Response to ‘Tolerance Versus Immunosuppression: A Perspective’
Year: 2008
Type: editorial
Abstract: We have read with interest the editorial comments by Dr. Halloran and colleagues (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) on our recent report in the New England Journal of Medicine (NEJM) on the induction of tolerance of HLA-mismatched renal transplants (2Kawai T Cosimi AB Spitzer TR et al.HLA-mismatched renal transplantation without maintenance immunosuppression.N Engl J Med. 2008; 358: 353-361Crossref PubMed Scopus (854) Google Scholar). We welcome this opportunity for discussion on some of the issues raised. The uniqueness of our findings relative to the previous case reports cited by Halloran et al. should be emphasized. What we consider novel about our most recent results is 1) that these patients received HLA-mismatched transplants, and 2) that the conditioning was non-myeloablative. In fact, it was in a paper in AJT in 2006 that the ability to intentionally induce organ allograft tolerance in a series of HLA-matched patients with non-myeloablative conditioning was first demonstrated (3Fudaba Y Spitzer TR Shaffer J et al.Myeloma responses and tolerance following combined kidney and nonmyeloablative marrow transplantation: in vivo and in vitro analyses.Am J Transplant. 2006; 6: 2121-2133Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar). In order to enable their refutation of the claim that tolerance has been achieved, Halloran et al. have first provided their own definition of immunologic tolerance, and then declared that neither our data, nor those of Sir Peter Medawar, are satisfactory to meet their definition. In addition to calling attention to the questionable usefulness of setting up a ‘straw man’ definition in this way, we feel obliged to also point out that, in our opinion, Halloran et al. have misquoted and misinterpreted the very experiments they are describing. In particular, they claim that‘this protocol induces mixed allogeneic chimerism, which is itself immunosuppressive’. We know of no evidence that mixed allogeneic chimerism is immunosuppressive. The main advantage of mixed chimerism over full chimerism is indeed the immunocompetence that is conveyed (4Ildstad ST Wren SM Bluestone JA Barbieri SA Sachs DH Characterization of mixed allogeneic chimeras. Immunocompetence, in vitro reactivity, and genetic specificity of tolerance.J Exp Med. 1985; 162: 231-244Crossref PubMed Scopus (248) Google Scholar,(5Ruedi E Sykes M Ildstad ST et al.Antiviral T cell competence and restriction specificity of mixed allogeneic (P1 + P2—P1) irradiation chimeras.Cell Immunol. 1989; 121: 185-195Crossref PubMed Scopus (65) Google Scholar). Even the article by Hofmann et al. that they cite states that‘the protocol does not render animals immunodeficient’ (6Hofmann B Tao K Mai L West LJ Acceptance of related and unrelated cardiac allografts in neonatally tolerized mice is cardio-specific and transferable by regulatory CD4+ T cells.J Heart Lung Transplant. 2004; 23: 1069-1076Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar); In addition, even if mixed chimerism were immunosuppressive, the chimerism in our patients was transient, and none remained chimeric long-term (2Kawai T Cosimi AB Spitzer TR et al.HLA-mismatched renal transplantation without maintenance immunosuppression.N Engl J Med. 2008; 358: 353-361Crossref PubMed Scopus (854) Google Scholar). Finally, all four tolerant patients have shown evidence of full immunologic recovery both in vivo and in vitro, and none have had significant infectious complications. Most dramatic was the first patient’s full recovery from disabling viral warts that had plagued her during her previous transplant on immunosuppressive drugs. Her MLR and CML show donor-specific non-responsiveness and all of her lymphoid subsets are normal. This certainly is not the expected picture of graft acceptance due to immunosuppression. Four of the first five patients treated on our protocol have been off of all immunosuppressive drugs from 2 to 5 years, without evidence of rejection. We submit that absence of rejection without immunosuppression meets the essential criteria for clinically relevant tolerance. While it is still too early to know whether their current state of drug-free normal renal function will be permanent, we have seen no deterioration in renal function in any of these patients since discontinuation of immunosuppression. These observations are reassuringly consistent with those made in our pre-clinical studies in non-human primates, in which tolerant recipients have had stable renal allograft function for over 10 years following discontinuation of immunosuppressive therapy (7Cosimi AB Sachs DH Mixed chimerism and transplantation tolerance.Transplantation. 2004; 77: 943-946Crossref PubMed Scopus (90) Google Scholar). Even the fourth patient in the present series, who does have a low level of anti-class II antibody, has been monitored closely over the past 3 years, with serial biopsies which have shown no progression of the minimal glomerulopathy, revealed by electron microscopy (2Kawai T Cosimi AB Spitzer TR et al.HLA-mismatched renal transplantation without maintenance immunosuppression.N Engl J Med. 2008; 358: 353-361Crossref PubMed Scopus (854) Google Scholar). Given that 3 of the first 5 patients fit even the AJT’s editors’ definition of tolerance, and the fact that the fourth patient has normal renal function more than 2 years after discontinuing immunosuppressive drugs, we see the results of this small trial as much more encouraging than this editorial by Halloran and colleagues would appear to suggest. Indeed, we and the ITN consider these results sufficiently positive to justify continued ITN-sponsored evaluation of this approach to tolerance induction in the clinic.
Institution: Massachusetts General Hospital
Language: English
Subfield: Transplantation
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,300
OpenAlex ID: W2076730876