Components of the Immune System. Our immune system consists of many components, which all play a part in protecting us from infection. the major components are:
  • Bone marrow
  • Thymus
  • Spleen
  • Lymphatic system
  • White blood cells
  • Antibodies
  • Complement system
White blood cells the function of these is to protect our body from infections: viruses, bacteria, fungi and parasites. There are many types of white blood cells each with their own role, and whilst some are more important than others it is essential that all cells function correctly.

Lymphocytes are a type of white blood cells. They are an essential part of our immune system. There are various types of lymphocytes: B cells, T helper cells, T-Killer cells and Natural Killer cells.

Important Parts of our Immune System:
  • Thymus T cells are called "T cells" because they come from the Thymus which is found behind the sternum.
  • The Lymphatic System is made up of lymph nodes, liver and spleen linked by fine vein-like channels called lymphatics. Lymphocytes circulate in the blood and lymphatics to and from organs.
  • Bone Marrow is a sponge-like tissue inside our bones. T cells along with other blood cells are produced here before going to the Thymus.

T cells are an essential part of what we call a cell-mediated immunity. It is an immune response which does not involve antibodies. B cells produce antibodies.

The development of T cells. T cells originate from bone marrow along with many other blood cells. they then populate the thymus and mature there. Only few cells complete the process and become mature T cells which enter our blood stream and start functioning.
So how do T Cells work?

First T cells are produced in the bone marrow.


Thymus is where T cells mature and after the process is finished they begin to function.

When a virus or bacteria is encountered, T helper cells are activated.


They start to divide and rapidly produce protein called "cytokines". This protein will attack infected cells and attract more lymphocytes to fight the infection.

So, how is the immune system related to ATLL (Adult T cell leukaemia)

Patients with ATLL have an increased number of T cells in the blood or lymph nodes due to their rapid division and prolonged life. This leads to many problems. Cancerous T cells do not function properly, and this makes the immune system weaker and the patient more susceptible to infections. The presence of this extensive amount of T cells also leads to an increased chance of blood clots, this is referred to as leukaemia which literally means “white blood”.

An ATLL sufferer may also have a condition called lymphoma. This is when cancerous T cells are only found in lymph glands and due to this, glands increased in size dramatically. Although the blood is normal, the lymph system can not function properly because all the normal cells are being replaced by cancerous T cells


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What is ATLL?

ATLL (Adult T cell leukaemia/lymphoma) is a rare blood cancer seen only in people infected with Human T-Lymphotropic Virus type I and was first described in Japan in the mid 1970s. The virus, HTLV-I, was discovered by researchers trying to find infectious causes of cancer. ATLL affects a type of white blood cells (part of the immune system) called T-lymphocytes. There are two types of lymphocytes found in the blood: B-lymphocytes (B-cells) and T-lymphocytes (T-cells), both are important in fighting viral, fungal and bacterial infections.

In the ATLL, the cancerous (or malignant) T-cells increase in number either by dividing faster than they normally do or by living longer than normal or perhaps a mixture of both. this overgrowth of T-cells can interfere with the normal production and growth of other cells in the bone marrow (sponge like tissue inside our bones) reducing the numbers of these and therefore interfering with other functions of the blood such as carrying oxygen and fighting infections. In addition, especially when there are excessive numbers of white cells in the blood, the blood is more sluggish and there is an increased risk of blood clots or thrombosis. this is seen in leukaemia, which means "white blood".

Sometimes the cancerous T-cells are only found in the "glands" and the blood appears normal. this is called a lymphoma, which literally means swelling of the lymph gland. the tumour may start in a single lymph gland but usually when the illness appears many lymph nodes are affected. the lymph glands are connected by channels called lymphatics and T-cells of course also circulate in the blood. With the normal cells of the lymph nodes being replaced by the lymphoma cells (T-cells in ATLL) the normal function of the lymph node in combating infection deteriorates.

ATLL can present as a leukaemia, as a lymphoma or with a mixed pattern. Sometimes the lymphoma cells are only found in abnormal patches of skin - this is called cutaneous lymphoma. It is also possible for one type to progress to another type.

