R01AI174273

Graft extracellular vesicles as promoters of anti-donor immunity in cardiac and skin transplantation - Summary

The innate and adaptive immune response against allografts is the main impediment to successful transplantation. Heart transplantation is the best option for selected pediatric and adult patients with end-stage heart failure, however, the threat of rejection remains high, despite improvements in immunosuppressive therapies, conditioning regimens, and medical care.

Importantly, currently used interventions are not donor-specific and therefore may cause increased risk of infections and cancer. A deeper understanding of the basis of allo-recognition is needed for the development of novel donor-specific therapies to treat graft rejection, minimizing the harmful side effects.

Recent studies have challenged the dogma that initiation or re-activation of anti-donor immunity in graft-draining secondary lymphoid tissues (SLTs) depends mainly on donor Ag-presenting cells (APCs) mobilized from the grafts. Increasing evidence and our preliminary studies indicate that heart and non-vascularized skin allografts release extracellular vesicles (EVs) carrying donor-Ag that traffic to the SLTs where the graft EVs stimulate donor-reactive B cells and T cells.

Despite increasing information during the past 5 years on the role of graft EVs on elicitation of anti-donor immunity and their potential use as biomarkers in transplantation, the mechanisms in vivo by which graft EVs interact with recipient's immune cells in graft-draining SLTs and promote anti-donor immunity remain largely unknown.

The family of EVs encompasses vesicles with different biogenesis, size, and composition that includes exosomes and microvesicles. Although growing evidence indicates that EVs represent a mechanism by which cells horizontally transfer proteins, mRNAs, non-coding RNAs, and lipids, the function of EVs in vivo remains an enigma.

Therefore, we propose to investigate the mechanisms in vivo by which graft EVs initiate or re-activate in graft-draining SLTs, the innate and adaptive immune responses that lead to rejection of allografts. We will analyze these mechanisms in mouse experimental models of cardiac and non-vascularized skin allografts.

We hypothesize that "graft EVs constitute a cell-free platform that by multiple mechanisms initiates or re-activates the anti-donor immune response in the recipient's SLTs". This application will investigate these mechanisms in situ and in vivo using transplant models in mice and a translational model in humanized mice.

We will test our hypothesis in the following aims: Aim 1 will investigate the origin of graft EVs and their effects on recipient APCs in graft-draining SLTs, Aim 2 will analyze the mechanisms by which graft EVs generate anti-donor B cell immunity in SLTs, and Aim 3 will analyze how graft EVs elicit anti-donor T cell immunity in SLTs and its relevance to transplantation in humans.

Our 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.

University Of Pittsburgh - Of The Commonwealth System Of Higher Education

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93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Pittsburgh, Pennsylvania 15213 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 406% from $655,927 to $3,318,431.