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HLA-RELEASING METALLOPROTEINASE IN ALLOGRAFT REJECTION

Award Number: R01AI045761
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: 03/01/2005
PERIOD OF PERFORMANCE END DATE: 02/28/2012

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HLA-RELEASING METALLOPROTEINASE IN ALLOGRAFT REJECTION - We have previously described the metalloproteinase-mediated pathway of soluble MHC class I release and proposed its role in transplantation. We found that the release of soluble MHC class I is mediated by a disintegrin and metalloprotease family member, ADAM17. Endothelial cells (EC) co-cultured with allogeneic T cells up-regulate specific activation markers and both the expression and activity of ADAM 17. This activation is driven by interferon-gamma and culminates in the release of soluble MHC class I proteins by EC. However, at least one other metalloproteinase distinct from ADAM17 is fully capable of releasing soluble MHC class I. Its activity may be regulated by cytokines in a tissue-specific manner. Screening of a human leukemia expression library with our mAb that blocks the release of soluble MHC class I led to identification of a novel protein BC036469 with yet unknown function. This ubiquitously expressed protein may participate in the mechanism of soluble MHC class I release by mediating specific enzyme/substrate interactions and its function may be regulated by cell-specific cytokines in different tissues. Three independent aims are designed to address these questions. First, we will identify cytokine-inducible metalloproteinases capable of processing MHC class I by using a panel of ADAM-deficient cell lines and by DNA microarray analysis. Second, the function of BC036469 protein will be determined by overexpressing wild-type and deletion mutants, and by disrupting expression of the endogenous protein with specific siRNA. Finally, we will determine the sites required for productive enzyme/substrate interactions within alpha 3 and transmembrane domains of MHC class I and test the ability of specific peptides to inhibit the interaction. The predicted role of soluble MHC class I in antigen presentation will be tested using the trans- vivo delayed-type hypersensitivity assay in the linked suppression model of immune regulation by HLA-A2- restricted CD8 low avidity T regulator cells controlling transplantation tolerance.


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: 2011 ( Subtotal = $0 )
2011	2009	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07101	ESSEX	USA	Allergy and Infectious Diseases Research	000	9	2/11/2011	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2009 ( Subtotal = $622,618 )
2009	2009	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	001	9	9/14/2009	NON-COMPETING CONTINUATION	$32,770
2009	2009	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07107	ESSEX	USA	Trans-NIH Recovery Act Research Support	002	9	9/23/2009	SUPPLEMENT FOR EXPANSION	$294,924
2009	2009	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07107	ESSEX	USA	Allergy and Infectious Diseases Research	000	9	3/2/2009	NON-COMPETING CONTINUATION	$294,924
														Subtotal = $622,618

Issue Date FY: 2008 ( Subtotal = $327,694 )
2008	2008	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07101	ESSEX	USA	Allergy and Infectious Diseases Research	000	8	2/28/2008	NON-COMPETING CONTINUATION	$327,694
														Subtotal = $327,694

Issue Date FY: 2007 ( Subtotal = $329,454 )
2007	2007	PUBLIC HEALTH RESEARCH INSTITUTE OF NEW YORK CITY	225 WARREN STREET, SUITE E230F	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	6	3/6/2007	NON-COMPETING CONTINUATION	$0
2007	2007	UNIVERSITY OF MEDICINE & DENTISTRY OF NEW JERSEY	65 BERGEN STREET	NEWARK	NJ	07101	ESSEX	USA	Allergy and Infectious Diseases Research	000	7	6/26/2007	OTHER REVISION	$329,454
														Subtotal = $329,454

Issue Date FY: 2006 ( Subtotal = $326,780 )
2006	2006	PUBLIC HEALTH RESEARCH INSTITUTE OF NEW YORK CITY	225 WARREN STREET, SUITE E230F	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	5	4/21/2006	NON-COMPETING CONTINUATION	$326,780
														Subtotal = $326,780

Issue Date FY: 2005 ( Subtotal = $311,200 )
2005	2005	PUBLIC HEALTH RESEARCH INSTITUTE OF NEW YORK CITY	225 WARREN STREET, SUITE E230F	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	4	3/1/2005	COMPETING CONTINUATION	$311,200
														Subtotal = $311,200

Issue Date FY: 2001 ( Subtotal = $239,952 )
2001	2001	PUBLIC HEALTH RESEARCH INSTITUTE OF NEW YORK CITY	455 FIRST AVE	NEW YORK	NY	10016	NEW YORK	USA	Allergy and Infectious Diseases Research	000	3	8/15/2001	NON-COMPETING CONTINUATION	$239,952
														Subtotal = $239,952

Issue Date FY: 2000 ( Subtotal = $232,962 )
2000	2000	PUBLIC HEALTH RESEARCH INSTITUTE OF NEW YORK CITY	225 WARREN STREET, SUITE E230F	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	2	8/3/2000	NON-COMPETING CONTINUATION	$232,962
														Subtotal = $232,962

Issue Date FY: 1999 ( Subtotal = $226,179 )
1999	1999	PUBLIC HEALTH RESEARCH INSTITUTE OF NEW YORK CITY	225 WARREN STREET, SUITE E230F	NEWARK	NJ	07103	ESSEX	USA	Allergy and Infectious Diseases Research	000	1	8/31/1999	NEW	$226,179
														Subtotal = $226,179

Grand Total All Awards = $2,616,839

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HLA-RELEASING METALLOPROTEINASE IN ALLOGRAFT REJECTION

Award Number: R01AI045761

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: 03/01/2005

PERIOD OF PERFORMANCE END DATE: 02/28/2012

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