Here’s a cautionary tale. Many readers know that H5N1 infection is capable of causing a sudden over activity of the immune system, manifested in a so-called cytokine storm. Over active immune systems have been implicated in many other diseases, as well, although the type of “over activity” isn’t the same. Autoimmune diseases, like rheumatoid arthritis or lupus erythematosus are caused by the body making antibodies to its own tissues. As in cytokine storm, an immune system that normally functions to protect us, makes us sick. To damp down the inappropriate activity, drugs like steroids are used to modulate the immune reaction. Steroids have also been used to treat cytokine storm, to varying but usually modest or no success. Still, many readers here equate “over active immune system” with cytokine storm. It is a dangerous way to think.
In August we posted here about a case series in The New England Journal of Medicine describing a drug trial that went suddenly and terribly wrong. Six patients were infused with an experimental drug to treat the over active immune system that produces rheumatoid arthritis. The drug, TGN1412, worked by stimulating a receptor, CD28, on the surface of a key cell in the immune system, a T helper cell (Th cell). Th cells are master signalling cells, releasing chemicals that tell one or another type of immune cell to do things, that affect the tightness of blood vessel walls to allow inflammation fighting cells from the blood to get into the tissue and attack invaders, or to reverse some process that another signal has started. The many different chemical signals involved in this back and forth in the immune system are called cytokines and chemokines.
Th cells are induced to do these things by a fail-safe double key mechanism. Th cells first must recognize a foreign protein that is presented to them by another type of immune cell, called an Antigen Presenting Cell (APC). Th cells are very fussy. They must have a proper introduction to the foreign protein by the APC. They recognize the protein by a lock and key arrangement with a specialized receptor on their surfaces, called a T cell receptor (Tcr). Tcr’s are specific for particular proteins in the same way that antibodies are specific for foreign materials (Tcr’s only recognize proteins, though; antibodies can recognize other kinds of molecules as well). Thus Th cells are part of the adaptive immune system. They are not part of the generic, innate immune response. They are trained or adapted to recognize specific proteins, by virtue of previous exposure.
But recognizing the foreign protein via presentation by an APC is not sufficient. Ordinarily there is a second requirement, a non-specific one that is given by a molecule on the surface of the APC. That molecule (B7) must make contact with the CD28 receptor on the surface of the Th cell. When both of these buttons are pushed (the Tcr and CD28) the Th cell becomes activated. It starts giving off signals. Two signals are required because activated Th cells are very powerful weapons, only to be used under the right circumstances. In addition, you don’t want them to keep signalling for help. So there is some kind of negative feedback system where some signals given by the Th cell activate other T regulatory cells whose job it is to damp down the immune response after a suitable lag.
Now to the drug, TGN1412. It was noticed that in many immune diseases there seemed to be a deficiency in the T regulatory cells. Therefore the immune response wasn’t damped down in general and immune disease resulted. It was also found that if you could stimulate the CD28 receptors with a “superagonist” you could preferentially expanded the T regulatory cells. A superagonist is a molecule capable of turning on the Th cell by hitting CD28 without needing to have the Tcr stimulated. The generic key alone is sufficient if that key is a superagonist instead of B7. TGN1412 is a CD28 Th superagonist.
Tests in animals showed it did just what they hoped. In 2005 the scientists developing the drug for a biotech company reported their results in the scientific literature:
We have recently shown that superagonistic monoclonal antibodies with specificity for CD28 (CD28 superagonists) are capable of activating and preferentially expanding Treg cells over conventional T cells in vitro and, importantly, also in vivo. Moreover, therapeutic application of CD28 superagonists elicited profound therapeutic effects in various animal models of autoimmunity, including experimental autoimmune encephalomyelitis (EAE) and adjuvant arthritis (AA) of the Lewis rat. Adoptive transfer experiments with Treg cells from CD28 superagonist-treated rats proved that protection from EAE is, indeed, mediated by CD28 superagonist-activated Treg cells.
Therefore, effective targeting of CD4+CD25+ regulatory T cells makes CD28 superagonists a promising novel tool for the treatment of human autoimmune diseases. (From the abstract)
In other words, it worked to dramatically reduce the effects of autoimmune disease in two animal models. The autoimmune process in these diseases is not the same as cytokine storm, except that it is the result of an over active immune system. The objective was to calm the activity of the immune system, and that seemed to work in animals.
In the spring of this year the drug was tested on humans. Six subjects received doses of the drug lower than given the animals because this was a safety trial. This is what happened:
Around 60 to 90 minutes after the men received their injections, their bodies were flooded by a surge of inflammatory chemicals called cytokines, which combat severe infections like those seen in patients with blood poisoning. The cytokines caused severe inflammation.
1 hour – simultaneously, the six men begin suffering excruciating headaches, shivering, back pain, gut pain, diarrhoea, swelling and nausea
4 hrs – all have fevers, are flushed, their blood pressure drops dangerously low and their hearts start to race. Blood tests show their lymphocytes and monocytes are fast vanishing.
5 hrs – one patient begins fighting for his breath. All suffer lung pain. They are all given steroids and other medications to ease inflammation.
12 hrs – the patient fighting for his breath is so bad that he has to be taken into intensive care and put on a ventilator to keep him alive.
Suntharalingam [physician supervising the trial] decides to take all the volunteers into intensive care as a precaution.
24 hrs – two people are on ventilators, and the four others need support with breathing.
48 hrs – the four least affected men start to recover, but all six begin to suffer multi-organ failure, and have to be attached to kidney machines, one of them for a fortnight.
Thereafter, the men began to recover and their lymphocyte and monocyte counts began to creep up again. (New Scientist)
Thus the immune calming turned into a cytokine storm.
. . . scientists note that the trial illustrates how incredibly potent some immune-altering agents can be. “The immune system is capable of extraordinary power and we must be very careful when we tinker with it,” says Louis Weiner who studies immunotherapy at Fox Chase Cancer Center in Philadelphia, Pennsylvania. (Nature)
It might be that H5N1 somehow produces a CD28 superagonist like TGN1412. Or maybe not. The immune system is complicated. We do not understand most of it. It is not as simple as calming an over active immune system.
As I said, a cautionary tale.