Past Funded Research Project 

The Role of Endogenous, Antigen-Specific, Auto- and Alloreactive Tregs in Transplantation Tolerance

Primary Investigators: Dr. James Young

Institution: University of Chicago

Funding began in 2015.

This study was funded in 2015, with a focus on research of the role that a very specific cell plays in the rejection of a transplanted heart. This study has 5 publications to date. The researchers found that they were wrong in their original hypothesis, which looked at T Regs, but they have since found a different protein that seems promising in providing a better understanding of the immune system in order to stop the immune response before it starts.

 

Please read below to learn more about this research project.

What is the major problem being addressed by this study?
Following heart transplantation, the immune system of the patient, consisting of T cells, B cells, and other cells, will recognize the donated heart as foreign and attack it in a process known as rejection. Rejection is the primary cause of heart failure following transplant. During rejection, most T cells promote inflammation and cell death in the transplanted organ, but a small subset of these cells, known as Tregs, actually inhibit rejection and promote tolerance to the donor organ. Many clinical researchers wish to use Tregs in organ transplantation to enhance survival of the grafted organ, but despite extensive research, many questions remain as to the role that different Treg populations play, and how to promote their survival and function in patients.

What specific questions are you asking and how will you attempt to answer them?
First, I want to know whether the Tregs which help to mediate tolerance to a transplanted organ are specific for antigens which are not shared between the donor and the patient play a dominant role, or are Tregs which recognize antigens which occur in both the donor and patient the main source of tolerance? Clinical researchers are attempting to use both populations of Tregs but it is unclear which strategy may be more successful. To address this, I will use a new method, using specially-bred mice wherein Tregs specific for either shared or heart-specific antigens can be tracked, and their function analyzed. Second I want to know how these Tregs respond to clinically-used drugs. I will use two different drugs in heart-transplanted mice and look at the response of the Treg populations.

What is the long-term biomedical significance of your work, particularly as it pertains to the cardiovascular area?
What major therapeutic advance(s) do you anticipate that it will lead to? The research that I will perform will significantly enhance our understanding of what is likely the single most critical cell population for tolerance to heart transplant grafts. Knowing the precise population of cells responsible for tolerance to transplanted hearts will guide researchers and clinicians and will lead to greatly improved survival following heart and other solid organ transplants. Furthermore, my research will also examine the interaction between clinically-used drugs and Tregs, which will improve our knowledge of when it is best to use these drugs, and will also improve heart transplant outcomes.

Aim 1: I hypothesize that both allo- and self-reactive Tregs expand during the induction and persist during the maintenance phases of allograft tolerance. I will use 2W+ donors and/or recipients to test whether endogenous Tregs responding to 2W allo- or autoantigens expand and accumulate in the peripheral lymphoid organs and allograft during tolerance.

Aim 2: I hypothesize that during tolerance induction, graft-reactive Tregs differentiate into effector Tregs that are IL-2 independent and CTLA-4-dependent. In contrast, autoreactive Tregs already exist as effector Tregs prior to transplantation. I will use two clinically-relevant drugs, anti-CD25 and CTLA-4Ig, at the induction or maintenance phases of tolerance to test the dependence of each subset of Tregs on IL-2 and CD28 signals during the induction and maintenance of transplantation tolerance.

A major challenge in organ transplantation is the inability to achieve robust, stable tolerance to the graft in humans, although this is frequently achieved in animal models. FoxP3+ regulatory T cells (Tregs) play a critical role in the induction and maintenance of experimental transplantation tolerance, but despite extensive research, critical gaps in our knowledge remain. Previous studies of Tregs in organ transplantation have been limited either to bulk, non-antigen-specific Tregs, or to seeded populations of transgenic antigen-specific Tregs that may not accurately reflect endogenous Tregs. I propose to use a novel mouse model wherein grafts express a minor antigen, 2W, and for which high-affinity Class II 2W: I-Ab tetramers are available to track endogenous, antigen-specific Tconv and Tregs. Use of donors or recipient mice expressing 2W will allow me to interrogate the relative roles of alloreactive, autoreactive, and bystander Tregs in transplantation tolerance, as well as their function under immunosuppressive drugs currently in use in the clinic. To the best of my knowledge, no one has studied these questions in a transplantation model. My central hypothesis is that both graft-specific and self-reactive Tregs differentiate, expand, and contribute to the development and maintenance of transplantation tolerance. I propose two specific aims to test this hypothesis.

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