Autoimmune hepatitis (AIH) is a chronic disease characterized by recurrent hepatocellular injury, circulating autoantibodies, and autoreactiv T-cells. Despite established guidelines for the diagnosis of AIH, key triggers and immunologic pathways are poorly understood. Therapy remains dependent on chronic glucocorticoids with numerous associated adverse effects. Further, disease monitoring is sub-optimal and there is a need for predictive immune biomarkers to link immunopathogenesis to the clinical status. Macrophage Migration Inhibitory Factor (MIF) is a pro-inflammatory cytokine that mediates the host response to infection and stress by activating key innate and adaptive immune pathways. MIF's bioactivity and MIF polymorphisms have been implicated in many autoimmune disorders. Applying this to the field of hepatology, the applicant initiated the first investigation of MIF autoimmune liver diseases. This K08 proposal is directly based on that work, now published in Hepatology, under the hypothesis that MIF plays an active role in AIH by directly inducing and sustaining the inflammatory cascade through interactions with T-cells. Anti-MIF therapy and MIF modulation by a neutralizing MIF receptor (CD74) are hypothesized to be protective. Further, MIF polymorphisms are hypothesized to correlate with disease severity, and longitudinal serum MIF and CD74 levels may reflect AIH disease activity. Accordingly, the aims of this proposal are to: 1) Define the rol of MIF in signaling pathways of immune-mediated liver inflammation in a mouse model of T-cell hepatitis~ 2) Define the cellular mechanisms responsible for release of the MIF receptor CD74 and its modulating effect on MIF bioactivity~ and 3) Define the relationship of functional MIF genetic polymorphisms, and MIF and CD74 serum levels, to the disease course in AIH patients. Supporting data indicates that MIF absence in knockout mice protects against T-cell liver injury, and that a small-molecule MIF inhibitor is similarly protective. The circulating formof CD74 inhibits MIF bioactivity and is released from hepatic cells following stimulation i vitro. Finally, a genetic-clinical relationship between a high-risk MIF allele (-173*C) nd increase in both serum ALT and prednisone requirements was found in AIH patients from the US and from Japan. Based on these results, the K08 proposal will define a key mechanistic role for MIF in the immunoregulation of AIH, enabling new strategies for therapy and disease management. To accomplish this, a mentored and integrated five-year strategic plan for research and training will enable the applicant to experimentally test these hypotheses and to develop into an independent investigator devoted to translational hepatology. The application of MIF to AIH is novel and independent from the focus of both co-mentors, Drs. James Boyer and Richard Bucala. The collaborative environment at Yale University, combining training experience in hepatology and immunobiology, represents an ideal setting in which to conduct this mentored career development project in translational hepatology.

Public Health Relevance

Autoimmune hepatitis is a challenging disease that causes significant liver damage and can range in severity from chronic, mild blood test abnormalities to acute, life-threatening injury. Not enough is known about how the immune system produces this damage, or how to best manage the disease over time. This proposal will study an important immunologic inflammatory protein, Macrophage Migration Inhibitory Factor (MIF), to determine how it participates in autoimmune hepatitis, whethr modifying this protein's activity can be protective, and if it could serve as a marker for disease activity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK099412-04
Application #
9394005
Study Section
Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
Program Officer
Saslowsky, David E
Project Start
2015-01-01
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520