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AUTOIMMUNE DISEASE AND NEONATAL TOLERANCE

Award Number: R01AI041747
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: 01/01/1997
PERIOD OF PERFORMANCE END DATE: 12/31/2009

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AUTOIMMUNE DISEASE AND NEONATAL TOLERANCE - DESCRIPTION (provided by applicant): Adult neonatal thymectomized (NTx) mice develop, depending upon the day of thymectomy, a spectrum of autoimmune phenomenon ranging from autoantibodies (DOTX and D3Tx) and wasting disease (DOTx) to organ-specific autoimmune diseases (D3Tx) such as autoimmune ovarian dysgenesis (AOD) and autoimmune gastritis (AG). The uniquely distinguishing feature of NTx-induced autoimmunity is it dependency upon the disruption of neonatal thympoiesis and establishment and maintenance of a peripheral CD4+CD25+ T suppressor cell repertoire required for the prevention of autoimmune disease, importantly, D3Tx does not lead to autoimmune disease in all strains of mice indicating that this process is genetically controlled. In this regard, we have identified linkage of D3Tx-induced AOD and its intermediate phenotypes, anti-ovarian autoantibody responsiveness, oophoritis, and atrophy, to five quantitative trait loci (QTL) designated Aodl-Aod5 and to H2 and Gasa2, a QTL controlling susceptibility to D3Tx-induced AG. The working hypothesis underlying our genetic studies on D3Tx-induced AOD is that one or more of the QTL controlling susceptibility to D3Tx-induced autoimmunity plays a role in the genesis and/or functionality of CD4 +CD25+ suppressor T cells mediating peripheral tolerance to self antigens. Toward this end, we have established, or are in the process of establishing, panels of interval specific bi-directional recombinant congenic lines encompassing each of the AOD QTL. To date, we have shown that Aod1 is comprised of two linked QTL (Aodla and Aod1 b)with opposing allelic effects on susceptibility to autoimmune oophoritis; and that stefin A1 (Stfal) and A2 (Stfa2), inhibitors of cathepsin S, a cysteine protease required for autoantigen presentation and the development of autoimmune disease following D3Tx, are candidates for Aod1b. In this application we will: 1) complete the congenic mapping for each of the AOD QTL at a resolution of 1 cM or less and 2) directly assess the IL2 structural polymorphism as a candidate for a shared autoimmune disease QTL underlying Aod2, Idd3, and eae3.


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: 2009 ( Subtotal = $277,004 )
2009	2009	UNIVERSITY OF VERMONT	223 WATERMAN BUILDING	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	000	11	12/5/2008	NON-COMPETING CONTINUATION	$249,304
2009	2009	UNIVERSITY OF VERMONT	223 WATERMAN BUILDING	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	001	11	6/3/2009	NON-COMPETING CONTINUATION	$27,700
														Subtotal = $277,004

Issue Date FY: 2008 ( Subtotal = $277,004 )
2008	2008	UNIVERSITY OF VERMONT	223 WATERMAN BUILDING	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	000	10	12/18/2007	NON-COMPETING CONTINUATION	$277,004
														Subtotal = $277,004

Issue Date FY: 2007 ( Subtotal = $282,368 )
2007	2007	UNIVERSITY OF VERMONT	223 WATERMAN BUILDING	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	000	9	12/19/2006	NON-COMPETING CONTINUATION	$282,368
														Subtotal = $282,368

Issue Date FY: 2006 ( Subtotal = $290,802 )
2006	2006	UNIVERSITY OF VERMONT	223 WATERMAN BUILDING	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	000	8	1/31/2006	NON-COMPETING CONTINUATION	$290,802
														Subtotal = $290,802

Issue Date FY: 2005 ( Subtotal = $310,800 )
2005	2005	UNIVERSITY OF VERMONT	223 WATERMAN BUILDING	BURLINGTON	VT	05405	CHITTENDEN	USA	Allergy and Infectious Diseases Research	000	7	12/22/2004	COMPETING CONTINUATION	$310,800
														Subtotal = $310,800

Issue Date FY: 2001 ( Subtotal = $241,454 )
2001	2001	UNIVERSITY OF ILLINOIS URBANA CAMPUS	809 SOUTH WRIGHT STREET	CHAMPAIGN	IL	61820	CHAMPAIGN	USA	Allergy and Infectious Diseases Research	000	5	1/5/2001	NON-COMPETING CONTINUATION	$241,454
														Subtotal = $241,454

Issue Date FY: 2000 ( Subtotal = $234,421 )
2000	2000	UNIVERSITY OF ILLINOIS URBANA CAMPUS	809 SOUTH WRIGHT STREET	CHAMPAIGN	IL	61820	CHAMPAIGN	USA	Allergy and Infectious Diseases Research	000	4	1/12/2000	NON-COMPETING CONTINUATION	$234,421
														Subtotal = $234,421

Issue Date FY: 1999 ( Subtotal = $227,594 )
1999	1999	UNIVERSITY OF ILLINOIS URBANA CAMPUS	809 SOUTH WRIGHT STREET	CHAMPAIGN	IL	61820	CHAMPAIGN	USA	Allergy and Infectious Diseases Research	000	3	12/18/1998	NON-COMPETING CONTINUATION	$227,594
														Subtotal = $227,594

Issue Date FY: 1998 ( Subtotal = $220,966 )
1998	1998	UNIVERSITY OF ILLINOIS URBANA CAMPUS	809 SOUTH WRIGHT STREET	CHAMPAIGN	IL	61820	CHAMPAIGN	USA	Allergy and Infectious Diseases Research	000	2	12/24/1997	NON-COMPETING CONTINUATION	$220,966
														Subtotal = $220,966

Grand Total All Awards = $2,362,413

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AUTOIMMUNE DISEASE AND NEONATAL TOLERANCE

Award Number: R01AI041747

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: 01/01/1997

PERIOD OF PERFORMANCE END DATE: 12/31/2009

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