Host Alloreactive Memory T Cells Influence Tolerance to Kidney Allografts in Nonhuman Primates

Abstract

Transplant tolerance, defined as indefinite allograft survival without immunosuppression, has been regularly achieved in laboratory mice but not in nonhuman primates or humans. In contrast to laboratory mice, primates regularly have high frequencies of alloreactive memory T cells (TMEMs) before transplantation. These TMEMs are poorly sensitive to conventional immunosuppression and costimulation blockade, and the presence of donor-reactive TMEMs in primates may account for their resistance to transplant tolerance protocols that have proven consistently effective in mice. We measured the frequencies of anti-donor TMEMs before and after transplantation in a series of rejecting and tolerant monkeys that underwent nonmyeloablative conditioning, short-term immunosuppression, and combined allogeneic kidney/cell transplantation. Transplants were acutely rejected in all the monkeys with high numbers of donor-specific TMEMs before transplantation. In contrast, long-term survival was observed in the recipients harboring lower frequencies of anti-donor TMEMs before transplantation. Similar amounts of TMEM homeostatic expansion were recorded in all transplanted monkeys upon hematopoietic reconstitution; however, only the tolerant monkeys had no expansion or activation of donor-reactive TMEMs after transplantation. These results indicate that the presence of high frequencies of host donor-reactive TMEMs before transplantation impairs tolerance induction to kidney allografts in this nonhuman primate model. Indeed, recipients harboring a low anamnestic reactivity to their donor before transplantation were successfully rendered tolerant via infusion of donor cells and short-term immunosuppression. This suggests that selection of allogeneic donors with low memory responses in recipients may be essential to successful transplant tolerance induction in patients.

Central memory CD8+ T lymphocytes mediate lung allograft acceptance

“…However, kidney transplantation experiments in nonhuman primates demonstrated that alloreactive memory T cells, generated through heterologous immunity, may represent a barrier to long-term graft survival in animals raised outside the confines of specific pathogen-free conditions (60,61). This has been suspected to be especially problematic in recipients with a high frequency of CD8 + memory T cells, due to rapid graft infiltration by this cell population (13,15).…”

Selective CD28 Antagonist Blunts Memory Immune Responses and Promotes Long-Term Control of Skin Inflammation in Nonhuman Primates

“…There was a consensus that memory T cells do not require CD28 costimulation for expansion during secondary responses (2), based on a few studies in vitro with strong and sustained nonphysiological TCR stimulation (3,4) and in vivo models in CD28-deficient mice (5,6) that present abnormal immunity. Some preclinical studies in macaques suggested also that memory T cells promote allograft rejection, particularly in costimulation blockade-based immunosuppressive regimens (7,8). However, in contrast to humans or baboons, CD4 + effector memory T lymphocytes (Tem) of macaques do not express CD28 (9,10) and might show different costimulation requirements for their activation than do human and baboon counterparts.…”

Bcl-2 Inhibition to Overcome Memory Cell Barriers in Transplantation

“…The memory T cell (Tm) compartment has been recognized as a major hurdle for the translation of immunomodulatory therapies (1): the adaptive immune system of laboratory mice-young animals that have barely been exposed to pathogens-mostly consists of na€ ıve lymphocytes, whereas in large animals and humans a progressive shift from na€ ıve to memory lymphocytes occurs during life after exposure to pathogens and as a result of a progressive thymic function decline (2,3). Tm are less dependent on costimulation (4) and are less efficiently inhibited by regulatory T cells (5).…”