Expansion of Allospecific Regulatory T Cells After Anergized, Mismatched Bone Marrow Transplantation

Transplantation of donor bone marrow cells treated to be tolerant to patient antigens results in expansion of regulatory T cells that suppress immune responses that mediate graft-versus-host disease. One of the most successful applications of regenerative medicine to date, hematopoietic stem cell transplants have healed numerous patients with blood-based disorders such as thalassemia, anemias, and certain cancers. Each of these maladies emanates from defective blood cells, which normally arise from stem cells in the bone marrow. Davies et al. have deduced the mechanism by which a particular treatment of bone marrow before infusion into a patient results in favorable outcome even when the donor and the patient are not matched for tissue antigens. Hematopoietic stem cell transplantation requires elimination of the patient’s faulty bone marrow with radiation or chemotherapy, after which the bone marrow niche is repopulated by the infusion of donor cells into the patient. Although it has been in use for decades, hematopoietic stem cell transplantation carries a number of risks. Among the most serious of these is graft-versus-host disease (GVHD), a complication that occurs when donor immune cells recognize the patient’s tissues—often liver, skin, or the gastrointestinal tract—as foreign, thus promoting inflammation and organ damage. This condition is a reversal of typical transplant rejection in which the patient’s immune cells reject the foreign donor tissue. GVHD often can be avoided if the donor and patient have completely matched major histocompatibility (human leukocyte) antigens. Such precise matching is not common, however, and many more patients could benefit from hematopoietic stem cell transplantation if partially matched patients and donors could be paired without fear of GVHD. To this end, scientists have developed several procedures that deplete, before infusion, donor immune cells including those that react against the patient’s organs (alloreactive cells). However, this process interferes with the reconstitution of crucial components of the patient’s immune system and thus suppresses their ability to fight infection or cancer. In a more incisive approach, scientists can remove or destroy only donor T cells specific for patient antigens before transplantation. Alternatively, donor T cells specific for patient antigens can be inactivated prior to transplantation by the process of alloanergization, by stimulation with patient antigens and simultaneous blocking of a cell surface receptor called CD28. Transplanting donor bone marrow containing immune cells that have been so treated (alloanergized) into patients results in less GVHD than expected and yet preserves the ability of the patient to fight infection. Davies et al. have closely examined the T cell populations in patients who have received alloanergized bone marrow transplants and find that the decreased incidence of GVHD is not just a result of the inactivation of alloreactive cells through the in vitro treatment. Transplantation of alloanergized bone marrow also results in an increase in a subset of T cells that suppress responses of other immune cells. Unexpectedly, the responses that are suppressed are specifically those directed at the patient tissues. Thus, any transplanted immune cells directed against patient tissues that might have survived in vitro inactivation are inhibited by these suppressive T cells. This extra benefit of anergized donor bone marrow cells is especially important because the ability to generate T cells that suppress responses to defined and controllable antigens could be harnessed in the treatment of other diseases in which unwanted immune responses cause pathology. Transplantation of hematopoietic stem cells from healthy donors can cure patients with many diseases. Donor T cells can protect against recurrence of infection and disease, but some of these (alloreactive) T cells recognize patient tissues as foreign, causing graft-versus-host disease. Removing T cells from donor grafts before transplantation reduces graft-versus-host disease but increases infection and disease recurrence. Inactivation of alloreactive T cells by inducing tolerance to patient cells (anergization) before transplantation preserves beneficial donor T cell effects while reducing graft-versus-host disease. We show that this approach also results in expansion of regulatory T cells that specifically suppress alloreactive donor T cell responses in the recipient. In addition to reducing graft-versus-host disease, antigen-specific regulatory T cells generated with this strategy could suppress unwanted T cell responses that cause rejection of solid organ transplants and tissue damage in autoimmune disorders.