By David N. Leff

¿We have met the enemy, and he is us.¿

In this case, ¿us¿ refers to the millions of men and women the world over who suffer from autoimmune diseases. They are victims of the immune system¿s friendly-fire attacks on its body¿s own tissues and organs. Among these numerous self-destructive maladies, the best known are multiple sclerosis, systemic lupus, rheumatoid arthritis and Type II ¿ non-insulin-dependent ¿ diabetes mellitus. (See BioWorld Today, March 15, 1999, p. 1.)

In this affliction, the immune system¿s T lymphocytes mount a search-and-destroy operation against the insulin-secreting beta cells of the pancreas.

Australian cellular immunologist William Heath chose Type II diabetes as a model in which to test strategies designed to protect the body against the ravages of autoimmune diseases. ¿Our overall finding,¿ he told BioWorld Today, ¿is more specific to the general response of T cells than it is to diabetes per se.¿ Heath is a senior research fellow at the Walter and Eliza Hall Institute of Medical Research, in Parkville, Victoria.

T lymphocytes ¿ T cells ¿ are the immune system¿s enforcers against attack by infectious viruses. When they desert to the cellular enemy, T cells, together with antibody-spawning B cells, carry out the autoimmune massacre of the body¿s ¿self¿ cells, tissues and organs.

¿We¿re trying to understand,¿ Heath said, ¿what controls the ability of a T cell to attack normal parts of the body.¿ The key clue he has been following is a little-understood antigen, CD30, on the surface of activated T cells. CD30, first identified in 1982, is a member of the tumor necrosis factor receptor family expressed on the surface of activated T and B cells.

Heath is senior author of a report in today¿s Nature, dated March 25, 1999, and titled: ¿Signalling through CD30 protects against autoimmune diabetes mediated by CD8 T cells.¿

¿Normally,¿ Heath explained, ¿to get a T cell to respond to something foreign, you have to have the antigen it¿s looking for put under the nose of the immune system by professional antigen-presenting cells. Naove T cells ¿ not yet activated ¿ see the antigen on these professional-type presenting cells, which activate them to attack that specific antigen.¿

Heath pointed out that, ¿when T cells get activated in this process, it actually leads to their eventual removal from the system.¿

¿In order to kill off the T cells,¿ Heath went on, ¿and get rid of them so they¿re not going to attack the body, you need first to activate them. Then, they¿re susceptible to being killed by a number of processes. CD30 isn¿t one of them. These T cells die because of the Fas cell-death mechanism. They also die by another apoptotic mechanism, which can be protected by a gene called bcl-2. The death process actually takes a fairly long time, so some of the activated T cells awaiting removal can wander through the body¿s tissues. Because, once activated as a T cell, it can go anywhere; they¿re not restricted to the lymphoid compartment.¿

Here is how Heath described his in vivo experiments that culminated in the ability of a scant 16 activated T cells, stripped of their CD30 cover, to wipe out an entire population of pancreatic beta cells.

¿Our aim was to find out how T cells activated against normal parts of the body are tolerized to spare these autoimmune attacks, how they are switched off,¿ he said. ¿The concept of our experiments was to make mice that express the antigenic ovalbumin [OVA] protein as a normal constituent of their body. Then, we put in T cells from another mouse in which all its T cells are against OVA, and asked, What do these T cells do? How are they controlled?¿

¿What we¿ve found so far,¿ Heath said, ¿is that they are controlled partly by Fas-mediated killing, partly by the other apoptotic mechanism, which we don¿t really understand [and which] bcl-2 can block ¿ and we haven¿t published that yet. But, in the process of being killed off by that cell-death mechanism, [it must] activate the T cell. At that point, we asked whether some other molecules were involved in removing the cells from the system; whether CD30 might be involved.

¿We could put in a million T cells directed against a mouse¿s own pancreas,¿ he said. ¿In most cases, they would all be killed off without any harm to the animal. The mouse has a system to control cells that might attack it. One of those things is Fas, and the second is CD30. It turns out that CD30 is incredibly important, because instead of having to put in a million cells to get some sort of damage, we actually put in as little as 160, and still those few cells could destroy all the islets in a pancreas.¿

To reach this vanishingly small magic number, Heath and his co-authors took T cells from a mouse, all of whose T cells were against OVA, and transferred them into animals that express OVA in the same pancreatic cells that make insulin. Then, they did a titration.

First, they put in 250,000 T cells from the knockout mice devoid of CD30. This caused diabetes within five days. Then, they tested successively fewer T cells ¿ 100,000; 20,000; 4,000 ¿ down to 160. With that number, about half of their mice became diabetic and half remained healthy.

¿At anything above 160,¿ Heath recalled, ¿virtually all of the mice became diabetic.¿

CD30 Works Both Ways

Heath and his co-authors suspect ¿that the CD30 mechanism is switched on and off, depending on whether it¿s a response to a self antigen, in which case you want that mechanism on, or if in response to a virus, you want that mechanism off,¿ he said.

¿The other thing besides viruses that CD8+ T cells can attack are tumors,¿ Heath said. ¿In most cases, a tumor is like a part of one¿s self. To the immune system, it looks like a tissue. Probably the CD30 mechanism is always switched on for T cells trying to attack tumors. And it would be very beneficial to switch it off, and instead of having to use a quarter of a million to destroy a pancreas, now you can get down to 160, if you can switch off CD30.

¿So, one thing we¿re now trying to do is switch off CD30 in some way, maybe by blocking its signal with a drug or an antibody that binds it, to facilitate attacks on tumors,¿ he said. ¿The flip side is that maybe in autoimmune diseases there are mutations in CD30, so it doesn¿t signal properly, and therefore you get the disease. Perhaps, if we now try to signal through CD30, we¿ll be able to switch the disease off.¿

Heath concluded: ¿So, on the one side, what we¿re thinking is that maybe we can block CD30 for responses to tumors and, on the other side, perhaps we can stimulate CD30 when we want to stop responses to tissues, as in rheumatoid arthritis or multiple sclerosis or diabetes.¿