To the Editor: It was with general agreement that we read your editorial and cautionary credo ‘do not try this at home’ (1Halloran PF Bromberg J Kaplan B et al.Tolerance versus immunosuppression: A perspective.Am J Transplant. 2008; 8: 1365-1366Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar). Tolerance-inducing protocols as routine are ‘not yet ready for prime time’ before more mechanisms are clarified. To attempt to reproduce the landmark neonatal mice tolerance work in 1953 of Billingham, Brent and Medawar in a human with a mature immune system, it seems obvious that an initial immunoablative state that entails some risk must be introduced. Where we disagree with you is in your statement referring to the work of Hofmann et al. ‘that such mice (chimeric from your previous sentence) accept third party heart transplants, that is, are immunosuppressed’. Admittedly, there may be an early spread of a nonspecific regulatory cell effect even in neonatal chimeric tolerance. Indeed, a regulatory effect of recipient suppressor cells was even described by Brent himself in adult mice years after their initial observations (2Kilshaw PJ Brent L Pinto M Suppressor cells in mice made unresponsive to skin allografts.Nature. 1975; 255: 489-491Crossref PubMed Scopus (111) Google Scholar). Certainly regulatory cells by their very nature are (nonspecifically) infectious (bystander inducing) in their local surroundings. However, even the more extensive earlier work by West and Tau of that same group (3West LJ Tao K. Acceptance of thirdparty cardiac but not skin allografts induced by neonatal exposure to semi-allogeneic lymphohematopoietic cells.Am J Transplant. 2002; 2: 733-744Crossref PubMed Scopus (16) Google Scholar) should not be interpreted as being associated with longlasting or even shortterm chimerism. Moreover, even in their skin graft survival data, 30% of the specific (BALB/c) donor (of the bone marrows and spleens) skin grafts were lost in the first 2 weeks and no longterm data after 60 days were reported (3West LJ Tao K. Acceptance of thirdparty cardiac but not skin allografts induced by neonatal exposure to semi-allogeneic lymphohematopoietic cells.Am J Transplant. 2002; 2: 733-744Crossref PubMed Scopus (16) Google Scholar). This may well mean that chimerism was not established, just as it could not be in many of the initial experiments by Medawar’s group between several fully MHC mismatched strains, that is, it did not work in many combinations. The Hofmann animals indeed may well not have been long-term chimeras, that is, keeping their grafts due to tolerance induced by (total) clonal deletion, but more by some active regulatory mechanism. This might have been associated with an element of ‘linked’ or infectious inhibition to nonspecific antigenic stimuli of third party heart grafts due to the ‘proximity’ of (bystanding) regulatory cells, perhaps what you referred to as ‘immunosuppressed’. In addition, there might have been the not inconsiderable positive effect of the evolution toward graft quiescence (absence of inflammation/danger) in the longer term accepted skin grafts (4Matzinger P Tolerance, danger, and the extended family.Annu Rev Immunol. 1994; 12: 991-1045Crossref PubMed Scopus (4013) Google Scholar). Were true long-term mixed chimerism established, implying bi-directional tolerance of these cells residing in the recipient, perhaps one might expect more donor specificity long term (Medawar chimerism model). As such, the earlier nonspecific ‘immunosuppression’ brought on by regulatory cell bystander effects might be minimized long term. This may even have occurred in our previous clinical reports of longer term results of simultaneous donor bone marrow and kidney transplantation in which an early immunosuppressed state appears to have resolved 1 or 2 years after transplantation (5Ciancio G Miller J Garcia-Morales RO et al.Six-year clinical effect of donor bone marrow infusions in renal transplant patients.Transplantation. 2001; 71: 827-835Crossref PubMed Scopus (120) Google Scholar). However, it may or may not have occurred in the groundbreaking tolerance work of the Cosimi, Sykes and Sachs group to which you addressed your editorial and to which they responded in the next (August) issue of the Journal.