Ian Nicholas Crispe, M.D., Ph.D.

The mission of the Crispe Lab is to dissect and understand the ways in which the immune system responds to antigens, virus vectors, and parasites in the liver. The immune system works differently in the liver, partly because this organ must receive food components, together with molecules synthesized by the large bacterial population that lives in the normal intestine. As a consequence of this continuous stream of foreign molecules, the liver’s innate and adaptive immune systems have a unique configuration in which the threshold for launching an immune response is higher. This adaptation creates a window of opportunity, which is exploited by well-adapted pathogens including malaria parasites. Therefore, we will reveal the mechanisms by which the liver stage of malaria evades immunity, and how the emerging experimental vaccine strategies provide protection. This knowledge will strengthen efforts to make a universally available malaria vaccine that eliminates the parasite at the liver stage, before it infects red blood cells and causes disease.

Cultures of two kinds of liver cells that both activate naïve T cells. Liver sinusoidal endothelial cells are on the left, and liver stellate cells on the right. Both were isolated by fluorescence-activated cell sorting.

Research

The Crispe lab works on the basic biology of immune responses, with a focus on responses in the liver. The lab has used bone marrow transplantation and experimental liver transplantation to reveal the unique immunological functions of the liver and the relative roles of leukocytes derived from the bone marrow, versus fixed tissue-resident cells. The liver contains a large population of macrophages, named Kupffer cells. While most macrophages are located in tissues, the Kupffer cells are unusual since they reside in the blood space; they therefore act as a filter, removing foreign matter from the blood. We investigate the origin and biological function of these cells, in particular their functions as regulators of natural killer cell activation, and as participants in immunological damage to the liver. These studies reveal a complex network of immune cross-talk which is disrupted during infections of the liver, such as hepatitis B and hepatitis C.

The outstanding research environment of Seattle BioMed allows the Crispe lab to extend its study of liver immunology to address the malaria parasite. In particular, how does this parasite avoid immune elimination during its essential stage of maturation inside liver cells, and how could we generate such immunity? In collaboration with Stefan Kappe's lab [8], the Crispe lab is dissecting the mechanism by which genetically-modified malaria parasites cause sterilizing immunity. They will determine how and where the malaria antigens are presented to the T cell system, which T cells are activated, and how they deliver protection. The biological insights from these studies will define “protective immunity” more precisely, so that human vaccine trials may look for the same modalities of immunity.

Themes

• Antigen presentation by liver-resident cells, including hepatocytes
• The activation and fate of liver-primed T cells
• The mechanism by which the immune system eliminates antigenic liver cells
• The role of Kupffer cells in regulating immunity and liver injury
• Liver immunopathology initiated by T cells
• Immune subversion by hepatitis viruses and malaria parasites

The National Institute of Allergy & Infectious Diseases (NIAID) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), both parts of NIH, currently provide support for Crispe’s research.