Immunotherapy is an array of treatment strategies based upon the concept of
modulating the immune system to achieve prevention and/or therapeutic goal. As
evidence of immune system involvement in the development of multiple sclerosis
(MS) has grown, trials of various new treatments to alter or suppress immune
response are being conducted. Most of these therapies are, at this time, still
considered experimental.
Clinical trials have shown that immunosuppressive agents and techniques can
positively affect the course of MS, at least while remaining on those treatments.
On the down side, generalized immunosuppression leaves the patient open to a
variety of viral, bacterial, and fungal infections.
The immune system is a complicated network of cells and organs. The bone marrow,
thymus gland, spleen and lymph nodes work together to defend the body against
attacks by "foreign" invaders. The immune system is the body's main
defense again infection and disease. The immune system can work against diseases,
including MS, in several ways. The immune system may recognize the difference
between healthy cells and cancer cells for instance, in the body and work to get
rid of the cancer cells. However, the immune system can't always recognize
cancer cells as "foreign".
Immunotherapy works on the immune system in various ways by repairing, stimulating
or enhancing the immune system's responses.
Over the years, MS investigators have studied a number of immunosuppressant
treatments. One such treatment, Novantrone (mitoxantrone), was approved by the
U.S. Food and Drug Administration (FDA) for the treatment of advanced or chronic
MS. Other therapies being studied are cyclosporine (Sandimmune),
cyclophosphamide (Cytoxan), methotrexate, azathioprine (Imuran), and total
lymphoid irradiation. Lymphoid irradiation is a process whereby the MS patient's
lymph nodes are irradiated with x-rays in small doses over a few weeks to
destroy lymphoid tissue, which is actively involved in tissue destruction in
autoimmune diseases.
Inconclusive and/or contradictory results of these trials along with the
potentially dangerous side effects, show the need that further research is
necessary to determine what, if any, role they should play in the management of
MS. Studies are also being conducted with the immune system modulating drug
cladribine (Leustatin).
Another potential treatment for MS is monoclonal antibodies (MAB or MoAb), which
are identical, laboratory-produced antibodies that are highly specific for a
single antigen. They are injected into the patient in the hope that they will
alter the patient's immune response. One monoclonal antibodies is
natalizumab (Tysabri) which was shown in clinical trials to significantly reduce
the frequency of attacks in people with relapsing forms of MS and was approved
for marketing by the FDA in 2004. Regarding MS, Tysabri is believed to work by
reducing the ability of inflammatory immune cells to attach to and pass through
the cell layers lining the blood-brain barrier.
Another experimental treatment for MS is plasma exchange, or plasmapheresis.
Plasmapheresis is a procedure in which blood is removed from the patient and the
blood plasma is separated from other blood substances that may contain
antibodies and other immunologically active products. These other blood
substances are discarded and the plasma is then transfused back into the
patient. Because its worth as a treatment for MS hasn't been proven, this
experimental treatment remains at the stage of clinical testing.
Bone marrow transplantation which is a procedure in which bone marrow from a
healthy donor is infused into patients who have undergone drug or radiation
therapy to suppress their immune system so they will not reject the donated
marrow. Injections of venom from honey bees are also being studied. Each of
these therapies carries the risk of potentially severe side effects.
Immunosuppression
This is the natural or induced active suppression of the immune response, as
contrasted with deficiency or absence of components of the immune system. Like
many other complex biological processes, the immune response is controlled by a
series of regulatory factors.
A variety of suppressor cells play a role in essentially all of the known
immunoregulatory mechanisms, such as maintenance of immunological tolerance;
limitation of antibody response to antigens of both thymic-dependent and
thymic-independent types, as well as to antigens that stimulate reaginic
antibody (antibodies involved in allergic reactions); genetic control of the
immune response; idiotype suppression; control of contact and delayed
hypersensitivity; and antigenic competition.
Some portions of the immune system itself have immunosuppressive effects on
other parts of the immune system, and immunosuppression may occur as an adverse
reaction to treatment of other conditions.
