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Adoptive Treg Therapy: Closer to the Clinic

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  2. Adoptive Treg Therapy: Closer to the Clinic
  3. SUMMARY AND ANALYSIS

CITATION Feng G, Nadig SN, Bäckdahl L, et al. Functional regulatory T cells produced by inhibiting cyclic nucleotide phosphodiesterase type 3 prevent allograft rejection.

CITATION Hippen KL, Merkel SC, Schirm DK, et al. Massive ex vivo expansion of human natural regulatory T cells (T(regs)) with minimal loss of in vivo functional activity.

CITATION Sagoo P, Ali N, Garg G, Nestle FO, Lechler RI, Lombardi G. Human regulatory T cells with alloantigen specificity are more potent inhibitors of alloimmune skin graft damage than polyclonal regulatory T cells.

Citations are from:Sci Trans Med 2011;3:40, 41, 42.

SUMMARY AND ANALYSIS

  1. Top of page
  2. Adoptive Treg Therapy: Closer to the Clinic
  3. SUMMARY AND ANALYSIS

Experimental tolerance and immunosuppression can be achieved by shifting the balance of regulatory to effector T cells. Traditional immunosuppression has taken a broad-based approach by depleting or inhibiting effector T cells through biologics and small molecule inhibitors. Alternatively, an increase in the number or potency of alloreactive regulatory T cells (Tregs) may lead to improvements in allograft survival. Three complementary reports from a recent issue of Science Translational Medicine show that this approach is moving closer to becoming a reality.

Ideally, adoptive therapy requires that alloantigen-specific Tregs be identified, isolated and expanded. Furthermore, the reinfused Tregs must retain suppressive function and genetic stability. It would be counterproductive if transferred Tregs differentiated into effector cells on transfer. Combined with a method of long-term storage of expanded/specific Tregs, therapy could be administered in timed cycles to maintain an allograft or for treatment of acute rejection.

Sagoo and colleagues describe a system that allows for expansion and isolation of functional allospecific Tregs. First, exposure of purified CD4+CD25+CD127lo/- cells to allogeneic dendritic cells in a mixed lymphocyte reaction resulted in an altered cell surface phenotype characterized by co-expression of CD69 and CD71. Importantly, isolated Tregs could be expanded up to 1,000-fold without phenotypic changes or loss of function. CD69+CD71+ Tregs had greater suppressive activity than polyclonally expanded Tregs both in vitro and in a humanized mouse model of skin transplant.

Feng and colleagues generated Tregs by adding cilostimide, an inhibitor of phosphodiesterase 3, during in vitro co-culture of naïve murine T cells with allogeneic antigen-presenting cells (APCs). With this system, they were able to enrich Tregs approximately 10-fold versus no inhibitor. Tregs generated in the presence of cilostimide expressed high levels of Foxp3 and functioned both in vitro and in vivo. Similarly generated human Tregs significantly reduced allograft vasculopathy of human arterial grafts.

Hippen and colleagues systematically worked out a method to reproducibly isolate and expand natural thymus-derived Tregs (nTregs) from peripheral blood. KT64/86 cells are artificial APCs (aAPCs) that have been stably modified to express high levels of B7-1 (CD86) and the high-affinity Fc receptor CD64, allowing for loading of the cells with high levels of stimulatory anti-CD3 antibody. Four cycles involving co-culture of magnetic bead-purified CD4+CD25hiCD127lo nTregs from human peripheral blood with aAPCs in the presence of IL-2 and rapamycin could expand these cells up to 50 millionfold. Expanded nTregs retained Foxp3 and were capable of reducing morbidity and mortality in a humanized mouse model of graft versus host disease (GVHD).

Numerous differences exist between the murine and human immune systems, and critical final evaluations of Treg stability and function need to be undertaken in the setting of a human allogeneic response. Importantly, each report used a mouse model lacking murine B, T and natural killer cells that could be adoptively transferred with human hematopoietic cells to address in vivo human immune responses. In these models, transferred human T effectors rejected allogeneic human skin and vascular tissue or mediated xenogeneic GVHD. In each of the reports, co-adoptive transfer of in vitro-generated and -expanded Tregs substantially reduced the effector response, suggesting that these methods could be used as part of a regimen to limit alloimmune responses in human solid-organ transplantation.

The improved understanding of CD4+ Treg specificity, expansion characteristics and homeostasis provided in these studies supports the feasibility of using Treg adoptive therapy in solid-organ transplantation, but several questions remain. How does current clinical immunosuppressive therapy alter activity of the transferred Tregs? Would co-transfer of other regulatory cells subsets—for example, Qa-1-restricted CD8+ Tregs or B-regulatory cells—improve outcomes to an even greater degree? Armed with humanized mouse tools, we can begin to dissect the optimal approach to adoptive therapy in human solid-organ transplantation.