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Who gets ATLL?

Most patients with ATLL live in the parts of the world where HTLV-I infection is most common, such as South-Western Japan, the Caribbean, West Africa and South America. In Europe, the majority of patients with ATLL are either immigrants from the Caribbean, Africa or South America or their families came from these regions.

Only persons infected with HTLV-I get ATLL but less than 5% of HTLV-I infected people will develop the disease during their lifetime. Put another way only 1 person in 1500 with HTLV-I infection will develop ATLL every year. Japanese HTLV-I carriers seem to have the highest chance of developing ATLL.

the interval between HTLV-I infection and the onset of lymphoma is long and measured in decades rather than years. In the UK, the average age of first presentation of a patient with ATLL is 50 years. there are some factors that make the development of ATLL more or less likely:

  • Time of HTLV-I infection; those infected at birth run the greatest risk
  • the number of T-cells infected with HTLV-I. the higher the number the greater the risk
  • the presence of atypical cells, so-called "flower cells" in the blood
  • Low level of antibody (substance produced in the body in response to foreign material) to a specific antigen (the protein that HTLV-I- infected cells display)
  • Genetic make-up of the infected person, which determines the ability of the person's immune system to defend against anything foreign to the body, including tumour cells
Environmental factors, such as, radiation, toxic chemicals, air quality, etc. do not seem to play a role in ATLL.

Types of ATLL

ATLL has been classified into four types according to the patient's symptoms and findings from his/her blood tests and tissue biopsy, such as the number and shape of abnormal T-lymphocytes:

Acute ATLL. the symptoms develop rapidly, and quite quickly ATLL becomes life-threatening if not treated. Common symptoms are: tiredness, skin rash, generalised lymphadenopathy (firm lumps found on the neck, armpits, groin) frequent infections. Examinations may also reveal enlargement of the liver and spleen. Blood tests show a raised white blood count, the typical abnormal cells (flower cells) and high levels of calcium in the blood. X-rays may show bone damage.

Lymphomatous ATLL. Is characterised by enlargement of lymph nodes anywhere in the body, for example, the neck, axilla, groin, stomach. the blood counts may be completely normal and very few or no abnormal T-cells are found in the blood. For some reason all the cancerous lymphocytes stay in the lymph nodes.

Chronic ATLL. the common symptoms are skin rash and tiredness but the condition may be detected on routine blood tests. Lymph nodes, liver or spleen may be enlarged but the disease gets worse much more slowly than with the acute or lymphoma types. the white cell count may be raised and abnormal T-cells are seen in the blood but the calcium in the blood is normal.

Smouldering ATLL. the disease is present in a very mild form and may be found on routine blood tests only showing abnormal T-cells in the blood but normal cell counts. there may be some skin lesions but lymph nodes, spleen and liver are normal.

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What are the symptoms?

the symptoms depend on which type of ATLL the patient has developed. the most common are: tiredness, weight loss, night sweats, skin rashes, appearance of lumps in the areas like neck, armpits, groin, sometimes stomach ache, fever, thirst.

How is ATLL diagnosed?

Usually the patient will present with one of more of the symptoms above which will suggest the diagnosis of a leukaemia or lymphoma. Various tests will be needed to confirm the diagnosis and in particular to show that the condition is ATLL and not some other type of lymphoma or leukaemia. the first steps are to look at the blood counts and examine the white blood cells under the microscope and to take a biopsy of an enlarged lymph node or abnormal patch of skin. If flower cells are seen or special stains show that the abnormal cells are T-cells it is important to test the blood for HTLV-I infection. If a patient with leukaemia or lymphoma has a high level of calcium in the blood it is important to test for HTLV-I infection to avoid missing the diagnosis of ATLL.

Further tests to determine the spread of the disease are usually required:
  1. CT scan of chest and abdomen to look for enlarged lymph nodes, liver and spleen
  2. Bone Marrow to look at the site of blood cell production
  3. Lumbar puncture to look for evidence of spread to the brain

How can it be treated?

Smouldering ATLL does not require treatment unless it evolves into another type. Regular check ups are required.

