FACT FILE

Lymphoma and the immune system

By Dr Lucy Wall, Senior Staff Nurse John Curran and Professor Barry Hancock

Lucy Wall is a Specialist Registrar in Medical Oncology at the Edinburgh Cancer Centre, Western General Hospital. She obtained a BA in immunology at Oxford University and then completed her medical training in London. Her interests include the development of biological therapies.

John Curran is a Senior Staff Nurse at the Edinburgh Cancer Centre, where he is involved in the planning and delivery of care and treatments. He has an interest in patient and carer information needs and education.

Barry Hancock is Yorkshire Cancer Research Professor of Clinical Oncology and Director of Cancer Research in Sheffield. He has always had a major interest in immunology and in further improving the outlook for patients with lymphoma, by clinical trials.  

Our bodies fight a daily battle against foreign organisms.  We have therefore developed sophisticated weapons to use in this war.  In this article we will first review the armoury (the defence mechanisms and cells) of the immune system, then summarise how lymphoma and its treatment may weaken these defences, and what we can do to protect ourselves from infection.  Finally we will look at how the immune system has been used to treat lymphoma, and ways it may be used in the future.

The defences of the immune system

The castle walls

To infect us, foreign invaders first need to gain entry into the body.  Our first line of defence is the skin and the mucosa (the lining of the eyes, the respiratory, alimentary and genito-urinary tracts).  If an organism can’t get into the body, no immune response is necessary.

The skin is quite thick and, in the absence of wounds, hard for organisms to get through.  The mucosa is not as good as the skin at blocking the entry of foreign organisms, so it has a number of back-up mechanisms to protect us.  Tears, saliva and other secretions wash away organisms from the mucosa before they can get a foothold.  These secretions are kept moving.  In the eyes this happens when we blink.  In the urinary tract, urine washes organisms away.  In the respiratory tract little hairs called cilia are constantly in motion, beating foreign particles out of the lungs into the back of the throat. 

The secretions on these surfaces are themselves adapted to fight infections.  Sticky mucus can stop organisms from reaching the mucosa and invading it.  The secretions are acidic and contain chemicals and enzymes to directly damage foreign organisms.  They also contain antibodies (see later).

The foot soldiers

If an organism gets past the skin or the mucosa, immune cells called macrophages are the next line of defence.  These are found throughout the body, but are more numerous in areas at high risk of infection.  They recognise foreign organisms due to common patterns on their surface.  They then ‘eat’ (engulf) them. 

In case they fail to recognise the invading organisms, they have two major back-up mechanisms.  Complement is a concoction of about 20 proteins existing in body fluids.  When complement comes into contact with microorganisms it changes form.  The complement can then cause the cell to die.  If this doesn’t happen, the altered complement on the surface of the cell is a marker to macrophages that the organism should be eaten.  Antibodies can act as a signal in much the same way (read on). 

Macrophages are only capable of dealing with small numbers of invading cells.  It is important to call for back up to increase the strength of the immune response as much as is necessary.  Complement, macrophages and other immune cells send out chemical messengers to call for reinforcements.

The cavalry

The neutrophils (small, short-lived immune cells) enter the tissues from the blood, and gather in large numbers at sites of infection. They recognise foreign organisms in much the same way as macrophages, then swallow the invaders and kill them.  They are particularly important in fighting off bacterial infections. 

When activated, neutrophils are much more powerful than macrophages at attracting other cells and causing inflammation.  Inflammation increases the strength of the local immune reaction to destroy the invading cells.

The SAS

Antibodies are specialised proteins of the immune system, which recognise and stick to foreign material.  B lymphocytes exist to produce antibodies.  During development, each B cell learns to make one type of antibody, which recognises a single foreign protein.  The B cell carries copies of that antibody on its surface.  If it comes into contact with the protein, it divides, making daughter cells, which produce the same antibody.  The cells take time to grow, so it can take several days for antibody production to reach its peak.  After the infection is over, most of the B cells die, but some live on as memory cells.  If the B cell meets the same organism again, the immune response is much quicker. 

