Liver Plays Significant Role in Peripheral Tolerance
James D. Perkins, M.D.
Professor of Surgery
Program Vice Chairman, Quality Assurance
Research in the field of transplantation currently centers on “tolerance,” that state in which the transplanted organ is accepted without compromise to the overall immune system. There are two types of tolerance: “central” and “peripheral.” Central tolerance occurs when immature lymphocytes encounter antigens and are deleted. Peripheral tolerance takes place in peripheral lymph organs, such as the lymph nodes and spleen, where mature lymphocytes encounter antigens under particular conditions.
The liver has long been known to have a positive effect on the induction of peripheral tolerance. For example, patients who receive a combined liver-kidney transplant experience significantly less rejection of the kidney than patients receiving a kidney transplant alone. In mice, liver allografts (unlike heart or kidney allografts) are accepted spontaneously without the need for immunosuppression. The tolerance induced by liver allografts in these animals subsequently protects future donor hearts or skin grafts from acute and chronic rejection.
The exact role of the liver in tolerance has been unclear, and much study is underway to determine what factors are involved. One factor is that the liver is an important hematopoietic organ and gives rise to all types of leukocytes, including extrathymic T cells, natural killer (NK) cells, natural killer T (NKT) cells, dendritic cells (DC), and granulocytes. In addition, tolerance itself is multi-faceted: induction of tolerance and maintenance of tolerance are probably two different processes, and each can be initiated through various means. For example, tolerance can be induced through the administration of intravenous medications, or through the oral ingestion of antigens (referred to as “oral tolerance” or “mucosal tolerance.”)
For the past two years, we have been using a murine transplant model to study the liver’s role in inducing and maintaining peripheral tolerance induced via oral antigens. Livers from BALB/c mice fed with OVA (ovalbumin; chicken albumin) at either a low dose or a high dose were transplanted into syngeneic recipients. OVA immunization and delayed-type hypersensitivity challenge were carried out, and liver cell populations and cytokine profiles were studied in the transplant recipients. This unique model allows for removal and insertion of various liver combinations and facilitates study of the liver’s role in the different mechanisms of peripheral tolerance.
Using our model, we have investigated the influence of the liver’s cellular environment on oral tolerance induction and have suggested, for the first time to our knowledge, that the liver plays a required role for induction of oral tolerance to high-dose antigen, but not to low-dose antigen. Our results have also demonstrated that the liver is sufficient to transfer oral tolerance, but once the tolerance is established, the liver is not necessary for maintenance of this tolerance.
Additionally, our results confirm other reports that different mechanisms of tolerance predominate depending on the dose of the orally administered antigen. The results for low-dose antigen suggest that regulatory T cells reside or differentiate in the gut or associated lymphoid tissue, and traffic to the liver and spleen after oral antigen administration and play an active role in low-dose tolerance induction. No unique functions of the liver in peripheral tolerance for low-dose-fed antigen are suggested by our studies.
An exciting possible interpretation of our findings is that mucosal tolerance to a high-dose antigen is transferred by an immunoregulatory cell population in the liver. While our data cannot confirm the existence of this putative population of regulatory cells, we are actively seeking to dissect the mechanism underlying these results.
The above represent a few of the many ideas stimulated by our research. We look forward to continued investigation into the roles of NKT cells, DC, and liver sinusoidal endothelial cells, as well as studying the relation of liver tolerance to the gut lymph system. The ultimate goal motivating our research is to provide a better quality of life for patients who need a transplant.
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