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IMMUNOLOGY
Method Hones Tolerance of Tissue TransplantsCuts in Tissue-injuring T Cells Prevent Rejection Without Global Immune SuppressionMany of us have witnessed the exclusive nightclub bouncer--the tall, heavy guy who lets in everyone he knows and keeps out almost everyone else. The immune system behaves in a similar way, keeping the body relatively free from foreign pathogens. Usually this works fine. But occasionally, as when a patient desperately needs a tissue transplant, the system can be more curse than blessing.
Xin Xiao Zheng (left), Terry Strom, and colleagues have identified a new treatment for creating immune tolerance of transplanted tissue in mice. The regimen, which may also benefit humans, is acute and does not compromise subsequent immune responses to other challenges. (Photo by Phil Farnsworth) Medicine has come up with a solution for this problem--remove the bouncer. Unfortunately, this allows everyone in, even the troublemakers, so patients on immunosuppressant drugs are left susceptible to infection and disease, usually for the rest of their lives. If only there were a way to replace the bouncer with a more discerning one. In October's Immunity, HMS assistant professor of medicine Xin Xiao Zheng and research fellow Alberto Sanchez-Fueyo, working with HMS professor of medicine Terry Strom at Beth Israel Deaconess, report a new modality for preventing transplant rejection, one that targets only cells involved directly in attacking the graft. The treatment enables the immune system to recognize and tolerate the foreign tissue without compromising its ability to fight off subsequent threats. Tipping the BalanceAt the heart of graft rejection lie tissue-injuring helper and killer T cells. These are born when precursors are costimulated by a foreign antigen and antigen-presenting cells of the immune system. Through several rounds of cell division, precursors mature into either tissue-killing cytopathic or tissue-protecting regulatory cells, which differ from each other in the types of receptor expressed on their surface.
"We suspected that growth factors that kill tissue-injuring T cells would actually strengthen the regulatory T cells that protect tissues from injury," added Zheng. If this idea worked, it would lead to an ascendancy of regulatory cells over cytopathic cells, and in the immune system, numbers are key, because cells cooperate in their response to threats. Tipping the balance in favor of regulatory cells would spur the immune system to tolerate, not reject, foreign tissue. Once this cellular ascendancy was established for a particular graft, the theory predicts that the treatment could be withdrawn, leaving a fully active immune system. To test this theory, Zheng and colleagues used interleukin-2 (IL-2) as the apoptotic signal and a mutant antagonist form of interleukin 15 (mIL-15) to block anti-apoptotic signals. Because these cytokines are notoriously short-lived, they tagged them with the very stable Fc fragment of immunoglobulins. Fc fragments activate complement and phagocytes, so any cells displaying these chimeras on their surface become targets for the innate immune system. In addition to death by apoptosis, the cytopathic cells should be engulfed and removed by circulating macrophages. To put theory into practice, Strom and colleagues tested the chimeric proteins in mouse models of immune disease. First they gave a cocktail of IL-2/Fc, mIL-15/Fc, and rapamycin, which augments the effects of IL-2, to irradiated mice injected with donor mouse lymphocytes. These lymphocytes recognize their new host as foreign and set about to destroy it. Zheng found that three days after receiving the treatment the host animals had only one third as many activated T cells as controls. Furthermore, if the chimeric interleukins were replaced by ones with inactive Fc fragments, the effect was less pronounced, showing that complement activation played a part in immunosuppression. To show that the cocktail killed tissue-injuring T cells, the authors tested the mice for apoptosis. In untreated animals, the apoptotic marker annexin V was detected only in cells that had undergone six rounds of cell division, but in treated animals, it was detected after one division, showing that apoptosis was induced in the earliest stages of proliferation. Developing ToleranceBuoyed by these results, the group turned their attention to more stringent models of allogeneic grafts. "We deliberately used models that are difficult to achieve tolerance in," noted Strom, "such as heart and islet grafts in the tolerance-resistant NOD diabetic mice, which are autoimmune prone."The treatment led to graft tolerance in the heart recipients tested. Six NOD mice retained allogeneic heart grafts through long follow-up, and pancreatic islet grafts fared well, too. In all cases (eight mice), islets survived for more than 110 days, and blood glucose levels returned to normal within three days of treatment. This is remarkable given that these animals already have a marked autoimmune response against islet cells, they typically mount a strong rejection response, and treatment was withdrawn three weeks after transplantation. The latter, plus each animal's acceptance of a second graft from the same donor but rejection of a graft from another donor, demonstrates that the cocktail succeeded in generating tolerance. Strom's group is hoping to test the regimen in humans. "There should be no major technical obstacles," noted Zheng, "since the proteins can easily be switched for human variants." They are testing such proteins in monkeys. Together with Vijay Kuchroo's lab at Brigham and Women's Hospital, Strom and colleagues also have back-to-back papers in November's Nature Immunology, describing the role of the protein Tim-3 in suppressing pro-inflammatory T cell responses. --Tom Fagan |
