Firmly Tilting the Balance of Clinical Transplant Immunity Toward Tolerance (2015)

The results achieved in the Stanford trial (Scandling et al, page 695), if confirmed, suggest that our community should reconsider long-held views on the adjunctive role of donor hematopoietic transplant–based strategies in clinical organ transplantation. The results achieved in the Stanford trial (Scandling et al, page 695), if confirmed, suggest that our community should reconsider long-held views on the adjunctive role of donor hematopoietic transplant–based strategies in clinical organ transplantation. Outstanding clinical outcomes in renal transplantation have been achieved by using regimens utilizing infusion of donor hematopoietic progenitor cells at the Massachusetts General Hospital (1.Spitzer TR Sykes M Tolkoff-Rubin N Long-term follow-up of recipients of combined human leukocyte antigen-matched bone marrow and kidney transplantation for multiple myeloma with end-stage renal disease.Transplantation. 2011; 91 (et al): 672-676Crossref PubMed Scopus (122) Google Scholar, 2.Kawai T Sachs DH Sykes M Cosimi AB Immune Tolerance N. HLA-mismatched renal transplantation without maintenance immunosuppression.N Engl J Med. 2013; 368: 1850-1852Crossref PubMed Scopus (141) Google Scholar, 3.Kawai T Cosimi AB Spitzer TR HLA-mismatched renal transplantation without maintenance immunosuppression.N Engl J Med. 2008; 358 (et al): 353-361Crossref PubMed Scopus (854) Google Scholar), Northwestern (4.Leventhal J Abecassis M Miller J Tolerance induction in HLA disparate living donor kidney transplantation by donor stem cell infusion: Durable chimerism predicts outcome.Transplantation. 2013; 95 (et al): 169-176Crossref PubMed Scopus (132) Google Scholar, 5.Leventhal J Abecassis M Miller J Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched combined kidney and hematopoietic stem cell transplantation.Sci Transl Med. 2012; 4 (et al): 124ra128Crossref Scopus (323) Google Scholar) and Stanford (6.Scandling JD Busque S Shizuru JA Engleman EG Strober S. Induced immune tolerance for kidney transplantation.N Engl J Med. 2011; 365: 1359-1360Crossref PubMed Scopus (90) Google Scholar, 7.Scandling JD Busque S Dejbakhsh-Jones S Tolerance and withdrawal of immunosuppressive drugs in patients given kidney and hematopoietic cell transplants.Am J Transplant. 2012; 12 (et al): 1133-1145Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar, 8.Scandling JD Busque S Dejbakhsh-Jones S Tolerance and chimerism after renal and hematopoietic-cell transplantation.N Engl J Med. 2008; 358 (et al): 362-368Crossref PubMed Scopus (412) Google Scholar). In this issue, outcomes of 38 renal transplant recipients infused with donor hematopoietic progenitor cells at Stanford are analyzed (9.Scandling JD Busque S Shizuru JA Chimerism, graft survival, and withdrawal of immunosuppressive drugs in HLA matched and mismatched patients after living donor kidney and hematopoietic cell transplantation.Am J Transplant. 2015; 15 (et al): 695-704Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar). None has suffered graft loss or graft-versus-host-disease (GVHD). Treatment-related complications have been mercifully rare. Of 22 HLA matched recipients, 17 patients achieved at least 6 months of chimerism and were successfully withdrawn from therapy despite eventual loss of chimerism in nine recipients. Only one patient with a lupus flare, not rejection, required resumption of maintenance immunosuppressive therapy. In the most recent cohort of HLA haplotype matched renal transplant recipients, a dose escalation study of infused donor T cells and CD34 progenitors was undertaken (9.Scandling JD Busque S Shizuru JA Chimerism, graft survival, and withdrawal of immunosuppressive drugs in HLA matched and mismatched patients after living donor kidney and hematopoietic cell transplantation.Am J Transplant. 2015; 15 (et al): 695-704Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar). Exceptionally robust chimerism was noted in patients infused with the highest doses of donor hematopoietic progenitors and T cells. In fact, 50-fold more donor T cells were used than in previous regimens applied to HLA matched recipients. Nonetheless, GVHD was not noted in this cohort. Taken at face value, the regimen given to the most recent cohort of recipients at Stanford may provide the best outcomes noted to date in HLA mismatched patients. This treatment regimen includes conditioning with total lymphoid irradiation, anti-thymocyte globulin and infusion of higher numbers of donor T cells and hematopoietic progenitors than previously employed. Using this protocol, a high proportion of renal allograft recipients tolerate withdrawal of immunosuppressive drug therapy long-term. The best outcomes with respect to successful immunosuppressive drug withdrawal are achieved in those recipients manifesting the most robust and long-lived mixed chimerism. While this correlation has been noted at Northwestern (4.Leventhal J Abecassis M Miller J Tolerance induction in HLA disparate living donor kidney transplantation by donor stem cell infusion: Durable chimerism predicts outcome.Transplantation. 