Engineering Thymic Selection to Control the Development of Alloreactive T Cells and Promote VCA Acceptance
Abstract
Transplantation of hands, arms, and face – vascularized composite allotransplantation (VCA) – is a technically challenging but feasible strategy to restore functionality and quality of life for patients that suffered devastating injuries or aggressive diseases. The functional restoration and social re-integration this approach provides are vastly superior to any currently available prosthesis. There is a significant problem that limits its wide application though. The immune system of the patient recognizes the transplanted tissues as foreign entities and aggressively attacks them until complete destruction is achieved. This requires (similarly to recipient of organ transplants) the life-long use of immunosuppressive drugs. Unfortunately, these drugs have debilitating side effects and cannot be used to the level they would be fully effective at; this causes the loss of approximately 50% of the transplanted organs by 5-10 years post-transplantation. The ideal solution would be an approach to re-train the immune system to accept the transplanted tissues (transplant tolerance). To date, the only clinically successful avenue of transplant tolerance induction has been through regimens based on the concomitant use of bone marrow transplantation (from the same donor of the transplanted organ). Unfortunately, these regimens carry considerable risks and toxicities and rely on the treatment of patients several days (if not weeks) before tissue transplantation (conditioning). They are then not amenable to reconstructive transplantation. Luckily, rodent studies (including ours) have shown that transplanted limbs contain viable bone marrow that, with proper manipulation, could substitute for the execution of bone marrow transplantation. The goal of this exploratory proposal is to obtain proof of principle of the efficacy of a novel approach to complement and optimize the capacity of bone marrow to promote indefinite transplant acceptance. Our approach derives from the novel understanding of the properties of a population that resides in the thymus (the organ where the lymphocytes of the immune system develop) and is named thymic epithelial cells (TEC). They work in concert with dendritic cells (DC) to prevent the development of lymphocytes that react against self-tissues. It is actually DC that originate from the transplanted bone marrow (in the aforementioned regimens) that colonize the thymus of the patient and purge all the transplant-reactive lymphocytes. Unfortunately, TEC do not origin from the bone marrow. Capitalizing on the activity of donor TEC could then be a major advantage in the regulation of alloreactivity. The Raimondi (Johns Hopkins) and Annoni (San Raffaele) laboratories have been working on two different but potentially complementary approaches for manipulating the function of TEC in a transplant recipient. The Raimondi’s lab is pioneering the engraftment of donor-derived TEC, while the Annoni’s lab is establishing a gene therapy-based approach to express donor proteins in the recipient TEC. Both approaches would constitute very innovative strategies to promote acceptance of limb transplants: the induction of a donor-recipient TEC hybrid thymus. With this strategy we expect to re-engineer the thymic environment and complement the work of donor DC, bone marrow-derived, to fully train developing lymphocytes to accept and protect the transplant. This result would happen without the need for any heavy pre-conditioning of the transplant recipient – a major advancement over currently explored regimens. In this Multi-PI proposal, the Raimondi and Annoni groups will work interactively using cutting-edge mouse models and techniques to understand: the respective capacity of the two approaches to affect alloreactivity, how to maximize their impact, and how they could enhance distinctive immunological properties of VCA to promote transplant acceptance. This unique project is designed to provide the des
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210977
Entities
People
- Andrea Annoni
Organizations
- San Raffaele Hospital
- United States Army