Comment on ‘Tolerance Versus Immunosuppression: A Perspective’

To the Editor: Halloran et al. (1Halloran PF Bromberg J Kaplan B Vincenti F Tolerance versus immunosuppression: A perspective..Am J Transplant. 2008; 8: 1365-1366Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar) 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.Itis now recognized that this protocol induced mixed allogeneic chimerism, which is itself immunosuppressive.Such mice accept third-party heart transplants,that is are immunosup-pressed’. In Medawar’s 1953 report (2Billingham RE Brent L Medawar PB Actively acquired tolerance’ of foreign cells..Nature. 1953; 172: 603-606Crossref PubMed Scopus (2244) Google Scholar), 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 (3Billingham RE Brent L Medawar PB Quantitative studies on tissue transplantation immunity III. Actively acquired tolerance..Phil Trans Roy Soc London, Ser B. 1956; 239: 357-414Crossref Google Scholar). Further, they observed that injection of allogeneic lymphoid cells resulted in ‘runt disease’ (4Billingham RE Brent L Quantitative studies on tissue transplantation immunity IV. Induction of tolerance in newborn mice and studies on the phenomenon of runt disease..Phil Trans Roy Soc London, Ser B. 1959; 242: 439-477Crossref Google Scholar), caused by alloreactive T cells in the to-lerizing 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 semial-logeneic 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 (5Mewhort HE Tao KS Maier S Brown J West LJ Persistant molecular chimerism is not required to maintain neonatally-induced cardiac allograft tolerance in mice..Am J Transplant. 2008; 8: 484Google Scholar). Thus, if indeed a state of immunosuppression allows third-party heart graft acceptance, it cannot be argued to be due to mixed allogeneic chimerism. There is evidence that fully allogeneic chimeras do have a degree of immunosuppression that reduces ability to clear certain viral infections (6Koehn BH Williams MA Borom K et al.Fully MHC-disparate mixed hemopoietic chimeras show specific defects in the control of chronic viral infections..J Immunol. 2007; 179: 2616-2626Crossref PubMed Scopus (14) Google Scholar). While donor hematopoietic cells could potentially contribute to thymic T-cell selection (7Zinkernagel RM Althage A On the role of thymic epithelium vs. bone marrow-derived cells in repertoire selection of T cells..Proc Natl Acad Sci U S A. 1999; 96: 8092-8097Crossref PubMed Scopus (75) Google Scholar), the currently accepted interpretation for reduced antiviral immunity is that in fully allogeneic chimeras, where donor and recipient are MHC mismatched, T cells mature and become restricted to the MHC type present in the thymus epithelium and therefore have reduced ability to kill infected donor hematopoietic cells of different MHC type. Partial MHC matching or semiallogeneic combinations, as in many neonatal tolerance studies, would reduce or eliminate this immunosuppression. Thus, contrary to the authors’ conclusions, there is currently no evidence that chimerism in general is immunosuppressive. The authors appear to castigate awarding the Nobel Prize to Peter Medawar for ‘a transplant strategy that does not actually fulfill our definition of tolerance’. Medawar’s work in tolerance was not a clinically directed strategy for organ transplantation, which did not exist at the time, thus could hardly be expected to fulfill the requisites of a definition formulated by AJT editors some 50 years later. As recalled by Brent (8Brent L The immunologic basis of allograft rejection. In: A History of Transplantation Immunology..London: Academic Press,. 1997; : 70-73Google Scholar), Medawar’s exposure to World War II soldiers who received skin grafts for treatment of burn injuries appears to have inspired his early interest in investigations that established the immunologic basis of allograft rejection. However, the work of Medawar and his group on immune tolerance originated from observations of immunologic development in cattle, and were not related to any potential clinical application. Indeed, as related by Brent (9Brent L Fetally and neonatally induced immunologic tolerance. In: A History of Transplantation Immunology..London: Academic Press. 1997; : 199Google Scholar), ‘The answer P.B. Medawar is said to have given to a question after one of his lectures on tolerance, that the phenomenon had absolutely no clinical applicability, was entirely realistic, for at that time (1957) Medawar could not have foreseen the great impact the concept of tolerance would have on the initiation of a helter-skelter search for methods to induce specific unresponsiveness in adult animals, including man’. Notwithstanding this disconnection from present-day clinical possibilities, Medawar’s formulation of theoretical concepts of tolerance, built upon observations of Owen (10Owen RD Immunogenetic consequences of vascular anastomoses between bovine twins..Science. 1945; 102: 400-401Crossref PubMed Scopus (865) Google Scholar), Burnet (11Burnet FM, Fenner F. Monograph. In: The Production of Antibodies, 2nd ed. Melbourne, London: Macmillan, 1949.Google Scholar) and others, and recognition of the consequences of antigen exposure during immune development, were profound, and contributed some of the most important scientific foundations in our field. An accurate understanding of the history of tolerance is central to future strategies in transplantation, even if Medawar’s models, as Halloran et al. have pointed out, may not be appropriate as the paradigm for the establishment of clinical tolerance protocols for organ transplantation.

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