Laboratory of Costica Aloman, MD

Liver disease rates are steadily increasing over the years. Liver diseases are recognized as the second leading cause of mortality amongst all diseases in the US.

Alcoholic liver diseases

Alcohol consumption causes a spectrum of clinical illness and morphological changes that range from fatty liver to hepatic inflammation (alcoholic hepatitis) and progressive fibrosis (alcoholic cirrhosis). Alcoholic liver disease has an incompletely known pathogenesis and specific treatments are lacking. It is an extremely common disease with significant mortality and morbidity. T cellular immune responses were shown to be affected and involved in these outcomes. Decreased resistance to infections and an abnormal systemic inflammatory response to infections are common events associated with alcohol consumption. Alcohol exposure has complex effects on gut permeability and the immune system, resulting in the activation of mononuclear phagocytes, steatosis, neutrophil recruitment, and altered cellular immune responses. Dendritic cells (DC), professional antigen-presenting cells, are emerging as an important regulator of tissue microenvironment. After four decades of research, we now know that DC arises from a hematopoietic lineage distinct from other leukocytes (including monocytes and macrophages), establishing the DC lineage as a unique hematopoietic branch. Several DC populations coexist in mice and humans with similar developmental pathways: (1) conventional DC (cDC) involved in antigen presentation; (2) plasmacytoid DC (pDC), characterized by a high capacity of cytokine production. pDC development and maintenance is under control of a transcription factor: E2-2. pDC release from marrow is dependent of CCR2. These data, combined with our central preliminary observation showing increased hepatic pDC in a well-established model of chronic alcohol consumption, sparked the idea of a potential effect of alcohol on pDC development with accumulation of hepatic pDC that reshapes the hepatic pro-inflammatory cytokine milieu and results in abnormal T helper 1 and Th17 cellular immune responses known to be present after chronic alcohol consumption.

Our long-term goal for this project is to investigate the effects of alcohol on DC homeostasis and its effect on immune and pathological characteristics seen in alcoholic liver disease. Our central hypothesis is that alcohol induces abnormal DC development and hepatic pDC accumulation.

Hepatocellular carcinoma

Hepatocellular carcinoma complicating advanced stages of hepatitis C virus infection is a major public threat and an important cause of mortality and morbidity that affects hundreds of millions of individuals worldwide. This study is the result of collaboration with the group of Andrea Branch from Icahn School of Medicine at Mount Sinai and investigates how a special enigmatic cell of the immune system, plasmacytoid dendritic cell, may change the immune system and increases the risk of this cancer in spite of hepatitis C cure. New insights expected to emerge from these novel studies could significantly increase our knowledge of how immune response impairs response to malignant transformation, thus providing the field with new therapeutic targets. This project was funded by Rush Translation Science Consortium/Swim Across America Foundation.

Hepatic Fibrosis

Today’s epidemic of end-stage liver disease due to hepatic fibrosis has precipitated an urgent need for new therapies and a better understanding of fibrosis biology. Hepatic fibrosis is the result of a tightly regulated interaction between immune and matrix-producing cells. Moreover, exciting data establish that fibrosis is reversible in humans and in animal models following the removal of the etiologic agent. Metalloproteinases, or MMPs, released from immune cells are critical to fibrosis regression. Dendritic cells, or DC, are the main professional antigen-presenting cells of the immune system and control innate and adaptive immunity. DC development and activity can be amplified by the protein fms-like tyrosine kinase 3 ligand, or Flt3L, which has already been tested in humans as cancer immunotherapy. DC also secrete interleukin-15, or IL‑15, which regulates NK and CD8⁺ T cells, cells that additionally modulate fibrosis. Despite their vital role in hepatic immune homeostasis, the contribution of DC to fibrosis regression is unknown. We found that Flt3L DC expansion accelerates fibrosis regression after the etiologic agent of hepatic injury was removed while IL1Ra on the HSC plays a role in modulation of hepatic fibrosis progression. Our long-term goal is to develop therapies for fibrosis using these new targets for both phases of fibrosis.

Circadian Rhythm and Immune Responses

Susceptibility to progressive alcoholic liver disease (ALD) and hepatic encephalopathy (HE) is poorly understood. ALD progression to cirrhosis is the leading cause of mortality and morbidity associated with alcohol use and development of HE is a sign of poor prognosis that correlates with mortality. Identifying the risk factors and clarifying the mechanisms involved in ALD and HE development and progression is a significant unmet need. Circadian disruption perturbs normal circadian oscillations in mononuclear phagocytes (MP) trafficking and function that potentiates alcohol-induced pathology in the liver and brain. This project is the result of close collaboration with Dr.Ali Keshavarzian and his group at Rush. It explores the cellular immunological mechanism involved in this event so able to develop targeted medications for hepatic and brain inflammation.

View a complete list of publications for Costica Aloman, MD, here.

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