4.1 Undesirable DefenceAn adult human being is made up of some 100 billion cells. The immune system's task is to protect these cells from enemies from within and without:

· Any pathogens or foreign matter coming in from the outside are supposed to be rendered harmless.

· Any of the body's own cells which change pathologically or become unusable are supposed to be eliminated.

In either case, there may also be undesirable defence reactions: against foreign tissue when organ transplants are made, against the body's own tissue in the case of autoimmune diseases.

Organ TransplantsNormally, organs donated by another person are fought by the recipient's immune system using the same weapons it otherwise directs against pathogens. The transplanted organ is rejected. The decisive breakthrough in transplant medicine did not come until scientists succeeded in "outwitting" the recipient's immune system. By and large, the rejection reaction can be suppressed by careful selection of suitable donor organs and the administration of medications. The immune system tolerates the foreign organ almost as if it belonged to the system's own body. This enables many people to live an almost normal life for years, even with a donated kidney or heart. However, the patients must take medications which keep the immune system at bay (immunosuppressives) for the rest of their lives, making them more susceptible to infections.

Liver transplant

Rheumatoid arthritis

Autoimmune DiseasesThe immune system has highly effective weapons at its disposal which it can deploy to eliminate cells infected by viruses or cancer cells. But these defence measures can also turn against the body's own healthy tissue if it is erroneously classified as "foreign." Generally speaking, any organ or tissue can be affected by autoimmune reactions.

· Brain cells are attacked by multiple sclerosis.

· Cartilage and bone substance is attacked by rheumatoid arthritis.

The cells in the pancreas gland which produce insulin are attacked in Type I diabetes.

The immune reactions against implanted and the body's own organs are extremely similar. The basic difference is found in the targets for the attack sought out by antibodies and T cells. After a transplant, they attack foreign antigens; their attack against the body's own antigens results in autoimmune diseases.

4.2 The Rejection of Foreign Organs

Production of T cells (model)

T cells play the major role in the rejection of donated organs. They coordinate the defence measures much as they do during an infection, and cause the antibodies and cytotoxic T cells to destroy the transplant. This undesirable immune reaction is related to the task of the T cell troops. They are supposed to examine body tissue for suspicious properties, but not intervene unless there is really an infection. The T cells acquire this ability in the thymus gland, a key organ of the lymphatic system.

T cells, like all other white blood cells (leukocytes), are formed from stem cells in the bone marrow. Comparable to blanks, these precursor cells go through several development stages and ultimately mature in the thymus gland. A T cell bears a large number of receptors built exactly alike. These receptors recognize only one characteristic molecule which the target cell displays on its surface like an identity card. When the T cell receptor and molecule fit together like a key in a lock, the target cell has been identified.

The immune system must be armed to fight all imaginable enemies. It begins preparing for this difficult task during the development of the embryo. The first step is the production of precursor T cells which are suitable for every potential molecular form.

The required diversity of T cell receptors is created by a random process during which the appropriate genes are varied. In principle, there is a matching lock for every possible molecular key.

Test Station Thymus GlandBefore the immature T cells are ready for service, they are subjected to a thorough test in the thymus gland.

· Each T cell is inspected to see if it could find target cells at all, which identify themselves by MHC molecules. If the receptor of a T cell does not match any MHC molecule, it is more or less blind and is decommissioned.

Cytotoxic T cell (model)

Depending on whether the receptor binds to an MHC-I or an MHC-II molecule, a cytotoxic T cell or a T helper cell is formed.

T helfer cell (model)

· All T cells are also tested to determine if they recognize harmless antigens from their own body. In this case, the defence could go out of control and start destroying the body's own tissue. So normally such dangerous T cells are also destroyed.

animated film

The T cell test in the thymus gland is shown in simplified form as an animated film. MHC-I molecules are square, while MHC-II molecules are circular in shape.

The rigorous selection process in the thymus glands ensures that the body's own cells are spared attack as much as possible. Only mature T cells which are specialized in the fight against foreign antigens and tissue remain. This protects us from pathogens, but it also leads to major complications during organ transplants. About 20% of the T cells recognize foreign tissue.

MHC Molecules, the Identity Papers of the Cells. The abbreviation MHC stands for major histocompatibility complex. The MHC molecules are also called HLA, human leukocyte antigens. They can be easily found on the surface of white blood cells. This is where you find the variations of MHC molecules typical for every human being. They differ from one person to the next. They are exactly the same only in the case of identical twins. In this exceptional case, there is no rejection reaction when an organ is transplanted.