2013; 95 (et al): 169-176Crossref PubMed Scopus (132) Google Scholar), the magnitude (a peak of 70% in all lineages) of chimerism in the Stanford study is exceptional. Clearly treatment regimens based on infusion of donor hematopoietic stem cells and other cell types such as T (9.Scandling JD Busque S Shizuru JA Chimerism, graft survival, and withdrawal of immunosuppressive drugs in HLA matched and mismatched patients after living donor kidney and hematopoietic cell transplantation.Am J Transplant. 2015; 15 (et al): 695-704Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar) or facilitator cells (4.Leventhal J Abecassis M Miller J Tolerance induction in HLA disparate living donor kidney transplantation by donor stem cell infusion: Durable chimerism predicts outcome.Transplantation. 2013; 95 (et al): 169-176Crossref PubMed Scopus (132) Google Scholar, 5.Leventhal J Abecassis M Miller J Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched combined kidney and hematopoietic stem cell transplantation.Sci Transl Med. 2012; 4 (et al): 124ra128Crossref Scopus (323) Google Scholar) are a work in progress at several institutions. This report rekindles consideration of potential necessity for robust multilineage hematopoietic chimerism in the creation of robust not metastable transplant tolerance in humans. In mouse allograft models, robust and everlasting mixed multilineage hematopoietic chimerism serves as a biomarker and for massive and selective deletion of donor anti-recipient T cell clones (10.Sykes M Sachs DH. Mixed allogeneic chimerism as an approach to transplantation tolerance.Immunol Today. 1988; 9: 23-27Abstract Full Text PDF PubMed Scopus (152) Google Scholar). Thus, central tolerance is the basis of tolerance in this preclinical setting. In clinical practice and in keeping with studies in mouse models, successfully engrafted recipients of well-matched allogeneic hematopoietic progenitor cell transplants can later receive organ allografts from the same recipient years after the hematopoietic transplant without institution of immunosuppressive therapy (11.Sayegh MH Fine NA Smith JL Rennke HG Milford EL Tilney NL. Immunologic tolerance to renal allografts after bone marrow transplants from the same donors.Ann Intern Med. 1991; 114: 954-955Crossref PubMed Scopus (224) Google Scholar). Does a high incidence of robust but not necessarily permanent, mixed hematopoietic chimerism provide evidence that at least temporary massive deletion of donor reactive clones has taken place or is this phenomenon “just” a biomarker for success? Clearly peripheral-type transplant tolerance can be achieved through manipulations that create a state of enduring functional supremacy of donor reactive regulatory T cells over donor reactive effector T cells although total or near total depletion of donor reactive T cells is not achieved (12.Starzl TE Demetris AJ Trucco M Cell migration and chimerism after whole-organ transplantation: The basis of graft acceptance.Hepatology. 1993; 17 (et al): 1127-1152Crossref PubMed Scopus (667) Google Scholar). Nonetheless, peripheral tolerance to MHC mismatched transplants requires that the normal, naturally occurring apoptotic depletion (not total deletion) of donor reactive, antigen activated proliferating T cells be intact (13.Li Y Li XC Zheng XX Wells AD Turka LA Strom TB. Blocking both signal 1 and signal 2 of T-cell activation prevents apoptosis of alloreactive T cells and induction of peripheral allograft tolerance.Nat Med. 1999; 5: 1298-1302Crossref PubMed Scopus (651) Google Scholar). Given the unusually high proportion of T cells that are activated by donor alloantigens as compared to conventional “nominal” antigen, it is not surprising that partial depletion of donor reactive T cell clones is a prerequisite to the creation of transplant tolerance even in circumstances of regulatory T cell dependent peripheral tolerance. In order for donor reactive regulatory T cells to gain functional superiority over donor reactive effector cells, it is necessary to deplete, not necessarily delete, the expansive population of donor reactive T cells (Figure 1). The results to date in clinical renal transplantation suggest that enduring near total deletion of donor reactive T cells has not yet been routinely achieved. On the other hand, the correlation between the magnitude and duration of mixed chimerism and ability to successfully withdraw patients from immunosuppression suggest, but do not prove, that the success achieved to date has been achieved at least in part by resetting the proportion of donor reactive regulatory to effector T cells (Figure 1). In short, the results achieved in the Stanford trial, if confirmed, suggest that our community should reconsider their long held views on the adjunctive role of donor hematopoietic transplant-based strategies in clinical organ transplantation. Successful GVHD-free engraftment of hematopoietic cells may not be just an adjunctive measure at least in well-matched recipients. It may be a primary vehicle to achieve the best outcomes, as complications associated with this highly successful approach appear a less formidable barrier to long-term survival of our patients than maintenance immunosuppression. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.