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First Naïve, Later Delinquent: How Immune Maturation Benefits and Jeopardizes Transplantation


links image SIMON URSCHEL, MD
2013 ISHLT Annual Meeting Program Committee Member
simonurschel@med.ualberta.ca


Children are different, a rarely disputed fact. However, medical research and science persistently under appreciate the hints on how to improve transplant outcomes hidden by nature within the developmental stages of the maturing immune system.

Heart-transplanted infants are immunologically forgiving and rarely cause concern about rejection or graft vasculopathy. This is well documented in the ISHLT registry data: children receiving heart transplantation below 1 year of age have the best long-term graft survival of all age groups, despite the high mortality immediately after transplant, which is mostly associated with severe pre-transplant illness with 10-15% coming off ECMO support and associated non-cardiac pathologies of children with congenital heart disease. The current 1 year conditional survival within 21.3 years is almost twice as long as documented in adults, and taking into account the improvements from era to era, the estimated survival projections for the current generation of newborns requiring transplant are amazing.

links imageThis is not where it ends: the lesser need for immune suppression is common clinical knowledge, though not as well documented in literature as the more frequent use of CNI as monotherapy. Equal clinical outcomes for infant recipients of ABO-incompatible organs were shown recently unanimously in multiple long-term studies from various centers [1]. In fact, on the immunological level there is some indication that the tolerance towards the persistently present non-self-blood group antigen may also modulate the immune response towards other donor antigens. Class II HLA antibodies develop significantly less frequently in infants after ABO incompatibility compared to same age recipients of ABO compatible organs [2], the opposite of what would be expected from the addition of another non-self-antigen. The secret of this paradox remains unsolved although there is emerging evidence that the lack of responsiveness to polysaccharides in infancy plays a key role.

The chronically underestimated B cell system shows much more functional deficit than his older brother, the T cell response. Memory B cells are vastly absent at birth and rarely reach adult proportions earlier than 5 years later. Subsequently, responses to polysaccharide vaccines such as pneumococcus are found to be vastly absent in the first 18 months of life; consequently, invasive infections from bacteria hiding within polysaccharide capsules are more frequent and severe in these young children than any time later in life. Further contributing factors may include high prevalence of regulatory B cells and changes in the repertoire of effector and regulatory T cells associated to thymectomy. Thymectomy? The simple reason why cardiac surgeons remove an organ that fills about 50% of the upper mediastinum is that it is in the field of sight for the repair of a congenital heart defect And while it sounds fairly radical (or careless?) to the average immunologist, and the impact on later development of allergies, autoimmunity, persistent CMV infection and accelerated immunosenescence remains to be clarified, thymectomy may indeed support the capability of the young child to accept a foreign organ better than anyone later in life.

The thymus, or better its final involution, may also be a major contributor to another peculiarity of the maturing human organism: the unacceptably high rate of graft loss during adolescence, which exceeds the average of younger children and older adults up to ten-fold [3]. Of course there are major non-immunological contributing factors in this age period when group-intoxication with legal and illegal substances becomes much more popular than regular intake of a calcineurin inhibitor at 8:00 AM. Nevertheless, our teenagers would clearly support the statement that it's not all their fault. The thymus involutes in response to increasing plasma concentrations of sex hormones, which themselves share some immune modulatory effects of corticosteroids. Lymphocytes have specific receptors for sex hormones as well as growth factors. The impact of the female hormonal cycle and especially pregnancy on a variety of autoimmune disorders, as well as flares of chronic infections, is well recognized as is the reduced need for immune suppression in the pregnant transplanted woman. Therefore, it seems obvious that the changes associated with this turbulent and hormone-soaked period are not limited to behaviour, mental and cognitive alteration, growth and metamorphose of almost every other organ in the body, but do include changes in the immune system. In vitro and animal data are increasingly available; however, there is an imminent lack of clinical research exploring the impact of natural changes in our patients and possibly pointing the way to therapeutic interventions.

It is time to recognize and appreciate the advice that can be drawn from natural maturation of the immune system. Exploring and understanding the mechanisms will open the door for ways to transfer the benefits of the immature immune system of the infant to the older patient. The challenges of adolescence need to be better defined on an immunological level and taken into account for a personalized and adapted immunosuppressive regimen. The pediatric project within the Canadian National Transplant Research Project will take a first step in that direction; however, there is still a long, but likely very rewarding, way to go.



Disclosure Statement: The author has no conflicts of interest to disclose.


Dr. Urschel is an Assistant Professor of Pediatrics and Immunology, a Consultant Pediatric Cardiologist, and a member of the West Research Group Cardiac Transplantation in the Departments of Pediatrics, Surgery, and Immunology at the University of Alberta, Edmonton, Alberta, Canada.


References:

  1. Urschel S, Larsen IM, Kirk R, et al. Abo-incompatible heart transplantation in early childhood: An international multicenter study of clinical experiences and limits. J Heart Lung Transplant. 2013;32:285-292
  2. Urschel S, Campbell PM, Meyer SR, et al. Absence of donor-specific anti-hla antibodies after abo-incompatible heart transplantation in infancy: Altered immunity or age? Am J Transplant. 2010;10:149-156
  3. Foster BJ, Dahhou M, Zhang X, et al. Association between age and graft failure rates in young kidney transplant recipients. Transplantation. 2011;92:1237-1243