To hell and back – it’s a very hard road which takes the patient away from the self combustion happening within them to be able to reach a place where the body no longer fights against itself, shortens its own life and really makes life not worth living. Such a patient accepts the need to be fed parenterally over a long time, needs to defy swollen limbs, palpitations and difficulty in breathing – in order to be able only a few years later to live out a normal life. Such a patient needs to be extremely tolerant of suffering.
“Immune reset” as the last hope
For many months he has dispensed with life outside the boundaries of his sheltered house. He has abstained from using public transport and visiting the cinema or theatre, because lurking everywhere are germs with which the immune system may no longer be ready to deal. An immune system similar to that in infants, having to relearn from the beginning what is good and evil, self and foreign.
The patients at the Charité (Berlin) who undergo an “Immune reset” suffer from various autoimmune diseases: usually multiple sclerosis, systemic sclerosis or systemic lupus erythematosus (SLE). Internal organs have often already been attacked, as happens with lupus, and immunosuppressants show hardly any effect. With SLE the primary problem is that the plasma memory cells have been programmed incorrectly and incessantly produce autoantibodies. Andreas Radbruch from the German Rheumatism Research Centre sheds light on one risky path out of the dilemma: “If one does not reboot the immune system, there will be no healing”.
New naive immune system
This treatment strategy was pioneered by Alberto Marmont from Genoa in 1996. He employed autologous transplantation from haematopoietic stem cells in the treatment of SLE patients – and was successful. Experience in replacing the body’s own immune system with a new one out of the box already existed in oncology departments. Myeloablative treatment is used in eradicating tumour cells. After this “reset” command applied to bone marrow was also successful with autoimmune diseases, doctors and scientists at first assumed that the blocking of attacks on the body’s own system was due to immunosuppressive effects. Now however, it seems clear that the cure is associated with a clearing out of the body’s defence system back to a naive and self-tolerant state.
More than 2,000 patients with severe autoimmune conditions have now undergone the procedure. More than half of them manage without medications and special therapy aimed at their previously carried disease. The rate of transplant-related deaths has now declined from approximately thirteen to six percent. Why does this immune reset in many cases however function incompletely? With SLE, the pathogenic autoantibodies originate from both circulating and from memory plasma cells. Only the former respond well to immunosuppressive drugs and to treatment using belimumab or rituximab, which are specifically targeted at B-cells. Vaccination studies however show that complete eradication of all memory cells is not possible. In the bone marrow and in the secondary lymphoid organs there are apparently still safe hiding places for immunological memory.
Cleverly hidden memories
In order to at least remove immunological memory to a large extent, the patient has to go through a very aggressive radical chemotherapy. One component of this lethal cocktail is anti-thymocyte globulin (ATG), which has the function of making persistent memory cells inoperative. With the help of complement and the cell’s own suicide program (apoptosis), the plasma cells die off.
Before immunoablation however the removal of stem cells is carried out, using for instance CD34 surface marker. This serves as the basis for the reconstruction of the defence system.
When the immune system starts running anew, it resembles the development of the defence system in toddlers. First off, the innate immune system brings with it natural killer cells (NK cells). Little data exists however on the other cell populations in this branch of the body’s defence. Among the T-cells of the acquired immune system the memory cells come first; only after about one year do naive T-cells reach pre-transplantation levels. Only after about two years does the entire T-cell receptor repertoire include new regulatory cells.
Two year regeneration
In B cells, behaviour is the opposite: here naive B-cells tend to appear in the early stages. It takes about three years before the memory cells return to normal levels. Therein however, according to previous studies, the immune system seems to learn anew to distinguish between “self” and “foreign”, ie to re-learn immunological tolerance for the body’s inherent structures. Autoantigenic activity disappears in most cases, or at least substantially diminishes, when clones are still present and get reactivated. In most cases memory of antigens from prior infections emerges, memory to fight the body’s own structures however does not.
Nevertheless, these patients with an adolescent immune system are once again not only susceptible to everyday infections, but also to pathogens which previously had no chance against immunity acquired from a vaccination. These vaccinations must also be repeated anew. It may take two to three years before the immune system is again intact. During this time, everything which is associated with infection risks is taboo: doorknobs, crowds, buses and subways. The present mortality rate of six per cent, says Andreas Radbruch, is still too high to accept the method as clinical routine.
Multiple sclerosis: From wheelchair to skis
In addition to SLE, there have also been encouraging developments with other autoimmune diseases: in 1999 researchers in Ottawa, Canada, made what was at the time the first attempt to observe the (re)formation of autoimmunity in the human system in multiple sclerosis cases. “We totally failed in this aim”, says Mark Freedman in describing the approach he had planned – with a smile. Nonetheless the rate of successful therapy in curing the disease, and in terms of patient improvement, in his clinic is pretty impressive: 23 of 24 transplant patients have until now not suffered a relapse. For most of them their condition has come to a standstill; with some patients symptoms have been returning.
Looking worldwide, approximately 900 patients have now undergone the strenuous therapy. With 70 percent of them on average the disease has not progressed over the last five years. With MS, the mortality rate over 17 previous studies associated with the transplant stands at only about two per cent. Jennifer Molson from Ottawa developed multiple sclerosis at 26: not too long after that she was in a wheelchair and needed help washing, dressing and eating. She was “sick enough” to attempt a stem cell transplantation in 2002. For more than a year she could not leave her home. The chemotherapy caused cognitive disorders, baldness and a shingles infection. The subsequent 14 years then brought with them an amazing story of progress. Now Molson goes skiing and kayaking and produces skilful moves on the dance floor.
Nevertheless, the picture presented by previous studies is still not as clear as doctors and researchers wish it to be. Most studies are not controlled and are only observational studies. At present, as far as the doctors in Ottawa are concerned the “immune reset” procedure is only employed where previous therapies on patients with very active disease have failed. The course of neurological degeneration in MS is to all appearances due at least in part to non-inflammatory factors on which the immune system has no influence. Thus the loss of neurological function continues in some patients even after transplantation.
Selective memory cell killing
In various research centres doctors are currently experimenting with diverse forms of immunoablation that might not carry quite so many – sometimes even fatal – side effects. The milder the chemotherapy, the greater however is the risk that autoreactive clones evade treatment. Yet even with a heavy course of chemotherapy a few autoreactive clones will probably always remain. Andreas Radbruch and colleagues are therefore working on being able to selectively switch off memory cells. There are appropriate antibodies and gene activity regulators at the German Rheumatism Research Centre which could be a useful adjunct to this work.
Instead of using haematopoietic stem cells, mesenchymal stem cells might also be used in the future to rebuild the body’s defence system. Mark Freedman in Ottawa and Jeffrey Cohen in Cleveland are planning the first clinical trials with this in mind. Their optimism stems from the fact that, although haematopoietic stem cells are able to rebuild the immune system, other stem cells could provide relevant factors involved in neurological regeneration for instance with MS. The respective preclinical data stokes this hope.
It is an extremely hard procedure that patients with SLE, scleroderma or MS have to endure in order to lead a life without the constant attacks by the defence system against the body itself. The risks are high, and no one knows whether the autoreactive clones might simply resurface after ten years or more and cause a relapse. But the reports (for now) about “cured” patients provide encouragement to further extend and travel along this risk-laden path.