4.3 Rejection Reactions

Transplanted organs are basically at risk from two defence processes: the hyperacute and the acute rejection.

The Hyperacute Rejection Reaction

Blood cells

The hyperacute rejection can begin within only a few minutes after the transplant. This is the case if the recipient has already formed antibodies against surface structures of the donated organ - if, for example, the blood types are incompatible. The antibodies attach themselves to the blood cells transferred with the organ and destroy them with the support of the complements. Blood clots are quickly formed. The transplanted organ is no longer supplied with blood and dies. However, this fast, violent form of rejection can usually be avoided by checking the blood types of donor and recipient for compatibility before performing the transplant.

The Acute Rejection ReactionThe acute rejection frequently occurs some days or several weeks after the transplant. This undesirable immune response is caused primarily by activated T cells which react to the foreign antigens and MHC molecules of the donated organ. In particular, cytotoxic T cells as well as antibodies attack the transplant. The immune defence acts much as it does during a virus infection, the only difference being that endogenous tissue is destroyed.

animated film

The acute rejection reaction can be reduced to a minimum if the tissue properties (MHC molecules) of donor and recipient are as similar as possible. Moreover, the immune reaction can be suppressed by the administration of medication, preventing a premature destruction of the transplant. The successes of modern transplant medicine have given many people a new lease on life.

The Eurotransplant International Foundation acts as a clearing house for organ donations in Austria, Belgium, Germany, Luxembourg, Slovenia and The Netherlands. Transplant centres, tissue typing laboratories and hospitals in which organ transplants are performed participate in this international cooperation. The organs of brain-dead donors are first typed. Eurotransplant then takes data such as blood type antigens and tissue properties and searches the waiting list for a suitable recipient.

Transplants in Germany as of 31/12/ 2000 (cadaver donations)

Patients ...

Kidney

Liver

Heart

Lungs

... on waiting list

9510

600381

270

... transplanted

1641

692407147

Prof. Rudolf Pichlmayr (†),Medical School of HanoverStatement on tissue compatibility

Medications for the Rejection of OrgansEven when the tissue of the donor and recipient is highly compatible, medication is required to keep the immune system at bay. The successes achieved in transplanting kidneys is proof that this often works. More than 90% of these organs continue to function for more than one year without provoking any notable rejection reactions. This success comes from the use of immunosuppressives, but this medicine must be taken for the rest of the person's life.

The administration of these medicines is a balancing act:

· If the immunosuppressive dosages are too high, the door is opened wide to otherwise harmless infections, and the risk of cancer increases.

· If the immunosuppressive dosages are too low, the prevention of the rejection is not effective enough.

Target of the Attack: T CellsThe two most important substances, Cyclosporin A and FK 506, suppress the activity of the T cells. As a consequence of the inhibition by the messenger substance interleukin 2, they cannot reproduce properly. The power of the helper T cells and the cytotoxic T cells is sharply reduced, and attacks on the transplanted organ are largely eliminated. However, the immune system is also unable to move against pathogens with full force. This is also the case for artificially produced antibodies which are supposed to block the T cell receptors. They would then be more or less blind to foreign matter and would no longer attack it.

4.4 Alternatives to Organ DonationsMore than 14,000 people are waiting for a replacement organ in Germany alone. But fewer than 2,000 people every year are prepared to donate their organs. Many fear that they will erroneously be declared brain dead or have other reservations. This scarcity of organs means death for many on the waiting list, or forces chronically ill patients to suffer unnecessarily. This is why alternatives are required.

Artificial heart

Organs Made of PlasticsArtificial hearts or kidneys have long been used as transplants. However, there have been strong reactions to the plastic by the body. The artificial organs are very expensive and do not perform the functions even remotely as well as natural organs. Artificial hearts have proven themselves best as a temporary solution. They give the patients more time to wait for a new organ.

Cultivated OrgansSo far, the dream of replacement livers or replacement pancreases from the test tube has remained just that. Organs cultivated from single cells and which can take over complex functions are still far in the future. One possibility would be the cultivation of any tissue from embryonic stem cells. But there are ethic reservations about this procedure. Besides, it is questionable whether it will ever be possible to cultivate completely functional organs from stem cells, despite encouraging results from animal experiments. As of today, it has only been possible to produce skin and cartilage tissue by reproducing endogenous cells. The advantage: the tissue is not rejected because the donor and recipient are

Artificial skin

identical.

