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Comment on ‘Tolerance Versus Immunosuppression: A Perspective’

Halloran et al. (1) note the importance of clarifying issues related to tolerance to avoid misinterpretation by transplant clinicians and patients seeking alternatives to immunosuppressive drugs. Thus, we believe it is important to highlight several inaccuracies in this editorial. The authors note ‘the term tolerance was introduced into transplantation with the report of skin graft acceptance in mice that had received neonatal injections of donor mononuclear cells. It is now recognized that this protocol induced mixed allogeneic chimerism, which is itself immunosuppressive. Such mice accept third-party heart transplants, that is are immunosuppressed’. In Medawar’s 1953 report (2), recipients were not neonates, but fetal mice and chicks; tolerizing cells were clumps of cells and debris derived from testis, kidney and spleen. Medawar’s group later found that neonatal mice were sufficiently immature to be susceptible to tolerance induction, thus, intrauterine injection with its high rate of fetal loss could be avoided (3). Further, they observed that injection of allogeneic lymphoid cells resulted in ‘runt disease’ (4), caused by alloreactive T cells in the tolerizing inoculum, now known as graft-versus-host disease (GVHD). An altered protocol of semiallogeneic cell injection did not cause GVHD, and was used for decades by investigators studying neonatal tolerance. Persistent chimerism was often but not always noted, and skin graft acceptance did not always correlate with donor cell persistence. In this setting, ‘mixed allogeneic chimerism’ as in coexistence of dual populations of fully allogeneic cells, was obviously not the case, but rather chimerism was persistence of semiallogeneic cells in parental strain hosts. As cited, work from the West laboratory showed that acceptance of third-party as well as donor-type heart grafts was induced in a similar neonatal tolerance model. However, the cited work used fully allogeneic fetal liver cells, notable for absence of persistent chimerism (5). Thus, if indeed a state of immunosuppression allows third-party heart graft acceptance, it cannot be argued to be due to mixed allogeneic chimerism.