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Post-Transplant Inflammatory Response

Award Number: R01AI040459
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: 04/01/1997
PERIOD OF PERFORMANCE END DATE: 11/30/2029

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Post-Transplant Inflammatory Response - Abstract Acute allograft rejection is a T cell mediated immune response that continues to undermine the success of transplantation to treat end-stage organ disease. Two key factors contributing to acute and chronic allograft injury and graft loss are ischemia-reperfusion injury (IRI) and heterologous immunity by heterologous memory T cells with reactivity to graft alloantigens, but whether these factors are connected and how has not been tested. Reperfusion of ischemic tissues is an inherent component of transplantation and quickly induces an acute inflammatory response that directs the infiltration and activation of many types of leukocytes into the tissue. Clinically, the presence of donor-reactive memory T cells in the peripheral blood of kidney transplant patients prior to transplant is associated with increases in acute rejection and delayed graft function resulting in poorer graft survival. Studies performed during the last funding period indicated that heterologous memory CD8 T cells rapidly infiltrate cardiac allografts and are activated by graft allogeneic class I MHC molecules to proliferate and produce IFN-γ and other inflammatory factors mediating graft tissue injury. The infiltration and activities of these memory CD8 T cells are markedly increased in allografts subjected to longer duration of cold ischemic storage (CIS) prior to transplant and require helper signals generated by donor-reactive CD4 T cells that infiltrate the allograft. The resulting increases in the IRI and activation of these memory CD4 and CD8 T cells promotes costimulatory blockade resistant memory CD8 T cell mediated rejection of the allografts. These and our preliminary results have led us to propose the hypothesis that reperfusion of allografts subjected to prolonged CIS initiates a TLR9-dependent cycle of graft inflammation promoting pre-existing donor- reactive memory CD4 T cells to generate helper signals required for heterologous memory CD8 T cell activation to proliferate and express functions mediating acute graft injury and rejection. The hypothesis will be tested in two specific aims: first, we will test the role of TLR9 signaling in activating innate immune components that promote donor-reactive memory CD4 cells to generate help required for heterologous CD8 T cell responses to mediate graft rejection; and, second, we will test the source and role of IL-21 in heterologous memory CD8 T cell activation to express functions mediating acute graft injury. The proposed experiments in this renewal application will connect IRI with pre-existing donor-reactive memory CD4 and CD8 T cell activation in allografts and provide novel insights into mechanisms underlying an important and poorly understood clinical problem. We anticipate these studies will identify new targets for development of therapeutic strategies to inhibit innate immune enhancement of pre-existing/heterologous donor-reactive memory T cells in grafts and the acute graft injury mediated by these activated memory T cells.


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: 2025 ( Subtotal = $505,876 )
2025	2025	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	002	26	5/1/2025	COMPETING CONTINUATION	$0
2025	2025	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	26	11/15/2024	COMPETING CONTINUATION	$505,876
2025	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	001	25	5/1/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $505,876

Issue Date FY: 2024 ( Subtotal = $483,002 )
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	25	11/9/2023	NON-COMPETING CONTINUATION	$434,702
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	001	25	6/20/2024	NON-COMPETING CONTINUATION	$48,300
														Subtotal = $483,002

Issue Date FY: 2023 ( Subtotal = $483,002 )
2023	2023	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	24	11/14/2022	NON-COMPETING CONTINUATION	$483,002
														Subtotal = $483,002

Issue Date FY: 2022 ( Subtotal = $483,002 )
2022	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	23	11/17/2021	NON-COMPETING CONTINUATION	$483,002
2022	2018	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	001	20	9/23/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $483,002

Issue Date FY: 2021 ( Subtotal = $483,002 )
2021	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	22	11/13/2020	NON-COMPETING CONTINUATION	$483,002
														Subtotal = $483,002

Issue Date FY: 2020 ( Subtotal = $481,252 )
2020	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	002	21	4/8/2020	COMPETING CONTINUATION	$0
2020	2020	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	21	12/20/2019	COMPETING CONTINUATION	$481,252
2020	2018	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	001	20	4/8/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $481,252

Issue Date FY: 2018 ( Subtotal = $396,250 )
2018	2018	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	20	11/17/2017	NON-COMPETING CONTINUATION	$396,250
														Subtotal = $396,250

Issue Date FY: 2017 ( Subtotal = $396,250 )
2017	2017	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	19	11/4/2016	NON-COMPETING CONTINUATION	$396,250
														Subtotal = $396,250

Issue Date FY: 2016 ( Subtotal = $396,250 )
2016	2016	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	18	11/23/2015	NON-COMPETING CONTINUATION	$396,250
														Subtotal = $396,250

Issue Date FY: 2015 ( Subtotal = $396,250 )
2015	2015	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	17	11/20/2014	NON-COMPETING CONTINUATION	$396,250
														Subtotal = $396,250

Issue Date FY: 2014 ( Subtotal = $396,250 )
2014	2014	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	16	11/20/2013	COMPETING CONTINUATION	$356,625
2014	2014	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	001	16	6/6/2014	COMPETING CONTINUATION	$39,625
														Subtotal = $396,250

Issue Date FY: 2012 ( Subtotal = $378,564 )
2012	2012	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	001	15	5/30/2012	NON-COMPETING CONTINUATION	$37,856
2012	2012	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	15	11/15/2011	NON-COMPETING CONTINUATION	$340,708
														Subtotal = $378,564

Issue Date FY: 2011 ( Subtotal = $378,564 )
2011	2011	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	14	11/17/2010	NON-COMPETING CONTINUATION	$344,149
2011	2011	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	001	14	6/6/2011	NON-COMPETING CONTINUATION	$34,415
														Subtotal = $378,564

Issue Date FY: 2010 ( Subtotal = $382,388 )
2010	2010	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	001	13	5/24/2010	NON-COMPETING CONTINUATION	$34,763
2010	2010	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	13	11/16/2009	NON-COMPETING CONTINUATION	$347,625
														Subtotal = $382,388

Issue Date FY: 2009 ( Subtotal = $386,250 )
2009	2009	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	12	11/17/2008	NON-COMPETING CONTINUATION	$347,625
2009	2009	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	001	12	6/2/2009	NON-COMPETING CONTINUATION	$38,625
														Subtotal = $386,250

Issue Date FY: 2008 ( Subtotal = $386,250 )
2008	2008	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	11	11/30/2007	COMPETING CONTINUATION	$386,250
														Subtotal = $386,250

Issue Date FY: 2006 ( Subtotal = $336,161 )
2006	2006	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	10	4/19/2006	NON-COMPETING CONTINUATION	$336,161
														Subtotal = $336,161

Issue Date FY: 2005 ( Subtotal = $335,250 )
2005	2005	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	9	4/3/2005	NON-COMPETING CONTINUATION	$335,250
														Subtotal = $335,250

Issue Date FY: 2004 ( Subtotal = $344,250 )
2004	2004	CWRU-CLEVELAND CLINIC LERNER COLLEGE	9500 EUCLID AVENUE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	8	3/8/2004	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$344,250
														Subtotal = $344,250

Issue Date FY: 2003 ( Subtotal = $333,000 ) (Continued on the next page)
Grand Total All Awards = $9,201,895

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Post-Transplant Inflammatory Response

Award Number: R01AI040459

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: 04/01/1997

PERIOD OF PERFORMANCE END DATE: 11/30/2029

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