A DELICATE BALANCE - Part 3

Targeting T-Cells

Dr. Benoist and Dr. Mathis have focused their efforts over the last two decades on the actions of T lymphocytes, and the genes that control how aggressive these cells are in the body. Certain T-cells recognize molecules (auto-antigens) that target cells in the pancreas, and therefore bring about the destruction of the insulin-producing beta cells. Why do T-cells target pancreatic cells at all? “This is a million dollar question. We have ideas and clues, but no real answers,” Dr. Benoist says. Drs. Mathis and Benoist have found that a critical part of T-cells’ involvement in the destructive process are certain receptors on the cell surface known as T-cell receptors, which interact with molecules on the target cells (known as MHC class I or class II molecules). It is the interplay between the T-cell receptors and the MHC targets that determines the onset the immune system’s attack. “Why people with diabetes cannot control these aggressive receptors and cells is the key question,” Dr. Benoist adds.

Researchers in the Mathis/Benoist lab also have shown that a number of “dampening” genes help control the actions of the T-cells. Some have been clearly identified. The existence of others has been proven by genetic analysis, but their exact identity has yet to be formally pinpointed.

T-Cell

The Benoist/Mathis lab uses transgenic methods to modify the genetic composition of NOD mice, (which frequently develop a form of diabetes similar to that in humans) to create a series of mouse models having varying severity of diabetes depending on their genetic makeup. Some of the mice, for example, have resistance-inducing MHC class II molecules and, therefore, have less severe diabetes. In others the mice are protected from diabetes when a crucial sub-population of T-cells, important to triggering the start of the disease, are eliminated. In some mice, the diabetes is more aggressive, including those in which the effect of dampening molecules is reduced. The researchers have also produced mice in which all T-cells make a receptor directed against the beta cells, making it much easier to study the cells’ behavior. “We try to simplify the model of disease used in the laboratory to understand it more fully,” Dr. Benoist says. Some of these transgenic mouse models of diabetes are now used by many labs in the world.

It is through their studies in these specially bred nonobese diabetic (NOD) mice that Drs. Benoist and Mathis identified the T-cells receptor action as a main culprit. “While many other cells are involved, it appears that the T-cells call the shots on ordering the beta cell destruction and regulating how fast the diabetes progresses,” Dr. Mathis says.

“Once the molecular basis of T-cell activation is fully understood, it may be possible to develop specific treatments to regulate the activation of the autoimmune process,” says Dr. Benoist. “It may be impossible to prevent autoimmunity, but that might not matter if we can control its harmful consequences.” One day it may be possible to inject peptides (small proteins) to slow down or stop the activation of the immune system attack. Or, one day it may be possible to collect T-cells from a patient, modify them using genetic techniques, and transfer them back to the patient in a way that could help. Perhaps the patient would still have an autoimmune attack, but one that does not lead to killing of the beta cells, and could even dampen the killing by other, more aggressive, T-cells. This one day could lead to new drugs to control the autoimmune destruction process.

The researchers also are exploring whether virus or trauma has a role in triggering diabetes. “Possibly there is a link but this is not proven,” Dr. Mathis says. In mice they have observed loss in the beta cell function when the animals are stressed or develop a virus. “It seems that the immune system is poised for beta cell destruction, but kept in check. The infection unleashes it,” Dr. Benoist says. “The immune system has checks and balances in place that keep it in check most of the time. But some scientists believe that a virus, in susceptible individuals, may trigger an over stimulation of the immune system that can’t be brought back under check, leading it to destroy more than the invading organisms, namely in the case of diabetes, the pancreatic beta cells.”

Why do some patients with type 2 diabetes eventually need insulin to manage their blood sugar levels? The Benoist-Mathis team is exploring the notion that the constant stimulation of the beta cells may cause the cells to become tired and die, secondarily activating autoimmunity. As the beta cells break apart in the process of cell death, an overabundance of proteins associated with these cells builds up in the body, triggering an immune system reaction that attacks the still living beta cells, destroying them as well. “The stress of type 2 diabetes on the beta cells could lead to type 1,” Dr. Benoist says. “This results in a type 1 and one-half diabetes, or transitional cases of diabetes.”

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