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Function of stellate cells in immunity and T cell instruction

Award Number: R01AI083426
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2010
PERIOD OF PERFORMANCE END DATE: 04/30/2015

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Function of stellate cells in immunity and T cell instruction - Description: Hepatic stellate cells (HSC, or Ito cells) are star-shaped cells located in the liver. So far, primarily nonimmunological functions of stellate cells have been described including storage of vitamin A, regulation of hepatic blood flow and generation of liver fibrosis. We recently demonstrated that hepatic stellate cells are powerful antigen-presenting cells (APC) to activate T lymphocytes. However, the precise physiological role of stellate cells in liver immunology remains unclear due to the lack of convincing in vivo models. Therefore, the goal of this research proposal is to develop mouse models of stellate cell depletion. We will use these systems to study the impact of hepatic stellate cells on immunity and infection in vivo. Our preliminary data indicate that stellate cells mediate protection against bacterial infection of the liver. These findings bear implications for the treatment of severe liver diseases such as viral hepatitis and malaria. Moreover, we will analyze the function of stellate cells in T cell differentiation and instruction. The majority of the body's vitamin A is stored in hepatic stellate cells. A metabolite of vitamin A called retinoic acid is important for the generation of regulatory T cell subsets. Additionally, retinoic acid triggers lymphocytes to migrate to the gut. We provide evidence that stellate cells promote development of regulatory T cells in a retinoic aciddependent fashion. Moreover, we suggest that stellate cells in the liver induce migration of lymphocytes to the gut. Taken together, the APC function of hepatic stellate cells is the key to antigen-dependent T cell instruction. These instruction events determine the quality and location of immune responses. This concept describes the liver as a central check point in regulation of lymphocyte migration and response. Public Health Relevance: Hepatic stellate cells are important to trigger immune responses in the liver. Moreover, they regulate the lymphocyte traffic in the body. Thus, understanding the immunology of stellate cells will help to treat liver diseases.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2014 ( Subtotal = $495,582 )
2014	2014	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	6	4/14/2014	NON-COMPETING CONTINUATION	$495,582
														Subtotal = $495,582

Issue Date FY: 2013 ( Subtotal = $450,418 )
2013	2013	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	003	5	9/23/2013	NON-COMPETING CONTINUATION	$19,758
2013	2013	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	002	5	4/16/2013	NON-COMPETING CONTINUATION	$444,542
2013	2012	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	4	1/14/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$281,027
2013	2012	IMMUNE DISEASE INSTITUTE INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	3	1/14/2013	NON-COMPETING CONTINUATION	-$294,909
														Subtotal = $450,418

Issue Date FY: 2012 ( Subtotal = $519,750 )
2012	2012	IMMUNE DISEASE INSTITUTE INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	3	4/12/2012	NON-COMPETING CONTINUATION	$519,750
														Subtotal = $519,750

Issue Date FY: 2011 ( Subtotal = $519,750 )
2011	2011	IMMUNE DISEASE INSTITUTE INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	2	6/9/2011	NON-COMPETING CONTINUATION	$47,250
2011	2011	IMMUNE DISEASE INSTITUTE INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	4/26/2011	NON-COMPETING CONTINUATION	$472,500
														Subtotal = $519,750

Issue Date FY: 2010 ( Subtotal = $525,000 )
2010	2010	IMMUNE DISEASE INSTITUTE INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	4/23/2010	NEW	$525,000
														Subtotal = $525,000

Grand Total All Awards = $2,510,500

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Function of stellate cells in immunity and T cell instruction

Award Number: R01AI083426

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2010

PERIOD OF PERFORMANCE END DATE: 04/30/2015

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