Allograft tolerance, known since the work of Medawar,¹ has been pursued as the "Holy Grail" of transplantation since the world's first adult heart transplant in Cape Town, South Africa in 1967 by Dr. Barnard.² Since then, the number of heart transplants performed in both adults and pediatrics has increased and clinical outcomes have improved dramatically. However, much of how we perform and manage patients after heart transplantation remains unchanged since the 1980s.

Infant heart transplantation, in particular, has outstanding short and midterm outcomes with the median survival now approaching two decades.³ The predominant strategy remains based on immunosuppression of the recipients' immune system. Unfortunately, decades-long immunosuppression has unavoidable complications such as calcineurin medical renal disease, increased susceptibility to infections, and cancer. The infant population with complex congenital heart disease (CHD) is still plagued by the highest wait list mortality, yet the least utilized donor population.³ There is clearly a need in pediatrics to develop new strategies pre- and post-transplant to improve survival, particularly for infants. The infants' immune system, which is still in its late developmental stages postnatally, having not been exposed to the world, is naïve and remains potentially quite plastic. This may allow strategies promoting regulation and even tolerance to alloantigens (HLA).

The team at Duke Health, led by cardiothoracic surgeon Dr. Joseph Turek, have taken advantage of the immune system in an infant who had unrepairable CHD and immune deficiency in the form of almost complete athymia. They performed the first human infant heart-thymus transplantation with the intent of restoring both normal cardiac physiology and potentially establishing a form of central donor allograft tolerance. Duke Health has been a world leader in the treatment of immunodeficiencies for decades and where Dr. Louise Markert pioneered the use of cultured thymus tissue for the treatment of infants with congenital athymia.⁴ Thymic implantation is routinely performed there for infants with thymus defects such as in patients with DiGeorge sequence and CHARGE syndrome as well as genetic cause of thymic aplasia. Commonly, patients with congenital athymia also have associated CHD. Thymic donor tissue is processed ex vivo and then implanted into the immunodeficient recipient who may require additional preparation for the thymic allograft. Duke's immunological expertise was utilized to fill a gap in knowledge in a novel arena for an infant requiring heart transplantation. After institutional review boards (IRB) and U.S. Food and Drug Administration (FDA) investigational new drug (IND) approval, the team is now managing care for a unique infant who is now 7 months since heart/thymus transplantation using conventional immunosuppression. However, the patient appears to be demonstrating peripheral recipient T-cells presumably educated by the donor thymus, thus far proving a successful 'proof of principal'. The next milestones will include a protocol to access allograft reactivity, the withdraw of immunosuppression, and surveillance for complications.

Acute rejection is highest particularly in the first 6 months post transplantation. Presumably, most of this risk is because of 'direct presentation' of passenger leukocytes for solid organs (and coronary endothelial cells) which dominates the allo response early post-transplant.⁵ This unique heart-thymus transplant recipient is already a success because there has been no primary graft failure or acute cellular rejection using only conventional immunosuppression. Donor thymic implantation could have had a potential to stimulate an allo response and increase the risk of early rejection particularly in a child such as this who was incompletely athymic. The next complication could also take the form of increased risk for antibody mediated rejection (AMR), as young infants do not make antibodies well. There is also potential for development of early transplant vasculopathy, particularly at the 1-year milestone. The continued lack of any of these processes will certainly be encouraging.

Permanent thymic engraftment providing recipient T-cells with education to donor HLA antigen is a long-term endpoint. Overtime, donor thymic dendritic cells may become depleted losing graft function.⁶ Graft versus host disease (GVH), also a possibility, is now less likely at 7 months post-transplant despite the patient's maintenance immunosuppression. As we know, allograft tolerance is difficult to achieve in humans for a variety of reasons not the least of which is the calcineurin based immunosuppression which can inhibit regulatory T-cells as well as effector T-cells.^7,8 The team, at the 1-year mark, plans to embark on an immunosuppression withdrawal protocol should T-cell reconstitution be robust and allograft reactivity be absent; details of the withdraw protocol are currently unavailable. As we wait for confirmatory evidence, we are all optimistic for a future leap in knowledge.

At superficial glance one may conclude that this patient was a rare circumstance. One-of-kind, even. However, many infants with CHD are immune-deficient. During cardiovascular surgery, the thymus is often removed with a median sternotomy. We are still unclear of the full extent of the effects of this practice.⁹ It seems intentional thymectomy may be but a step away. Harvesting donor thymus is certainly within our surgical technical ability at the time of heart procurement. The question remains whether donor thymic education of recipient T-cells (central tolerance) can provide a level of useful T-cell regulation and deletion of harmful effector allo reactive T-cells. Although their patient had both immunodeficiency and CHD, other congenial heart patients may not be so different. A more generalizable approach for a broader group of patients requiring infant heart transplantation could be on the horizon.

We applaud Dr. Turek and the Duke Health team for their accomplishment and look forward to the next chapter.

References

1. Billingham RE, Brent L, Medawar PB. Actively acquired tolerance of foreign cells. Nature 1953;172:603-06.
2. Brink JG, Hassoulas J. The first human heart transplant and further advances in cardiac transplantation at Groote Schuur Hospital and the University of Cape Town - with reference to : the operation. A human cardiac transplant: an interim report of a successful operation performed at Groote Schuur Hospital, Cape Town. Cardiovasc J Afr 2009;20:31-35.
3. Dipchand AI. Current state of pediatric cardiac transplantation. Ann Cardiothorac Surg 2018;7:31-55.
4. Markert ML, Gupton SE, McCarthy EA. Experience with cultured thymus tissue in 105 children. J Allergy Clin Immunol 2022;149:747-57.
5. Pietra BA, Gill RG. Immunobiology of cardiac allograft and xenograft transplantation. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2001;4:123-157.
6. Pilat N, Wekerle T. Transplantation tolerance through mixed chimerism. Nat Rev Nephrol 2010;6:594-605.
7. Auchincloss H Jr. In search of the elusive Holy Grail: the mechanisms and prospects for achieving clinical transplantation tolerance. Am J Transplant 2001;1:6-12.
8. Issa F, Strober S, Leventhal JR, et al. The Fourth International Workshop on Clinical Transplant Tolerance. Am J Transplant 2021;21:21-31.
9. Afifi A, Raja SG, Pennington DJ, Tsang VT. For neonates undergoing cardiac surgery does thymectomy as opposed to thymic preservation have any adverse immunological consequences? Interact Cardiovasc Thorac Surg 2010;11:287-91.

Clinical Topics: Cardiac Surgery, Congenital Heart Disease and Pediatric Cardiology, Invasive Cardiovascular Angiography and Intervention, Cardiac Surgery and CHD and Pediatrics, Cardiac Surgery and Heart Failure, Congenital Heart Disease, CHD and Pediatrics and Interventions, CHD and Pediatrics and Quality Improvement, Heart Transplant, Interventions and Structural Heart Disease, Heart Failure and Cardiomyopathies

Keywords: Infant, Calcineurin, Drugs, Investigational, Ethics Committees, Research, DiGeorge Syndrome, Thymectomy, CHARGE Syndrome, Central Tolerance, Endothelial Cells, Graft vs Host Disease, Sternotomy, T-Lymphocytes, Regulatory, Transplant Recipients, Transplantation Tolerance, United States Food and Drug Administration, Neoplasms, Heart Transplantation, Allografts, Dendritic Cells, Isoantigens, HLA Antigens, Pediatrics, Surgeons

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