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Thymus-Derived Treg Infusion to Prevent Graft Rejection in Heart-Transplanted Children: Initial Exploration of a New Therapeutic Arsenal to Boost Immune Tolerance

Bernaldo de Quirós, Esther1; Pérez, Verónica A.1; Clemente, Maribel2; Gil-Jaurena, Juan Miguel3; González, María Teresa3; Pion, Marjorie1; Lombardi, Giovanna4; West, Lori J.5,7; Levings, Megan6,7; Correa-Rocha, Rafael1

doi: 10.1097/01.tp.0000520350.40197.6b
205.3
Free

1Laboratory of Immune-regulation, 'Gregorio Marañón' Health Research Institute (IISGM), Madrid, Spain; 2Cell Culture Unit, 'Gregorio Marañón' Health Research Institute (IISGM), Madrid, Spain; 3Pediatric Cardiac Surgery Unit, 'Gregorio Marañón' Health Research Institute (IISGM), Madrid, Spain; 4MRC Centre for Transplantation, King's College, London, United Kingdom; 5Alberta Transplant Institute, University of Alberta, Edmonton, AB, Canada; 6Childhood Diseases Research Theme, BC Children's Hospital, Vancouver, BC, Canada; 7Canadian National Transplant Research Program investigator, CNTRP, Edmonton, AB, Canada.

This work was supported by grants from Instituto de Salud Carlos III (ISCIII) co-financed by FEDER funds (PI15/00011; ICI14/00282).

Introduction: Immune graft rejection is the main obstacle to successful transplants. Immunosuppressive drugs fail to prevent chronic rejection and also impair the immune system, resulting in reduced lifetime survival rates. Transfer of regulatory T cells (Treg) has acquired growing interest in attempts to achieve indefinite graft survival [1]. The limited Treg numbers that can be purified from peripheral blood, along with low survival and limited suppressive capacity of expanded Treg obtained from adults, constitute important drawbacks for the effectiveness of this strategy.

Methods: We established a collaboration amongst several teams working in the field to overcome current barriers and make Treg therapy a reality equipped to achieve indefinite graft survival. The major innovation is the employment of thymus, the site of Treg generation, as a new source of Treg [2]. Our goal is to perform a first-in-human trial treating heart-transplanted children with autologous thymus-derived Treg (thy-Treg) to prevent graft rejection.

Results: We purified Treg from thymuses discarded routinely during cardiac surgeries in children with congenital diseases, obtaining massive quantities of thy-Treg with >98% purity. The final thy-Treg product shows high suppressive capacity, decreasing the proliferation of CD4+ and CD8+ T cells in co-cultures by more than 70%. Next, we propose to conduct a clinical trial transferring thy-Treg to heart-transplanted children. In the first instance, thymuses removed during transplant surgery will be processed in GMP-conditions, and autologous thy-Treg will be infused back to the patient at day +10, when immunosuppressant doses are routinely reduced. Due to the high quality and quantity of these thy-Treg and the favorable features of the pediatric immune system, we are confident that this strategy will boost Treg-mediated tolerance and reduce the incidence of graft rejection.

Conclusion: Thymic tissue constitutes an alternative source of Treg that could be employed as cellular immunotherapy to prevent rejection. The massive quantity of Treg obtained from thymus, their high suppressive capacity, stability and survival, could overcome the drawbacks of employing Treg from peripheral blood. We propose that thy-Treg will constitute a therapeutic arsenal with infinite possibilities for the treatment of immune-related diseases, including graft rejection or autoimmune disorders.

FIGURE 1

FIGURE 1

This work was supported by grants from Instituto de Salud Carlos III (ISCIII) co-financed by FEDER funds (PI15/00011; ICI14/00282).

FIGURE 2

FIGURE 2

References:

1. Safinia N, Scotta C, Vaikunthanathan T, Lechler RI, Lombardi G. Regulatory T Cells: Serious Contenders in the Promise for Immunological Tolerance in Transplantation. Front Immunol. 2015 Aug 31;6:438.

2. Dijke IE, Hoeppli RE, Ellis T, Pearcey J, Huang Q, McMurchy AN, Boer K, Peeters AM, Aubert G, Larsen I, Ross DB, Rebeyka I, Campbell A, Baan CC, Levings MK, West LJ. Discarded Human Thymus Is a Novel Source of Stable and Long-Lived Therapeutic Regulatory T Cells. Am J Transplant. 2016 Jan;16(1):58-71.

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