Liver Tolerance and the Manipulation of Immune Outcomes

Holz, Lauren E.; McCaughan, Geoffrey W.; Benseler, Volker; Bertolino, Patrick; Bowen, David G.

doi:10.2174/187152808784165225

Cited by 14 publications

(12 citation statements)

References 105 publications

(167 reference statements)

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“…These results showed that, after low-dose rAAV treatment, direct activation of OT-I T cells exclusively by OVA-expressing hepatocytes was able to prime CTLs by week 1 and that these CTLs were not silenced at week 3. It was unexpected that hepatocytes could induce OT-I development into cytotoxic effectors by direct-presentation, as we have shown consistently in the past that naive CD8 Des T cells exclusively activated by hepatocytes developed poor CTL function and/or died prematurely, resulting in undetectable CTL activity in vivo (18). However, the outcome of intrahepatic Des T-cell activation had never been assessed in the setting of low H-2K b antigen expression.…”

Section: A Threshold In the Number Of Antigen-expressing Hepatocytesmentioning

confidence: 99%

Antigen expression level threshold tunes the fate of CD8 T cells during primary hepatic immune responses

Tay

Wong

McDonald

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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115

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CD8 T-cell responses to liver-expressed antigens range from deletional tolerance to full effector differentiation resulting in overt hepatotoxicity. The reasons for these heterogeneous outcomes are not well understood. To identify factors that govern the fate of CD8 T cells activated by hepatocyte-expressed antigen, we exploited recombinant adenoassociated viral vectors that enabled us to vary potential parameters determining these outcomes in vivo. Our findings reveal a threshold of antigen expression within the liver as the dominant factor determining T-cell fate, irrespective of T-cell receptor affinity or antigen cross-presentation. Thus, when a low percentage of hepatocytes expressed cognate antigen, high-affinity T cells developed and maintained effector function, whereas, at a high percentage, they became functionally exhausted and silenced. Exhaustion was not irreversibly determined by initial activation, but was maintained by high intrahepatic antigen load during the early phase of the response; cytolytic function was restored when T cells primed under high antigen load conditions were transferred into an environment of low-level antigen expression. Our study reveals a hierarchy of factors dictating the fate of CD8 T cells during hepatic immune responses, and provides an explanation for the different immune outcomes observed in a variety of immune-mediated liver pathologic conditions. rAAV | CTL | TCR | cytotoxicity T he liver is acknowledged to possess unique tolerogenic properties, which have likely evolved to maintain immunological unresponsiveness toward food-derived and microbial antigens that enter the circulation via the gut (1, 2). This tolerogenic capability of the liver is demonstrated in animal models of liver transplantation, in which liver allografts are accepted across complete MHC mismatch barriers and are able to protect other donor tissues from rejection (reviewed in ref.3). In humans, the tolerogenic hepatic environment is likely to contribute to impaired immune clearance of the hepatitis B virus (HBV) and hepatitis C virus (HCV), which result in persistent infection in a significant proportion of exposed individuals and are associated with major morbidity and mortality. In contrast, effective immune responses to hepatotropic pathogens leading to resolution of infection are observed in most hepatitis A and E virus infections, the majority of individuals infected with HBV during adulthood, and a minority of those infected by HCV (reviewed in refs. 4, 5). The liver is also susceptible to a variety of autoimmune-mediated conditions (6). Collectively, these observations indicate that effective immune responses can be initiated and/or sustained in the liver despite its apparent predisposition toward the generation of tolerance. Unfortunately, there is no small animal model in which to study the parameters that determine the balance between intrahepatic immunity and tolerance in viral hepatitis. Thus, the factors that shape immune outcome have not yet been identified.By studying the fate of ...

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Section: A Threshold In the Number Of Antigen-expressing Hepatocytesmentioning

confidence: 99%

Antigen expression level threshold tunes the fate of CD8 T cells during primary hepatic immune responses

Tay

Wong

McDonald

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

115

View full text Add to dashboard Cite

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“…In the absence of a spleen, transfused RBCs are shunted to the liver, an organ thought to be more tolerogenic than immunogenic [105]. Recent studies in mice have demonstrated that a spleen is critical for primary immune responses to transfused RBCs [106], though non-responsiveness may not equate to long-term tolerance.…”

Section: Recipient Factorsmentioning

confidence: 99%

Factors Influencing RBC Alloimmunization: Lessons Learned from Murine Models

Ryder

Zimring

Hendrickson

2014

Transfus Med Hemother

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Red blood cell (RBC) alloimmunization may occur following transfusion or pregnancy/delivery. Although observational human studies have described the immunogenicity of RBC antigens and the clinical significance of RBC alloantibodies, studies of factors influencing RBC alloimmunization in humans are inherently limited by the large number of independent variables involved. This manuscript reviews data generated in murine models that utilize transgenic donor mice, which express RBC-specific model or authentic human blood group antigens. Transfusion of RBCs from such donors into nontransgenic but otherwise genetically identical recipient mice allows for the investigation of individual donor or recipient-specific variables that may impact RBC alloimmunization. Potential donor-related variables include methods of blood product collection, processing and storage, donor-specific characteristics, RBC antigen-specific factors, and others. Potential recipient-related variables include genetic factors (MHC/HLA type and polymorphisms of immunoregulatory genes), immune activation status, phenotype of regulatory immune cell subsets, immune cell functional characteristics, prior antigen exposures, and others. Although murine models are not perfect surrogates for human biology, these models generate phenomenological and mechanistic hypotheses of RBC alloimmunization and lay the groundwork for follow-up human studies. Long-term goals include improving transfusion safety and minimizing the morbidity/mortality associated with RBC alloimmunization.

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“…The liver holds a distinct cellular and molecular environment [20] and structural changes of tumor microenvironment of CRC often occur once metastasize to the liver [21]. Recent studies have demonstrated the involvement of MSCs as an important cellular element within tumor microenvironments [22].…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal Stem/Stromal Cells Exert Trophic Effect on Colorectal Cancer Metastasis to the Liver

Hernanda¹,

Gonzalez²

2016

J Liver

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Colorectal Cancer (CRC) is the third most common cancer in the world. CRC tends to metastasize to the liver, which may occur in 20% to 70% of patients and represents the major cause of death. Mesenchymal Stem/stromal cells (MSCs) have shown to be able to migrate to CRC site and play an important role in tumor progression. We have previously identified a resident MSC population in the liver. Therefore, this study aims to investigate whether there is infiltration of MSCs into patient CRC Liver Metastasis (CRC-LM) and their potential effects on tumor cell growth. By culturing resected patient CRC-LM tissue, we observed the emerging of fibroblast-like cells. Further phenotype and functional characterization confirmed their bonafide MSCs features. In situ staining with a well-established MSCs marker showed a significant enrichment of candidate MSCs in patient CRC-LM, particularly the tumor-stromal area. Moreover, MSCs secreted trophic factors significantly increased colony formation and growth of a metastatic CRC cell line. In summary, we found infiltration and enrichment of MSCs in CRC-LM patient, which could in turn nourish tumor cells.

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Liver Tolerance and the Manipulation of Immune Outcomes

Cited by 14 publications

References 105 publications

Antigen expression level threshold tunes the fate of CD8 T cells during primary hepatic immune responses

Antigen expression level threshold tunes the fate of CD8 T cells during primary hepatic immune responses

Factors Influencing RBC Alloimmunization: Lessons Learned from Murine Models

Mesenchymal Stem/Stromal Cells Exert Trophic Effect on Colorectal Cancer Metastasis to the Liver

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