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Mechanisms by which extracellular vesicles released by allografts promote anti-donor immunity

Award Number: F30AI197375
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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Mechanisms by which extracellular vesicles released by allografts promote anti-donor immunity - PROJECT SUMMARY/ABSTRACT This proposal aims to unveil the mechanisms by which graft-derived extracellular vesicles (EVs), carrying donor antigens (Ags) and immunoregulatory mediators, initiate the innate and adaptive immune responses that cause rejection of allografts. Transplant rejection remains a critical barrier to long-term graft survival, with chronic rejection affecting 50-80% of heart transplant recipients within five years. Current treatments, which broadly suppress the immune system, carry risks of infections, malignancies, and organ toxicity, while failing to address donor-specific immune activation—such as lingering anti-donor T cells inflicting persistent damage on allografts. Nonetheless, transplantation remains a life-saving intervention for end-stage organ failure. Recent findings by our group and others have challenged the established paradigm of allorecognition, which posited that donor antigen-presenting cells (APCs) mobilized from organ or tissue allografts to the graft-draining (d) secondary lymphoid tissues (SLTs) are the main initiators of anti-donor T- and B-cell alloimmunity. Our preliminary data reveal that graft-derived EVs, not donor APCs, represent the earliest platform by which allogeneic (allo)-Ags are relayed to the recipient’s APCs in SLTs. The family of EVs includes vesicles with different sizes, biogenesis, and composition (e.g. exosomes, microvesicles, etc) that facilitate local and systemic signaling by transferring proteins, Ags, immunoregulatory mediators, RNAs, and lipids between cells. During the past decade, it has been established that EVs are central mediators of horizontal cell-to-cell communication, although their functions in vivo remain largely unknown. This gap in knowledge and our preliminary findings on the role of EVs in allorecognition in transplantation led to my central hypothesis that “graft-derived EVs initiate the anti- donor immune response in recipient SLTs.” This application will investigate the role of graft-EVs in allorecognition in situ and in vivo using transplant models in mice. I will test my hypothesis with two aims: Aim 1 will investigate the cellular sources and cargo of graft EVs using skin and heart allografts from mice genetically engineered for in vivo tracking of fluoroprobe-tagged graft- EVs and their respective parent cells using two photon microscopy. This will be done in combination with proteomics analysis of the graft-EVs. Aim 2 will test if allo-EVs released under proinflammatory conditions activate and affect the phenotype, transcriptome, and function of the acceptor APCs (dendritic cells) in dSLTs (Aim 2A) and compare the ability of allo-EVs to activate naïve vs. memory T cells in SLTs (Aim 2B). My long-term goal is to understand how graft EVs function in vivo to provide new grounds for the development of EV-based therapies and disease markers of clinical relevance to transplantation and immune-mediated disorders. This fellowship will allow me to gain expertise in transplant immunology and the biology of EVs, gain proficiency in computational analysis in the fields of proteomics and transcriptomics, and acquire research mentorship tailored to my career goal of becoming a physician-scientist in the field of transplant immunology.


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: 2026 ( Subtotal = $55,114 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	1	4/3/2026	NEW	$55,114
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	001	1	4/13/2026	NEW	$0
														Subtotal = $55,114

Grand Total All Awards = $55,114

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Mechanisms by which extracellular vesicles released by allografts promote anti-donor immunity

Award Number: F30AI197375

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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