Human T regulatory cell therapy: take a billion or so and call me in the morning

Abstract

Immune system regulation is of paramount importance to host survival. In settings of autoimmunity and alloimmunity, control is lost, resulting in injury to vital organs and tissues. Naturally occurring, thymic-derived T regulatory (Treg) cells that express CD4, CD25, and the forkhead box protein 3 (FoxP3) are potent suppressors of these adverse immune responses. Preclinical studies have shown that either freshly isolated or ex vivo expanded Treg cells can prevent both local and systemic organ and tissue destruction. Although promising, human Treg cell infusion therapy has heretofore been difficult to implement in the clinic, and relatively few clinical trials have been initiated. This review will focus on the preclinical models that provide the rationale for current trials and it will address both the challenges and opportunities in human Treg cell therapy.

Figures

Figure 1. Clinical Applications of Human Treg Cells in Allo-HSCT

As a source of peripheral blood Treg cells, a nonmobilized apheresis unit is obtained from the HSCT donor 18–20 days prior to transplant (left). Non-Treg cell populations are depleted of CD8, CD14, and CD19 with either magnetic beads or flow cytometry techniques. Alternatively, a third-party UCB unit is used that does not require negative selection (right). Treg cells are enriched by CD25-positive selection. These populations can be expanded with CD3 and CD28 mAb-coated microbeads or a cell-based aAPC consisting of K562 cells transduced to express CD86 and an FcR (CD32 or CD64) upon which CD3 mAb is loaded. Exogenous IL-2, rapamycin, and an irradiated CD4+CD25 feeder layer were added to the culture for peripheral blood Treg cell expansion, whereas UCB Treg cell expansion required only supplemental IL-2. After quality control studies are completed, Treg cells are infused in the peri-HSCT period either in the context of GVHD prophylactic drugs or T cell mAb or in vitro T cell depletion. The approximate cell yields at each step are listed.