Transgene pigs

Animal OrgansA faster - but ethically disputed - solution to the organ crisis could be organs from animals. Pigs are a big favourite as they provide organs of a suitable size. Scientists are constantly improving their control of the particularly violent rejection reactions caused when organs from other species are transplanted (xenotransplantation) with the help of genetic technology. They are breeding pigs with human tissue properties whose organs will hopefully not be recognized by the recipient as foreign to the species. In addition, new immunosuppressives are being specifically developed for transplants of animal organs. The danger of infecting the recipient with possibly dangerous viruses during a transplant of humanized pig organs appears to have been warded off.

Animal organs can be made available in any desired quantity and for any purpose. They would not only eliminate the shortage of organs, but could also be used to treat other widespread organ diseases which today cannot be adequately controlled with medication. 4.5 Der Angriff auf den eigenen Körper

„The immune system prepares a frightening welcome for any undesired intruder: an entire army of highly specialized

attackers, well versed in strategy and equipped with toxic weapons. Every attack of the immune system is a life and

death struggle for anyone caught in the line of fire“Paul Ehrlich

Paul Ehrlich attempted to describe what would happen if this apparatus should turn against the cells of its own body with the words "horror autotoxicus." Today we know with certainty something that was not yet clear in Ehrlich's day, namely that there are indeed a number of diseases which are caused by various malfunctions of the immune system. We speak of autoimmune diseases (autoimmune = immune to oneself).

There are some autoimmune diseases which can spread throughout the entire body, but there are also some which are restricted to one organ and remain so. Any of the body's organs can be susceptible to autoimmune diseases.

Armed cytotoxic T cells can, if they are programmed erroneously, also destroy endogenous tissue.

Errors in the Recognition MechanismThe more complicated an apparatus, the more susceptible it becomes to errors. The immune system, which would otherwise be blind, orients itself on the complex biochemical recognition mechanism, which employs MHC to distinguish between foreign and own, friend and enemy. The immune system sets its sights on its "enemies" by recognizing certain surface markings of the "revealed" intruders and saving these markings in T and B cells. T cells are armed by contact with the recognition markings and can stimulate B cells to produce specific antibodies against the triggering pathogens. Errors in this system can cause endogenous or similar features to be saved as well. Then the body's own cells would become the targets of the immune system.

Erroneously Programmed T Cells - Type 1 DiabetesNormally all of the T cells which react to the body's own MHC molecules are weeded out and destroyed in the thymus gland. This does not happen in the bodies of patients

suffering from Type 1 diabetes. In their systems, T cells which react to the endogenous isles of Langerhans leave the thymus. The isles of Langerhans are distributed in the pancreas and have the important task of producing the hormone insulin. Insulin regulates the conversion of sugar into usable and saveable energy reserves. The misguided T cells have been programmed to destroy the isle cells and, consequently, the body's production of insulin. The person with this problem then lacks this vital hormone.

animated film

It is believed that the disposition to this disease is inherited. The responsible gene has been located on Chromosome 11. But massive production of the misguided T cells does not begin until there has been a virus infection (mumps and Coxsackie viruses are suspected). There are probably similarities between the antigens of these viruses and the corresponding structures on the isles of Langerhans. The T cells in question are first given the signal to start the defensive fight by the viruses, and the "innocent" isles of Langerhans are drawn into the battle.

Type 1 diabetes occurs mostly in young people under the age of 20. About 10% of all diabetics suffer from this form of the disease. The patient must observe a strict diet and inject the required quantity of insulin every day. Today it is also possible to implant healthy isles of Langerhans or to replace the pancreas completely. But this operation only has hope of success if the self-destructive T cells have been stopped beforehand.

T Cell Confusion - Multiple SclerosisThe T cells which cause multiple sclerosis are also aimed at a virus, e.g., a flu or herpes virus. But the MHC markings of this virus are similar to the protein building blocks found in the outer shell of the nerve ends in the brain and spinal cord, the so-called myelin sheaths, of the affected people. Once activated by the actual virus, the "armed" T cells also attack these myelin sheaths. The important nerve sheaths are first combated by the body's own immune cells in the proximity of the actual infection, later throughout the entire body.

The patient first suffers from massive perception and balance disruptions, then the gastro-intestinal tract functions become paralysed. No method has yet been found to heal MS. Three substances are available for treatment. Interferon-ß (IFN-b1a) is an endogenous messenger substance which is formed during viral infection and which, among other things, inhibits the multiplication of the virus. One problem of using Interferon-ß for treatment is that some people develop antibodies which counteract the effects of the interferon.