Suppression of the immune response may be specific to a particular antigen or
may be a response to a wide range of antigens encountered. The whole immune
response may be depressed, or a particular population of immunologically active
lymphocytes may be selectively affected. In some cases, the effect may be
greater on T lymphocytes (T cells) rather than B lymphocytes (B cells). If B
cells are affected, it may be on a specific subclass of antibody-producing
cells. Antigen-specific immunosuppression may be the result of deletion or
suppression of a particular clone of antigen-specific cells, or the result of
enhanced regulation of the immune response by antigen-specific suppressor cells.
It can also be the result of increased production of antiidiotypic antibody.
The result of any immune response is a balance between the action of effector
cells mediating the phenomenon and suppressor cells regulating the response.
Anything that reduces the regulatory function of suppressor cells will
functionally increase the immune response. As suppressor cells are derived from
rapidly turning-over precursor cells, and effector cells of T cell-mediated
immunity are derived from slowly dividing precursors, it's possible
preferentially to depress the action of suppressor cells without affecting
effector cells. This may be done by the use of alkylating agents such as
cyclophosphamide given before immunization. Cyclophosphamide used in this way
can increase a normal cell-mediated immune response, reverse immunological
tolerance caused by increased regulatory activity of suppressor cells, and even
reverse antigenic competition.
Immunocompromised or Immunodeficiency
This is a group of disorders in which part of the immune system is missing or
defective. Because of this, the body's ability to fight infections is impaired
(compromised) or entirely absent. As a result, a person with an immunodeficiency
disorder will have frequent infections that are generally more severe and last
longer than usual.
The 2 main types of immunodeficiency disorders are congenital
immunodeficiency (also called primary immunodeficiency) and
acquired immunodeficiency. This is also discussed in greater detail in the
Immune Disorders
section of this site.
Congenital immunodeficiency is present at the time of
birth, and is the result of mainly genetic defects. Even though more than 70 different
types of congenital immunodeficiency disorders have been identified, they rarely occur.
Congenital immunodeficiencies may occur as a result of defects in B cells,
T cells, or both. They can also occur in the innate immune system.
Acquired immunodeficiency is more common than congenital
immunodeficiency. It's the result of an infectious process or other disease. For
example, the human immunodeficiency virus (HIV) is the virus that causes acquired
immunodeficiency syndrome (AIDS). Sometimes it can be brought on by drugs
used to treat another condition.
Immunosuppressive Agents
These are drugs that inhibit or prevent activity of the immune system. They are
used in immunosuppressive therapy to treat autoimmune diseases or diseases that
are most likely of autoimmune origin such as MS. These drugs, however, carry
side-effects and risks with them. Because the majority of them act
non-selectively, the immune system is less able to resist infections.
Examples have included the use of azathioprine (Imuran), methotrexate
(Rheumatrex), cyclophosphamide (Cytoxan), cyclosporin (Sandimmune), cladribine
(Leustatin), mitoxantrone (Novantrone), total lymphoid radiation, monoclonal
antibodies, corticosteroids, intravenous gammaglobulin, plasma exchange and bone
marrow transplants.
The clinical success rate for these approaches to the management of MS patients
has been disappointing. The use of these drugs has remained limited and should
be considered only in very selected circumstances.
Immunomodulating Agents
Immunomodulating agents are substances that stimulate or indirectly augment the
immune system. Often these agents target key immune system cells and cause
secondary responses such as increased production of cytokines and
immunoglobulins.
Examples of immunomodulating agents are Avonex, Betaseron, Copaxone, Rebif and
Extavia. The clinical success rate has been good and the use of these types of
drugs has proven useful especially in the early stages of the disease.
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Biological response modifiers (BRMs) are substances that stimulate the body's
response to infection and disease. The body naturally produces small amounts of
these substances. Some antibodies, cytokines (proteins secreted by cells of the
immune system) and other immune system substances can be produced in the
laboratory for use in cancer treatment. They alter the interaction between the
body’s immune defenses and cancer cells to boost, direct, or restore the body's
ability to fight disease. Examples of BRMs include Interferons, interleukins,
colony stimulating factors, monoclonal antibodies, vaccines, gene therapy, and
non specific immunomodulating agents.
