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Harnessing endogenous mechanisms of thymic regeneration toboost immune function in recipients of hematopoietic cell transplant

Award Number: R01HL145276
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Even though the thymus is exquisitely sensitive to acute injury such as that caused by infection, shock, or common cancer therapies such as cytoreductive chemo- or radiation therapy, it also has a remarkable capacity for endogenous repair. Although there is continual thymic involution and regeneration in response to everyday insults like stress and infection, acute and profound thymic damage caused by common cancer therapies and the conditioning regimes used as part of hematopoietic cell transplantation (HCT), leads to prolonged T cell deficiency; precipitating high morbidity and mortality from opportunistic infections and may even facilitate cancer relapse. Furthermore, this capacity for regeneration declines further as a function of age. We have previously identified two independent pathways of endogenous thymic regeneration, centered on the production of the regeneration-associated factors (RAFs) IL-22 by innate lymphoid cells (ILCs), and BMP4 by endothelial cells (ECs); both of which mediate their regenerative effects by targeting thymic epithelial cells. Although we and others have previously identified dendritic cell (DC)-produced IL-23 as critical for controlling the production of IL-22 by ILCs, the underlying mechanisms that trigger the regenerative response via the production of these distinct RAFs is poorly understood. In our preliminary data we have demonstrated that deletion of the pattern recognition receptor NOD2 results in a significant increase in the production of IL- 22, IL-23, and BMP4, leading to improved thymus recovery after damage caused by total body irradiation. This suggests that under steady-state conditions, NOD2 signaling suppresses the production of these regenerative cytokines; but after damage this negative stimulus is removed, thereby enabling tissue repair by activating the production of RAFs. Based on these findings, we hypothesize that (a) intrinsic NOD2 signaling in DCs and ECs suppresses the production of IL-23 and BMP4, respectively; (b) NOD2-mediated suppression of RAFs is abolished after damage by the depletion of thymocytes; and (c) that this common pathway of regeneration can be exploited into a superior method to promote thymic function following HCT. Specifically, our proposal has the following aims: (1) To investigate the role of NOD2 in regulating endogenous thymic regeneration after acute damage; (2) To identify the regulators of NOD2 signaling that suppress the steady-state production of RAFs; and (3) To study if these pathways can be modulated as a means of improving T cell reconstitution following HCT. The mechanistic and pre-clinical studies outlined in this proposal not only have the potential to define important novel pathways underlying tissue regeneration, but could also result in innovative clinical approaches to enhance T cell reconstitution in recipients of HCT, as well as patients whose thymus has been decimated due to age, infection or other cytoreductive cancer therapies.


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: 2023 ( Subtotal = $570,505 )
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	001	6	3/3/2023	NON-COMPETING CONTINUATION	$57,050
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	000	6	12/31/2022	NON-COMPETING CONTINUATION	$513,455
														Subtotal = $570,505

Issue Date FY: 2022 ( Subtotal = $568,505 )
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	005	5	8/31/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$22,349
2022	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	004	4	8/31/2022	NON-COMPETING CONTINUATION	-$22,349
2022	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	000	4	12/31/2021	NON-COMPETING CONTINUATION	$511,654
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	003	5	7/5/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$56,851
2022	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	001	4	6/28/2022	NON-COMPETING CONTINUATION	-$350,652
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	002	5	6/30/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$350,652
														Subtotal = $568,505

Issue Date FY: 2021 ( Subtotal = $568,505 )
2021	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	000	3	12/31/2020	NON-COMPETING CONTINUATION	$511,654
2021	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	001	3	5/19/2021	NON-COMPETING CONTINUATION	$56,851
														Subtotal = $568,505

Issue Date FY: 2020 ( Subtotal = $568,505 )
2020	2020	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	000	2	1/17/2020	NON-COMPETING CONTINUATION	$568,505
														Subtotal = $568,505

Issue Date FY: 2019 ( Subtotal = $568,505 )
2019	2019	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	000	1	12/18/2018	NEW	$568,505
														Subtotal = $568,505

Grand Total All Awards = $2,844,525

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Harnessing endogenous mechanisms of thymic regeneration toboost immune function in recipients of hematopoietic cell transplant

Award Number: R01HL145276

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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