Multiple sclerosis patient

The substance Copolymer-1 is a synthetically produced mixture of various protein building blocks (peptides) which also occur in the sheath of the nerve fibres, the myelin. Copolymer-1 attracts the attention of the immune defence and draws it away from the myelin sheaths.

A new form of treatment is the injection of antibodies into the patient. The antibodies are derived from healthy donors. Plasma donations from more than 10,000 individual donors are mixed to produce a diverse cocktail.

Rheumatoid Arthritis (Rheumatism)Rheumatoid arthritis is one of many variations of the common disease rheumatism. "Rheumatism" is a general term for inflammation of the joints, the supporting and movement structures. It covers more than one hundred different diseases. Rheumatoid arthritis in particular has its origin in an autoimmune reaction which has not been clarified.

The cells of the joint membrane (synovialis) are the targets of the immune system. Phagocytes and T cells displaying antigens migrate in large quantities to these areas. They appear to react to a surface structure of the joint membrane cells. A violent inflammatory reaction which spreads more and more is the result. B cells and antibodies also participate in the reaction. A key role is played by the messenger substances TNF- and Interleukin-1 and -6.

Hand damaged by rheumatism

The joint membrane is seriously damaged by the cytokines which the immune cells release. Contusions form which grow into the joint, much like a tumour. The wild growth gradually destroys cartilage, bones and ligament structures of the affected joint. The deformation of the joints is accompanied by a painful restriction of movement. Finally, the joint is often completely stiff.

The so-called rheumatoid factor plays an odd role. It is an antibody which becomes active against endogenous antibodies, namely those of the class IgG. It is not clear what part it has in the development of the symptoms. But it is found in most rheumatism patients.

The therapy for rheumatoid arthritis has been limited to relieving the pain and keeping the inflammation area under control with inhibitors. But in the meantime there is a highly promising new approach. Modern medications intervene directly in the activities of the immune system.

The tumour necrosis factor (TNF- ) is one of the most "dangerous" messenger substances (cytokins) of the immune system. It activates phagocytes at the location of the inflammation which release breakdown enzymes. Two new substances inhibit TNF- . Etanercept acts like a receptor for TNF- ; it binds the destructive molecule. Infliximab is a monoclonal antibody which docks on to TNF- and blocks it in this way. So the most significant destructive processes in the joints can actually be stopped. The body tissue is given a chance to regenerate, at least in those places where it is still possible.

However, it has been determined that not all patients respond to the two medications. There are apparently deviations in the genetic code which are decisive for sensitivity to the medications. Even newer approaches attempt to block the cytokins which control the TNF- with interleukins.

Arthrosis of the thumb joint

Lupus

B Cell Confusion - LupusIn the case of lupus (correctly: systemic Lupus erythematodes (SLE)), antibodies attack the endogenous tissue. The B cells first react to a false signal and begin to form antibodies which are aimed at endogenous structures. In SLE, these structures are the surfaces of cells of the blood vessels and connective tissues. The antibodies dock onto the cells and clump together with them. So painful inflammations form.

Lupus has been treated with medications to inhibit inflammation. So the symptoms, but not the cause, of the illness can be alleviated. A new procedure attempts to remove the harmful antibodies from the patient's blood. A method which separates the blood plasma from the solid components of the blood (called plasmapheresis) is used for this. The harmful antibodies and the clumps are washed out of the patient's blood.

In the most serious cases resistant to therapy, a highly aggressive treatment method derived from cancer therapy has been used lately: high-dose chemotherapy followed by the transplant of autologous (i.e., taken from the patient beforehand) stem cells. The chemotherapy is supposed to destroy the destructive parts of the immune system. Then fresh, "innocent" immune cells are supposed to grow from the stem cells.

Stem cells

Patients with life-threatening SLE have already been treated in this way at the Charité in Berlin. After the transplant of the stem cells, they were free of disease symptoms. The typical auto-antibodies in the blood had disappeared and the inflammation symptoms had subsided. In cases in which patients are successfully treated, the immune system - at least temporarily - appears to stop furthering the disease. Apparently the self-destructive lymphocytes and the antibodies were successfully eliminated. But the experts do not yet dare to speak of a cure. About 300 stem cell transplants have been performed around the world as a therapy for autoimmune diseases. Unfortunately, some patients did not respond to the treatment, and some even succumbed to the consequences of the operation. Due to the considerable risks, the stem cell transplant will for the moment remain reserved for life-threatening forms of the illness.