Interferons
Interferons (IFNs) are a group of proteins called cytokines produced by white
blood cells, fibroblasts, or T cells as part of an immune response to a viral
infection or other immune trigger. The name of the proteins comes from their
ability to interfere with the production of new virus particles.
There are three types of interferons: Alfa, beta, and gamma. Alfa and beta
interferons, which are grouped together as type I interferon, are produced by
white blood cells and a type of connective tissue cell called a fibroblast.
Gamma interferon, or type II interferon, is manufactured T cells. Production
occurs when the T cells are activated such as during an infection.
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Interferon alpha (IFN-α) proteins are produced by leukocytes
and are mainly involved in innate immune responses against
viral infection. |
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Interferon beta (IFN-β) proteins are produced by fibroblasts
and are mainly involved in innate immune responses. The type
most widely used in MS treatment. |
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Interferon gamma (IFN-γ) , also known as immune interferon,
it has antiviral, immunoregulatory, and anti-tumor
properties. |
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Interleukins
Like interferons, interleukins are cytokines that occur naturally in the body
and can be made in the laboratory. Many interleukins have been identified.
Interleukin-2 has been the most widely studied in cancer treatment.
Interleukin-2 stimulates the growth and activity of many immune cells such as
lymphocytes.
Colony-Stimulating Factors (SF)
Colony-stimulating factors sometimes called hematopoietic growth factors,
usually don't directly affect tumor cells; rather, they encourage bone marrow
stem cells to divide and develop into white blood cells, platelets, and red
blood cells. Bone marrow is critical to the body's immune system because it is
the source of all blood cells.
Colony-stimulating factor's stimulation of the immune system may benefit
patients undergoing cancer treatment. Because anticancer drugs can damage the
body's ability to make white blood cells, red blood cells, and platelets,
patients receiving anticancer drugs have an increased risk of developing
infections, becoming anemic, and bleeding more easily. By using CSFs to
stimulate blood cell production, doctors can decrease the risk of infection or
the need for transfusion with blood products, due to chemotherapy treatment.
Monoclonal Antibodies (MAb or MoAb)
Monoclonal antibodies are monospecific antibodies that are the same because they
are made by one type of immune cell which are all clones of a unique parent
cell. Given almost any substance, it's possible to create monoclonal antibodies
that specifically bind to that substance; they can then serve to detect or
purify that substance. These antibodies are produced by a single type of cell
and are specific for a particular antigen.
Monoclonal antibodies are currently the most widely used form of cancer
immunotherapy.
Some ways that monoclonal antibodies are used in cancer treatment:
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Monoclonal antibodies that react with specific types of
cancer may enhance a patient's immune response to the
cancer. |
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Monoclonal antibodies can be programmed to act against cell
growth factors, thus interfering with the growth of cancer
cells. |
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Monoclonal antibodies may be linked to anticancer drugs,
radioisotopes, other BMRs or other toxins. When the
antibodies latch onto cancer cells, they deliver these
poisons directly to the tumor, helping to destroy it. |
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Gene Therapy
Gene therapy is an experimental treatment that involves introducing genetic
material into a person's cells to fight disease. Researchers are studying gene
therapy methods that can improve a patient's ability to recognize and attack
cancer cells. In another approach, scientists inject cancer cells with genes
that cause the cancer cells to produce cytokines and stimulate the immune
system. A number of clinical trials are currently studying gene therapy and its
possible application to the treatment of cancer.
Side Effects of Biological Therapies
Like any form of treatment biological therapies can cause a number of side
effects, which can vary widely from agent to agent and patient to patient.
Rashes or swelling may develop at the site where the BRMs are injected. Several
BRMs, including interferons and interleukins, may cause flu like symptoms
including fever, chills, nausea, vomiting, and appetite loss. Fatigue is another
common side effect of some BRMs. Blood pressure may also be affected. The side
effects of interleukin 2 can often be severe, depending on the dosage given.
Patients need to be closely monitored during treatment with high doses of
interleukin 2. Side effects of colony stimulating factors may include bone pain,
fatigue, fever, and appetite loss. The side effects of monoclonal antibodies
vary, and serious allergic reactions may occur.
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