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A little tolerance can go a long way. If the immune system, for instance, could be coaxed into tolerating foreign tissue rather than rejecting it outright, a variety of blood disorders could be treated by bone marrow transplants. Immune tolerance could also help extend these transplants to people who are currently too frail to receive them; in addition, it could facilitate the transplantation of kidneys, liver and other body organs.
An international team led by Weizmann Institute researchers has recently managed to induce a certain degree of immune tolerance by making use of so-called veto cells. These are naturally occurring immune cells that exert veto power over their own destruction: When attacked by the recipient’s immune cells, they launch a pre-emptive strike, destroying the attackers.
Lead study author Prof. Yair Reisner of the Institute’s Immunology Department has been studying veto cells for more than a decade, focusing on certain types known as CD8+. These cells exhibit the most potent veto activity of all, but they may be toxic to the patient because they can induce a complication known as graft-versus-host disease, in which the transplant attacks the host. Reisner’s team has found a way of circumventing this problem by generating a line of less toxic CD8+ veto cells. In the new study, reported in Blood, he and colleagues have now prepared the ground for using these cells in patients. According to the accompanying editorial entitled “Location, Location, Location,” the study has revealed the conditions in which the “promise of veto cells, as a cellular therapy, may finally be realized.”
As suggested in the editorial’s title, the scientists have determined the exact location in which veto cells exert their protective effect: the lymph nodes. The researchers have also revealed the mechanism of the cells’ action. It turns out that the cells cast their veto as soon as the recipient’s immune system T cells, which continuously patrol the body looking for foreign invaders, recognize the newly transplanted veto cells and latch onto them. That is precisely when the veto cells make their preemptive move: Equipped with ready-made poisons, they destroy the attackers, whose own poisons take longer to be produced. These details were revealed in collaboration with the lab of Dr. Guy Shakhar, also of the Immunology Department, thanks to an innovative two-photon microscopy system that made it possible to observe individual immune cells in a live mouse in real time.
The scientists further determined how to make sure veto cells reach their destination: Prior to transplantation, they must be grown in culture with the help of the biochemical interleukin-15, which preserves the “homing” receptor that guides them to the lymph nodes.
.jpg "Anti-donor immune T cells (green) attach themselves (blue arrows) to the donor’s veto cells (red); this binding leads to their destruction by the veto cells. Viewed under a two-photon microscope")
Indeed, in the study, veto cells successfully eliminated they type of recipient T cells that are responsible for much of the rejection. As a result, white mice tolerated skin grafts from black mice. Normally, such transplants require a drastic suppression of the recipient’s immune system with drugs and radiation to prevent rejection, but thanks to the tolerance induced by veto cells, the white mice did not reject the black patches even though their immune systems had been only mildly suppressed. Further research is needed to establish whether this approach can be as effective in humans as it is in laboratory animals.
Major and equal contributions to this study, conducted in Reisner’s lab, were made by graduate students Dr. Eran Ophir and Noga Or-Geva. In an earlier, preliminary study in Reisner’s lab, led by Ophir and Dr. Yaki Edelstein and published in Blood in 2010, the concept of using veto cells to induce tolerance had been established in a more artificial mouse model for bone marrow graft rejection.
Currently, bone marrow transplants are used only to treat disorders that are otherwise fatal because the treatment itself is risky. The major risk is infection, which stems from the suppression of the immune system in preparation for the transplant. But if the suppression can be mild, as was the case in the current study, bone marrow transplants could potentially be extended to such nonfatal disorders as sickle-cell anemia and thalassemia. They could also be made available to people who are presently unable to benefit from such transplants because they are too vulnerable to undergo a massive suppression of the immune system, such as elderly patients with leukemia or lymphoma. Moreover, the veto cell approach could be used to induce tolerance toward transplanted kidneys or other organs without the need for continuous immune suppression.
Prof. Yair Reisner's research is supported by the Belle S. and Irving E. Meller Center for the Biology of Aging, which he heads; the Leona M. and Harry B. Helmsley Charitable Trust; the Steven and Beverly Rubenstein Charitable Foundation; Roberto and Renata Ruhman, Brazil; the wstate of Samuel and Valerie Rodetsky; and the Estate of Lola Asseof. Prof. Reisner is the incumbent of the Henry H. Drake Professorial Chair in Immunology.
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