When antibodies bind to proteins on bacteria and viruses, they can block some of their functions, for instance sticking to and infecting other cells.  Macrophages and neutrophils recognise antibodies attached to foreign organisms, and use this as a signal to eat them.  Antibodies attached to the microorganisms also activate complement.  Antibodies are found in the blood, but are also found in the secretions on mucosal surfaces where they prevent the entry of foreign organisms into the body.  

The generals

T lymphocytes each have a cell surface receptor, a bit like an antibody in that it recognises a specific foreign protein.  All of our cells have a complex protein on their surface called the major histocompatibility complex (MHC), with special MHC proteins on the surface of immune cells.  T cells recognise foreign proteins attached to the MHC.  If the T cell comes into contact with a protein that it has been pre-programmed to recognise, it grows and divides into mature T cells and memory cells. 

Helper T cells produce chemicals and cell surface proteins to guide the immune response.  They boost the production of antibodies from B lymphocytes.  They also activate macrophages and neutrophils.  This may be necessary for them to destroy foreign organisms after they have been swallowed.  

Cytotoxic T cells recognise cells with foreign proteins attached to MHC on their surface and destroy them directly.  This sophisticated mechanism is very important in the fight against invaders growing inside our own cells like viruses and TB.  It is also one of the ways that we defend ourselves against changes in our own cells and the development of cancer.

How is the immune system affected by lymphoma and its treatment? 

The development of lymphoma

Lymphoma occurs when a group of lymphocytes grow too fast, ignoring the normal controlling mechanisms.  There is an increased risk of getting lymphoma, especially non-Hodgkin lymphoma, in people with an abnormally functioning immune system.  This is seen in some very rare immune diseases present from birth, as well as in people who have had organ transplants and in those infected with certain viruses like HIV.  However, there is no evidence that immune problems are the cause of lymphoma in most people.

The presence of lymphoma

Even without treatment, lymphoma can interfere with the working of the immune system.  In Hodgkin lymphoma, the T cells don’t seem to work properly, which slightly increases the risk from infections inside cells, like ‘cold sores’, ‘shingles’ and TB.  In non-Hodgkin lymphoma, some people get a problem with B cells and the production of antibodies.  This can increase the risk of infections like pneumonia and meningitis. 

All blood and immune cells are made in the bone marrow.  If lymphoma involves the bone marrow, it can reduce the production of these cells.  Normally there is enough spare capacity to make up for this.  If a lot of the bone marrow is involved, the main effect on immunity is due to the shortage of neutrophils.  This increases the risk of infection, particularly from bacteria.  Those with lymphoma involving the bone marrow should always quickly report high temperatures or other symptoms of infection to their doctors.

The treatment of lymphoma

Chemotherapy

Chemotherapy is usually given into a vein.  Drips and central lines (a kind of long-term drip tunnelled under the skin) can allow infectious agents to enter the blood directly.  They must therefore be carefully checked and cleaned whilst in place. (please call the Helpline if you would like to receive more information on central lines).

People on chemotherapy should generally take care to prevent the entry of infections.  Drinking plenty will keep the urine moving through the urinary tract.  Smoking can damage the function of the cilia (the minute hairs that beat particles out of the lungs), so people on chemotherapy should avoid cigarette smoke.  Coughing and sneezing spread infections through the air, so it is best to avoid people with colds and ‘flu.

Chemotherapy agents and other drugs can reduce the production of saliva and other mucosal secretions.  People on treatment may then experience dryness in the eyes, mouth and nose.  If the treatment also causes mouth ulcers, this provides a way for bacteria to enter the body and further increases the risk of infection. 

Many chemotherapy agents interfere with neutrophil production, so neutrophil numbers commonly fall 1-2 weeks after treatment. The longer the neutrophil count remains low, the higher the risk of infection.  Growth factors such as G-CSF (granulocyte colony stimulating factor) can be used to stimulate neutrophil development and so speed up neutrophil recovery from chemotherapy.  Neutrophils are especially important in fighting bacterial infections like pneumonia, septicaemia (blood poisoning), meningitis and urinary infections.  If the neutrophil count is low, the ability to kill invading bacteria is very reduced.  It is extremely important that those on chemotherapy seek medical help immediately if they develop a high temperature or other symptoms of infection.  They may need to be in hospital for intravenous antibiotics.

