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Implication of Galectin-3 to regulate Graft vs. Host Disease (GvHD) and Graft vs. Tumor (GVT) Responses

Award Number: R00HL155792
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Implication of Galectin-3 to regulate Graft vs. Host Disease (GvHD) and Graft vs. Tumor (GVT) Responses - Project Summary: Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective form of immunotherapy that is potentially curative for malignant (e.g. leukemia, lymphoma) and non-malignant conditions (e.g. anemia, immunodeficiencies). However, graft‐versus‐host disease (GvHD) remains a major deleterious side-effect for many patients. While studying GvHD in murine allo-HCT models, we surprisingly discovered an important role for Galectin-3 (Gal-3) in mitigating GvHD. Gal-3 is expressed by hematopoietic and non-hematopoietic cells and is known to influence innate and adaptive immunity. Interestingly, its contribution to GvHD is unknown. In murine allo-HCT experiments, recipient mice were reconstituted with T cell depleted bone marrow (TCD-BM) and T cells from wild type (WT) or Gal-3 deficient mice. I discovered that Gal-3 deficiency in donor T-cells significantly exacerbated the severity and mortality of GvHD and that Gal-3 is important for protecting recipient tissues from GvHD. Based on my preliminary data, the goal of this study is to explore a new paradigm regarding the role of Gal-3 in GvHD after allo-HCT. I hypothesize that Gal-3 is the key regulator of GvHD that modulates both donor and recipient hematopoietic and non-hematopoietic cell functions and decreases GvHD severity and mortality. Therefore, I will study murine models and human HCT patients to pursue three aims. Aim 1 will explore the cellular mechanism(s) by which Gal-3 signaling impacts GvHD. I will use Gal-3 deficient mice as donors to determine how Gal-3 signaling affects the functions of major T cell subsets known to dictate the onset and severity of GVHD, including CD4+, CD8+ and CD4+Foxp3+ regulatory T cells. Aim 2 will evaluate the therapeutic potential of manipulating Gal-3 signaling to modulate GvHD and the graft versus tumor (GvT) effect. To increase the translatability of this work, I established a xenotransplantation system using humanized NSG-HLA-A2 mice as HCT recipients to examine GvHD severity induced by human immune cells. Aim 3 will analyze the clinical association of Gal-3 with GvHD severity after allo-HCT. I will measure Gal-3 plasma levels in 200 de-identified allogeneic HCT patients and analyze the relationship between Gal-3 levels and clinical outcomes including GvHD incidence and severity, engraftment, and infection. In summary, this project will not only improve our understanding of the biology of allo-HCT, but my results may identify a new biomarker which will help identify patients at risk for developing severe GvHD after HCT. Moreover, this research may lead to a novel therapeutic rationale for modulating Gal-3 signaling to control GvHD. This project will be carried out under the supervision of the candidate's primary mentor Dr. Elizabeth Repasky, co-mentor Dr. Philip McCarthy, and advisory committee including Drs. Bruce Blazer, Pawel Kalinski, Theresa Hahn and Jonathan Bramson. By completing the training outlined in this application (K99), I will obtain the knowledge and skills required to take the initial steps toward scientific autonomy in the subsequent phase (R00), and successfully complete the transition from a postdoctoral trainee to an independent researcher.


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: 2024 ( Subtotal = $249,000 )
2024	2024	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Blood Diseases and Resources Research	000	5	5/29/2024	NON-COMPETING CONTINUATION	$249,000
														Subtotal = $249,000

Issue Date FY: 2023 ( Subtotal = $286,943 )
2023	2023	HEALTH RESEARCH, INC.	ELM & CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Blood Diseases and Resources Research	000	4	6/5/2023	NON-COMPETING CONTINUATION	$249,000
2023	2022	HEALTH RESEARCH, INC.	ELM & CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Blood Diseases and Resources Research	001	3	7/11/2023	EXTENSION WITH OR WITHOUT FUNDS	$37,943
														Subtotal = $286,943

Issue Date FY: 2022 ( Subtotal = $249,000 )
2022	2022	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Blood Diseases and Resources Research	000	3	5/7/2022	EXTENSION WITH OR WITHOUT FUNDS	$249,000
														Subtotal = $249,000

Grand Total All Awards = $784,943

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Implication of Galectin-3 to regulate Graft vs. Host Disease (GvHD) and Graft vs. Tumor (GVT) Responses

Award Number: R00HL155792

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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