Regulatory T Cell Infusion Can Enhance Memory T Cell and Alloantibody Responses in Lymphodepleted Nonhuman Primate Heart Allograft Recipients

Abstract

The ability of regulatory T cells (Treg) to prolong allograft survival and promote transplant tolerance in lymphodepleted rodents is well-established. Very few studies, however, have addressed the therapeutic potential of adoptively-transferred, CD4+CD25+CD127−Foxp3+ (Treg) in clinically-relevant large animal models. We infused ex vivo-expanded, functionally stable, non-selected Treg (up to a maximum cumulative dose of 1.87 billion cells) into anti-thymocyte globulin-lymphodepleted, MHC-mismatched cynomolgus monkey heart graft recipients before homeostatic recovery of effector T cells. The monkeys also received tacrolimus, anti-IL-6R mAb and tapered rapamycin maintenance therapy. Treg administration in single or multiple doses during the early post-surgical period (up to one month post-transplant), when host T cells were profoundly depleted, resulted in inferior graft function compared with controls. This was accompanied by increased incidences of effector memory T cells, enhanced IFNγ production by host CD8+ T cells, elevated levels of proinflammatory cytokines and anti-donor alloAb. The findings caution against infusion of Treg during the early post-transplant period following lymphodepletion. Despite marked but transient increases in Treg relative to endogenous effector T cells and use of reputed “Treg-friendly” agents, the host environment/immune effector mechanisms instigated under these conditions can perturb rather than favor the potential therapeutic efficacy of adoptively-transferred Treg.

Advances in the immunology of heart transplantation

“…Although there are cautionary notes that need to be considered with Treg immunotherapy, 12 50 years from now, when this article is rewritten for the 100th anniversary of the first heart transplant, the future author will likely recall this era in transplantation as the dawn of the age of cellular immunotherapy, with Tregs leading the way.…”

FOXP3-Positive Regulatory T Cells and Kidney Allograft Tolerance

“…In animal models of transplantation, they are ~10 times as potent in preventing rejection and inducing tolerance. As well, they should have only a very minimal risk of non-specific immunosuppression, though a previous study has shown that the infusion of Tregs, either in single or multiple doses, in conditions where host T cells were depleted, resulted in enhanced memory T cell and antidonor alloantibodies, leading to decreased allograft function (80). Three groups are using antigen-specific regulatory cells in solid organ transplantation studies.…”

Adoptive Cell Therapy with Tregs to Improve Transplant Outcomes: the Promise and the Stumbling Blocks

“…Recently, in a NHP (cynomolgus macaque) model of of MHC-mismatched heterotopic heart allografts, we infused ex vivo-expanded, polyclonal Treg following ATG-induced lymphodepletion [91]. Our rationale was that, in addition to rapamycin, the therapeutic effect of adoptively-transferred functional Treg would be enhanced in association with depleted endogenous effector T cells [92, 93].…”

“…Heart allograft recipient monkeys received immunosuppression in the form of lymphodepletion with ATG and maintenance with Tacrolimus, rapamycin and IL-6 receptor antagonist, as described [91]. In two recipients, multiple infusions of autologous polyclonal ex vivo expanded Treg were given between days 3 and 31 post-transplant (solid lines).…”