Modulating GVHD with Regulatory T Cells (Tregs)

The Holy Grail of allogeneic hematopoietic progenitor cell transplantation remains the separation of graft-versus-host disease from the graft-versus-tumor effect. Regulatory T cells (Tregs) may hold the secrets. The Scientific Committee session on Regulatory T Cells on Sunday at 7:30 a.m. will examine the role of Tregs on GVHD.

Dr. Stephen Blazar shows us that CD4+CD25+ Tregs are a naturally occurring population comprising 8-12 percent of CD4+ cells in rodents and a smaller percentage in humans. In rodents, depletion of donor or host Tregs augments GVHD lethality while supplementation of donor grafts with freshly isolated Tregs can down regulate GVHD lethality. Ex vivo protocols using T cell receptor signals and IL-2 can be utilized to expand Tregs which then can be utilized for GVHD therapy. The graft-versus-tumor effect appears to be preserved after Treg cell infusions. Techniques have been developed to permit human Treg isolation and expansion, and human clinical trials in BMT patients are in development.

In the same session, Dr. Maria Grazia Roncarolo discusses differences between naturally occurring Tregs and antigen-induced Type I regulatory (Tr1) cells. She describes results of studies indicating that induction and long-term maintenance of tolerance in vivo require a microenvironment in which effector T cells responses are down regulated and differentiation of Treg cells is permitted.

Dr. Rainer Storb discusses animal models of tolerance. Stable graft-host tolerance can be induced by short courses of combination immunosuppressives in canine models, despite major histocompatibility differences. Dogs who develop GVHD have T cells which react against host targets in vitro, while dogs without GVHD do not have such T cells. Regardless of whether the dogs are complete or mixed chimeras, this tolerance is not disrupted by infusions of large numbers of naïve donor T cells. The protection is presumed to be due to the Tregs in the recipient. However, if the donors are sensitized to their future recipient by skin grafts, donor lymphocytes result in acute GVHD in the complete chimeras and acute GVHD plus conversion to complete chimeras in the mixed chimeras. It therefore appears that sensitized T cells bypass normal regulatory mechanisms. Dr. Storb concludes that stable graft-host tolerance is likely maintained by Tregs.

Dr. Samuel Strober concludes the discussion of Tregs by discussing the importance of these cells in humans. The probability of developing GVHD and its severity may be influenced by the numbers of Tregs vs. the numbers of non-regulatory conventional T cells contained within the allograft. Host factors are also important. Clinical data implies that conditioning regimens containing total lymphoid irradiation and anti-thymocyte globulin prevents GVHD by altering the balance of residual host T cells in favor of Tregs.