Radiotherapy

The effects of radiotherapy on the immune system depend on the amount of radiotherapy that the person has had.  It is unusual to get infections after radiotherapy, except for total body irradiation with bone marrow transplantation. 

Steroids

Steroids are an important part of the treatment of lymphoma.  However, steroids themselves can have quite widespread effects on immunity.  Practically, the most important effect is an increase in the risk of infections with viruses like ‘cold sores’ and ‘shingles’, and fungi like ‘thrush’.  When big doses of steroids are given for a long time there is a risk of more serious infection like PCP (pneumocystis pneumonia); antibiotics may need to be given during chemotherapy to prevent this.  Steroids affect a lot of the body’s other systems too, so if a person gets an infection whilst on steroids, to help fight the infection the steroid dose may actually need to be increased.

Splenectomy

Splenectomy is the surgical removal of the spleen.  The spleen acts as a filter in the blood to remove foreign proteins and circulating immune cells.  The macrophages then process the foreign material, which appears on their surface to be recognised by T cells.  Without a spleen people are at increased risk of infections, particularly pneumonia and meningitis.  Those without a spleen often take antibiotics to prevent them from getting these infections.

Stem cell and bone marrow transplantation

All blood and immune cells are made in the bone marrow. High doses of chemotherapy and/or radiotherapy destroy these cells during treatment. They are then replaced by previously ‘harvested’ stem cells, which have the ability to develop into all of these cells. 

Immediately after a transplant, people have very little immunity and are at high risk of all kinds of infection.  This risk is higher the longer it takes the bone marrow to recover from the high dose therapy.  As the bone marrow recovers, the neutrophils recover first, allowing the body to fight bacteria.  This usually takes 2-3 weeks.  The recovery of the lymphocytes, and the ability to fight viruses and fungi, takes up to three months.  It may take more than a year for antibody levels to recover from a transplant.  Because of the destruction of memory cells, people may need to repeat their childhood vaccinations.

After the treatment of lymphoma

After the treatment of lymphoma minor changes in the immune system may be detectable for ever. There is no evidence that this is associated with an increased risk of infection.  The only people known to have a long-term risk of infection after the treatment of lymphoma are those who have had a splenectomy.  These people should receive special vaccinations and may be advised to be on long-term antibiotics. 

How can we use the immune system in the treatment of lymphoma?

Interferon is one of the proteins used by immune cells to communicate.  It increases the expression of MHC protein on cells, therefore increasing the T cell response to infection.  It also slows down the growth rate of a number of cell types.  Interferon injections have been used, together with chemotherapy, in the treatment of low grade non-Hodgkin lymphoma.

Antibodies can be extracted from the blood of healthy donors.  If people with poorly functioning immune systems come into contact with viruses such as chicken pox, they can be protected against infection by being given antibodies from donors. 

Antibodies can be made to specifically recognise the abnormal lymphocytes of lymphoma.  These antibodies attach to the malignant cells, which can then be destroyed by macrophages and neutrophils.  This is the basis of rituximab (Mabthera®) treatment.  Other antibody therapies for lymphoma are currently only experimental.  Antibodies can be attached to toxins or drugs to kill the abnormal cells directly.  Bexxar® and Zevalin®,  consist of radioactive antibodies directed to B lymphocytes. Bexxar is only available in clinical trials at present.

Dendritic cells are similar to macrophages, but are more powerful activators of T lymphocytes.  They can be purified from blood.  In experimental studies they have been exposed to lymphoma-related proteins in the laboratory and re-injected into the body.  The protein, together with the MHC on the surface of the dendritic cell, then activates T cells to mount an immune response against the lymphoma.  Other experimental studies have tried to introduce the abnormal protein or its DNA directly into the body to activate the immune system within the body.  This is the basis of vaccine therapies.

Summary

Our body has sophisticated ways to protect us against infections.  Lymphoma and its treatment disrupt these protective mechanisms.  It is important that those with lymphoma watch out for infections, particularly whilst on chemotherapy.  After the treatment of lymphoma the immune system should recover, although this may take over a year in those who have had transplantation.  Studies are ongoing as to how we may harness the immune system to improve the future treatment of lymphoma. 

Revised March 2005

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