmune liver damage. Our novel model system should be instrumental for studying mechanisms involved in the initiation, propagation, and precipitation of virus-induced autoimmune liver diseases.

Chemokines, such as CXCL10, promote hepatic inflammation in chronic or acute liver injury through recruitment of leukocytes to the liver parenchyma. The CXCL10 receptor CXCR3, which is expressed on a subset of leukocytes, plays an important part in Th1-dependent inflammatory responses. Here, we investigated the role of CXCL10 in chemically induced liver fibrosis. We used carbon tetrachloride (CCl4) to trigger chronic liver damage in wildtype C57BL/6 and CXCL10-deficient mice. Fibrosis severity was assessed by Sirius Red staining and intrahepatic leukocyte subsets were investigated by immunohisto-chemistry. We have further analyzed hepatic stellate cell (HSC) distribution and activation and investigated the effect of CXCL10 on HSC motility and proliferation. In order to demonstrate a possible therapeutic intervention strategy, we have examined the anti-fibrotic potential of a neutralizing anti-CXCL10 antibody. Upon CCl4 administration, CXCL10-deficient mice showed massively reduced liver fibrosis, when compared to wildtype mice. CXCL10-deficient mice had less B- and T lymphocyte and dendritic cell infiltrations within the liver and the number and activity of HSCs was reduced. In contrast, natural killer (NK) cells were more abundant in CXCL10-deficient mice and granzyme B expression was increased in areas with high numbers of NK cells. Further detailed analysis revealed that HSCs express CXCR3, respond to CXCL10 and secrete CXCL10 when stimulated with IFNγ. Blockade of CXCL10 with a neutralizing antibody exhibited a significant anti-fibrotic effect. Our data suggest that CXCL10 is a pro-fibrotic factor, which participates in a crosstalk between hepatocytes, HSCs and immune cells. NK cells seem to play an important role in controlling HSC activity and fibrosis. CXCL10 blockade may constitute a possible therapeutic intervention for hepatic fibrosis.

No abstract

No abstract

Anti-CD3 therapy of type 1 diabetes results in a temporary halt of its pathogenesis but does not constitute a permanent cure. One problem is the reinfiltration of islets of Langerhans with regenerated, autoaggressive lymphocytes. We aimed at blocking such a reentry by neutralizing the key chemokine CXCL10. Combination therapy of diabetic RIP-LCMV and NOD mice with anti-CD3 and anti-CXCL10 antibodies caused a substantial remission of diabetes and was superior to monotherapy with anti-CD3 or anti-CXCL10 alone. The combination therapy prevented islet-specific T cells from reentering the islets of Langerhans and thereby blocked the autodestructive process. In addition, the local immune balance in the pancreas was shifted toward a regulatory phenotype. A sequential temporal inactivation of T cells and blockade of T-cell migration might constitute a novel therapy for patients with type 1 diabetes.Type 1 diabetes (T1D) is a serious autoimmune-mediated disease characterized by the progressive destruction of insulin-producing b-cells in the islets of Langerhans in the pancreas. Several attempts have been made to block the autoimmune destruction of these b-cells. One of the most promising therapies targets T cells using anti-CD3 antibodies such as hOKT3g1, teplizumab, and otelixizumab (also known as ChAglyCD3), which have been evaluated in several clinical trials of patients with new and recently diagnosed T1D, including the DEFEND-1 study (otelixizumab) and the Protégé study (teplizumab) (1-4). Similar to preclinical animal models (5,6), treatment with anti-CD3 antibodies was effective in decelerating the pathogenesis of T1D in clinical trials (1,7,8). Administration of anti-CD3 antibodies results in the inactivation of conventional T cells and the expansion of previously constrained regulatory T-cell (Treg) populations (9,10). Unfortunately, in the majority of treated patients, prevention of the decline in b-cell function lasted no longer than 1-2 years (1,2,8,11,12). In addition, many patients did not respond to the treatment, for unknown reasons (13).Several combination therapies (CTs) to achieve long-term protection in the majority of patients with T1D have been assessed in preclinical models. In addition to anti-CD3 antibodies, several immunomodulatory agents have been used, including administration of nasal proinsulin (14), Lactococcus lactis-secreting interleukin (IL)-10/proinsulin (15), cyclosporine A and vitamin D3 analog (TX527) (16), IL-1 receptor antagonist (17), anti-CD20 antibody (18), fingolimod (FTY720) (19), the selective sphingosine 1 phosphate 1 modulator ponesimod (20), dipeptidyl peptidase-4 inhibitor MK626 (21), and HSP60 peptide p277 (22). Many of these CTs were superior to monotherapies. However, with the exception of CTs with anti-CD3 antibody/fingolimod tested in the LEW.1AR1-iddm rat model (19) and anti-CD3 antibody/ponesimod investigated in the NOD mouse model (20), none included blocking cell migration into the islets. To avoid side effects associated with traditional immunosuppressive drugs,...