Chronic ATLL may need treatment if it is causing symptoms.

Acute and Lymphoma types of ATLL always require treatment.

Modern therapies for ATLL are divided in to three categories:
  1. Chemotherapy
  2. Immunotherapy
  3. Stem cell transplantation/Bone marrow transplant
the treatment of ATLL is usually lengthy and complex, and consists of a combination chemotherapy followed by immunotherapy.

Bone marrow transplant may be the most effective treatment and has the possibility of curing ATLL, but it has lots of limitations and does not suit everyone.

the main principle of each therapy is described below:

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Chemotherapy works by blocking the malignant (tumour) cells' growth and causing them to die. This type of treatment is typically used first because it works quickly.

There are different types of chemotherapy for different cancers. the standard chemotherapy for ATLL is called CHOP - each letter standing for one of the four parts of the treatment. the drugs target tumour cells at different stages of their life cycle, so it is possible to make tumour disappear, however chemotherapy also affects healthy bloods cells and that leaves the patient vulnerable to infections until they recover again.

Chemotherapy has unwanted side-effects such as nausea, vomiting, sore mouth, tiredness, easy bruising and loss of hair. However, each person's reaction to chemotherapy is unique. Some people have very few side-effects, while the others may experience more. the side-effects stop once the course of therapy is completed. CHOP is usually started in hospital and then follow up treatment is given every three weeks as an outpatient. this treatment is given by a specialist team of doctors, nurses and pharmacists.

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Immunotherapy is an innovative therapy for this condition. Extensive research into cancer has shown that the immune system, the body's natural defence system, may play a central role in protecting the body against cancer and in combating cancer that has already developed. the principle of immunotherapy is to enhance the body's natural tendency to defend itself against malignant (cancerous) tumours.

Interferon-alpha (IFN-&alpha) is a naturally occurring substance made by blood cells to fight infections. It acts to make tumour cells more susceptible to immune attack. It also has a direct effect on the growth of the cancer cells, and can apparently stimulate some immune cells, such as, Natural Killer cells to kill cancer cells. IFN-&alpha is now widely used in the treatment of ATLL but only works in combination with other drugs particularly Zidovudine. Zidovudine was originally designed as an anticancer drug but found fame as the first effective treatment of HIV. More recently Zidovudine in combination with IFN-&alpha has been shown to be a better tolerated treatment for ATLL and gives patients longer time in remission (no evidence of leukaemia or lymphoma). this type of treatment is often continued indefinitely. It involves injections under skin, which many patients learn to give themselves. the frequency of injections varies from once daily to once weekly.

the following side-effects which are usually worse at first and lessen over time, may be experienced: flu-like symptoms, tiredness, loss of appetite, nausea, susceptibility to infections, depression. Simple treatments such as paracetamol and anti-sickness tablets can help prevent these side-effects.

Monoclonal antibodies are another innovative therapy for ATLL. Monoclonal antibodies are artificial antibodies against a particular target (the "antigen") on the cell. they are produced in laboratory from genetically engineered mice or bacteria that contain human antibody genes.

Monoclonal antibodies can be injected into patients to seek out the cancer cells or to enhance the immune response against the cancer. Antibodies are now being used to guide the delivery of cytotoxic drugs (drugs that are used in chemotherapy) or radioactive therapy to just the cancer cells without harming other cells: the result would be like a "guided missile", capable of seeking out a specific target-a cancer cell. In ATLL the T-cells have a cell marker called CD25 on their envelope (the outside of the cell). this has been targeted with an anti-CD25-antibody.

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Bone marrow transplantation is the replacement of a patient's bone marrow with a donor's stem cells (cells in a very early stage of development which later transform into main type of blood cells).

At present this is the only a method for ATLL treatment with a reported complete cure of the disease. But, before transplantation the patient must have intense chemotherapy to destroy (or ablate) their own bone marrow and the ATLL cells. this places the patient at high risk from infection as they have no immune system, until the donor stem cells have repopulated the bone marrow. the dangers attached to BMT means it has to be reserved for younger, fitter patients.

