Bone Marrow Cells May Play Role in Protecting Beta Cells from Attack



New York, NY, January 8, 2007 – JDRF researchers in Australia have found that bone marrow cells that circulate in the blood may play a role in teaching immune cells not to attack the beta cells in the pancreas. The discovery means that a malfunction in this “peripheral” immune tolerance mechanism might increase a person’s risk of developing type 1 diabetes and, more importantly, offers a potential strategy for preventing the disease.



The bone marrow cells make proinsulin, a protein that resembles insulin. When immune regulating cells in the blood encounter the bone marrow cells, their exposure to proinsulin trains them not to attack any cells expressing proinsulin or similar proteins. Type 1 diabetes develops when immune cells attack beta cells, which express insulin.



This research represents the first evidence that bone marrow cells may be involved in teaching immune cells to tolerate insulin-producing cells. Previously, scientists believed that this important lesson of tolerance is conveyed only in the thymus, when immune cells are developing.



The study was led by Parth Narendran, Ph.D., in the laboratory of Leonard Harrison, M.D., Ph., at the JDRF Center for Immunoregulation at the Walter and Eliza Hall Institute of Medical Research/University of Melbourne. It is published in the Proceedings of the National Academy of Sciences.



Two Layers of Protection: Central and Peripheral Tolerance

Immune cells learn how to recognize “self” in two stages. The first, called central tolerance, occurs as regulatory T cells mature in the thymus. As they develop, the T cells are exposed to most of the body’s proteins. T cells that react strongly against these proteins (called “self-antigens”) are deleted or neutralized before they leave the thymus so they don’t cause trouble later.



However, this process is not 100 percent effective. Some T cells aren’t deleted in the thymus and pose a danger when patrolling the body. And not every protein in the body is expressed in the thymus—some are specific to certain tissues, such as the pancreas or the brain. As a result, a small population of T cells are potentially destructive, or “self-reactive” because they were never taught that certain proteins were “self.”



That’s where the second-stage, peripheral tolerance, plays a role. When the T cells circulate the body, they encounter other cells, which carry fragments of the body’s proteins on their surface. T cells that are self-reactive are either deleted or neutralized. In most people, the two tolerance mechanisms keep T cells in check and prevent autoimmune disease from occurring.



Genetic Similarities

The JDRF researchers looked at whether the peripheral tolerance mechanism is involved in protecting the body’s insulin-secreting cells. By studying the genetic makeup of cells in the thymus, researchers noticed these cells contain repeating units of a DNA sequence in the region controlling insulin expression and protection against type 1 diabetes. The more these sequences appeared, the more the proinsulin gene was expressed and the less likely it was that type 1 diabetes would develop. Conversely, fewer sequences resulted in less proinsulin expression, making the disease more likely.



When the Australia researchers analyzed the genetic makeup of human bone marrow cells, they noticed that these cells also express the gene for proinsulin. They also found a correlation with the proinsulin gene sequence.



This suggests that the bone marrow cells may play a role similar to the thymus—making T cells tolerant of any cells that produce insulin. As a result, the authors note that “Immunological self,” may include not only thymic [cells] but also circulating, bone marrow-derived cells, “linking central thymic and peripheral tolerance.”



Although this finding will not lead to immediate clinical applications, knowing that bone marrow cells may play a role in immunological tolerance and type 1 diabetes offers another potential approach for modulating the immune system to prevent or slow the diesease. For example, gene therapy might be used to boost proinsulin expression in bone marrow cells in a laboratory, which could then be reinfused into people at risk for type 1 diabetes. The increased level of proinsulin expression would neutralize T cells that pose a danger to beta cells in the pancreas.

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Pre-Med Student