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Generation of Alloreactive-Anergized Tr1 Cells From Patients on Dialysis for the Induction of Renal Transplant Tolerance: Are We There Yet?

C linical tolerance induction is considered the “holy grail” for the long-term preservation of solid organ transplant function. Various immunoregulatory cell-based therapies have been introduced of which adoptive transfer with regulatory T cells (Tregs) has been considered a promising one. The Tregs appear to be a heterogeneous cell population and can be characterized by their origin of generation (thymus versus periphery), maturation, and functionality. Grossly, 2 Treg types can be distinguished within the CD4 T-helper cell population: CD4CD25FoxP3 naturally occurring Tregs (harvested as a polyclonal population of T cell receptors) and CD4 Tr1 cells (inducible from naive T-helper cells). Tr1 cells are considered peripheral Tregs that produce interleukin (IL)-10 and transforming growth factor-β specifically in response to the antigen to which they were initially primed in the presence of suboptimal costimulation. The cytokine profile (and transcription factor profile) of Tregs, including Tr1 Tregs, is dependent on the type of antigen and of immune response that needs to be inhibited. In the current issue of Transplantation, Petrelli et al describe their protocol for the generation of a Tr1-containing cell product from 13 uremic patients (11 on hemodialysis) on the waiting list for renal transplantation. The current study is part of a European Union consortium named “The ONE Study,” in which a multitude of tolerance-inducing cell therapies will be tested in humans. They initially used the same protocol that was proven effective in their previous randomized controlled trial (ALT-TEN) for the prevention of graft-versus-host disease, but found that the repressive capacity of the IL-10–producing dendritic cell (DC10)-primed peripheral blood mononuclear cells from uremic patients (which includes the Tr1 cells) was not sufficient. This clearly illustrates that tolerogenic protocols must be tailored for the specific situation of these patients. Therefore, a novel protocol was introduced that used purified CD4 cells instead of the total mononuclear cell fraction of the peripheral blood of uremic patients. These CD4 cells when primed with donor-derived IL-10–producing dendritic cells (CD4/DC10) resulted in a 10% fraction of CD4CD45RALAG3CD49b