What happens during the procedure is: a patient is given high doses of chemotherapy or radiotherapy to destroy all cells in his bone marrow. Afterwards bone marrow from a matched donor (often a relative) is given to the patient, which means he/she is receiving a source of healthy bone marrow, which will then produce healthy cells. the most suitable donor is usually patient's brother or sister whose bone marrow is a close match to the patient's. It is also possible for a non-relative to donate if they have similar to the patient's tissue type. this type of transplantation is called allogenic bone marrow transplantation.

The success of any single or combination therapy is judged by disappearance of the tumour or leukaemic cells from the patient's body for more than two months - this is called "remission".

Understanding the investigations for ATLL

The following investigations are used in the diagnosis and monitoring of ATLL:

Blood tests a blood sample is taken from the vein in the arm. It shows the number of different cell types circulating in blood enabling the doctor to check the effectiveness and safety of the therapy. Measuring the level of Calcium and an enzyme called LDH in the blood is a simple way to monitor the disease. Other blood tests are performed to check how vital body systems, such as, the kidneys, the liver, the heart, are coping with the disease and treatment.

X-ray involves the use of radiation (x-rays) to create an image of the body. It is a useful technique to determine whether cancer has spread to other organs. Enlargement of the liver, spleen and lymph nodes or 'holes' in the bones can be seen on X-rays.

CT scan (Computerised Tomography) uses an x-ray technique which is simultaneously processed by a computer to build up a very accurate, three-dimensional picture of the body's structures and organs. In ATLL it is used to determine the type of ATLL, the stage of the disease, responsiveness to treatment.

Tissue biopsy involves surgical removal of a small sample from solid tissue, such as the liver, lymph node or skin, to perform further study under a microscope. It is a necessary diagnostic technique when a solid tumour, like lymphoma is suspected. this technique enables a practitioner to check directly for cancerous cells within the investigated organ. Special stains are used to determine the exact nature of the cells in the biopsy.

Fine Needle Aspiration/Biopsy is another technique often used in diagnosis of ATLL. It is a type of biopsy in which cells are removed from a tissue, such as a lymph node or bone marrow through a thin needle so that they can be examined under a microscope.

HTLV-I antibody test this is very useful in the diagnosis, especially in patients with lymphoma, as ATLL is only seen in patients with HTLV-I infection.

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ATLL research in the UK and worldwide

Since its discovery in the early 80's, HTLV-I and related diseases, in particular, ATLL and HAM/TSP have been a focus of research by scientists and doctors around the world.

the aim of research into ATLL is to find ways to prevent disease development and to design more effective treatments.

Given that ATLL is an immuno-dependant tumour (depends on responses of a person's immune system to control the virus) modern ATLL research approach is to enhance the patient's own immune responses to fight the virus.

Immunotherapeutic treatments, such as monoclonal antibodies, are now being investigated.

In Japan, the USA and the UK monoclonal antibodies Daclizumab (anti-CD25), and Campath-1H, (anti-CD52) have or are being studied, alone or in combination with chemotherapy. Earlier studies showed some improvement in outcome and the latest studies are exploring this further.

Summary

Adult T-cell Leukaemia/Lymphoma (ATLL) is a cancer of white blood cells called T-cells exclusively affecting people infected with HTLV-I. In the UK the majority of infected people are descendants from the West Indies or West Africa. Only 1 infected person in 20 develops ATLL.

There are factors that make one person to be more susceptible to the disease than another. These include time of the infection (at birth or later in life), the amount of virus the person carries, the ability of person's immune system to respond to the infection.

ATLL varies in its forms from acute aggressive to chronic mild.

Acute forms are difficult to treat and survival has been measured in months rather than years. the only treatment that potentially offers cure is a donor bone marrow, but this treatment has a high early mortality rate (death rate) due to the procedure. Chemotherapy (CHOP) followed by Zidovudine plus Interferon-&alpha have been studied most extensively and shown to be better than chemotherapy alone. Usually 1-2 cycles of CHOP are given first to rapidly reduce the burden of lymphoma or leukaemic cells followed by an early switch to Zidovudine plus IFN-&alpha.

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Updated: February 2009