Successful Tolerance to Fully MHC Disparate Renal Allografts via Donor Hematopoietic Mixed Chimerism in Non-Human Primates

Abstract

To the Editor: Rodent studies clearly show that sharing of MHC genes between donors and recipients is regularly associated with improved allograft survival. This is essentially attributed to: (1) reduction of early inflammatory direct T cell responses involved in acute allograft rejection and (2) self-MHC molecules expression on donor cells promoting regulatory immunity. The precise contribution of donor/recipient MHC gene matching to transplant rejection or acceptance in clinical transplantation has been somewhat more difficult to define due to the use of intensive immunosuppression in all human allograft recipients. Nevertheless, most authors agree that improved long-term graft survival is generally expected in patients receiving MHC-matched renal allotransplants. Rodent studies also demonstrate that transplant tolerance is easier to accomplish when allogeneic tissues express some or all of the recipient's MHC proteins. Nevertheless, tolerance of fully allogeneic transplants is regularly achieved in laboratory-bred mice using a variety of procedures including donor specific transfusion, donor hematopoietic chimerism and lymphocyte costimulation blockade. In contrast, such tolerance in primates has proven to be much more arduous due presumably to the presence in these recipients of preexisting alloreactive memory T cells (TMEM). These TMEM undergo differentiation and clonal expansion following previous exposure to alloantigens through blood transfusion, pregnancy, a previous transplantation or via cross-reactivity with microbial antigens. A recent article in AJT by Ramakrishnan et al. 1, referring to a recent report from our group 2, suggested that we had achieved tolerance of renal allografts in non-human primates via mixed chimerism only in highly MHC-matched transplant pairs. This interpretation of our experience is not fully accurate. Indeed, we have reported an inverse correlation between the level of IL-2 and γIFN memory alloreactivity and the degree of MHC class II and I gene sharing among monkey pairs 3. However, this is not an absolutely consistent observation with a substantial number of fully MHC disparate donor–recipient pairs displaying low pro-inflammatory memory responses 3. This suggests that tolerance susceptibility vs. resistance in primates depends primarily upon the frequencies of pre-existing donor-specific TMEM rather than upon donor–recipient MHC matching. In support of this view, we have observed that over one third of the monkeys that became tolerant of renal allografts had actually received a highly MHC-mismatched (>4/6 CyLA mismatches) transplant 4, 5. In summary, the beneficial effects of MHC matching with regards to transplantation tolerance are undeniable. In addition, it is likely that harnessing anamnestic T cell alloreactivity in primates will be essential to successful tolerance of allogeneic transplants across MHC barriers in non-human primates and patients. G. Benichou*, O. Nadazdin, A. B. Cosimi, and T. Kawai Transplantation Research Center, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA *Corresponding author: Gilles Benichou, gbenichou@partners.org The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.