Reg N: 201404442
Honours Immunology 2 Assessment
Class Coordinator: Catherine Lawrence
18 August 2014
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Immunosuppressive Drugs
Molecular targets and clinical consequences of non-specific
and specific immunosuppressive drugs
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The immune system can, in specific situations, fail, acting in an undesirable manner.
In autoimmune diseases, the immune system fails to tolerate self epitopes and begins to act
against the own system. In inflammatory diseases, the role of the immune system is
unbalanced, causing direct damage to the carrier. Organ transplant rejection, however it
represents a physiological action of the organism, is an undesirable conduct of the immune
system for the good prognosis of the patient. Immunosuppressive drugs are those which
inhibit the activity of the immune system, thus preventing organ rejection and symptoms of
autoimmune and inflammatory diseases.
The objectives of the following work are: describe the structure and mechanisms of
action and discuss the clinical implications of non-specific and specific immunosuppressive
drugs.
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1- Non-specific Immunosuppressive Drugs
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Drugs whose effect is nonspecific act by generally suppressing the action of the
immune system. They interfere mostly in the effector phase of the immune system (phase
characterised by intense cell multiplication and interaction), inhibiting the promotion of both
B and T cells. By having nonspecific action, the role of non-specific immunosuppressive drugs
usually affects the metabolism of other cells, leading to the emergence of several side effects.
The main non-specific immunosuppressive drugs that will be presented and discussed
below are: Azathioprine (Imuran), Cyclophosphamide and Mycophenolic Acid.
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HONOURS IMMUNOLOGY 2 ASSESSMENT "1
Azathioprine (Imuran)
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In 1951, the drug was initially tested in its inactive form, 6-mercaptopurine (6-MP), by
Gertrude Elion (1918-1999) and George Hitchings (1905-1998). The original idea was to
promote a drug capable of inhibiting the nucleic acids production in microorganisms and
neoplastic cells. Subsequently, studies in transplanted dogs, conducted by other scientists,
demonstrated the immunosuppressive action of the drug (Rubin, 2007).
Currently the drug has several indications, being used in the treatment of leukemias,
inflammatory bowel disease, rheumatoid arthritis, and other diseases.
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Pathway
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The prodrug azathioprine (AZA), when administered, is initially converted into 6-MP.
This reaction can occur via two pathways, one dependant of the liver enzyme glutathione-S-
transferase (GST), and the other, a non-enzymatic reaction promoted by glutathione (GSH), a
compound present in the liver, red blood cells and intestinal wall. The GSH pathway
predominates at the physiological pH of 7.0 - 7.5 (Sahasranaman and Howard, 2008).
Subsequently, 6-mercaptopurine, still unable to exert biological function is converted
by various other enzymatic reactions present in the liver and intestine. Some of those
enzymes promote 6-MP activation, others promotes its inactivation. These reactions compete
with each other by using the same reagent, 6-MP.
Two important reactions are responsible for 6-MP inactivation. The first converts 6-
MP in 6-thiouric acid, metabolite found in urine and serum after administration of
azathioprine. The second reaction converts 6-MP into 6-methylmercaptopurine (6-MEMP),
this reaction is the main way of the drug inactivation. The reactions are catalysed by the
following enzymes, xanthine oxidase (XO) and thiopurine methyl transferase (TPMT),
respectively (Sahasranaman and Howard, 2008).
The activation reaction of the drug is catalysed by the enzyme hypoxanthine-guanine-
phosphoribosyltransferase (HGPRT), which converts 6-MP in the active form, 6-thioguanine
(6-TG). The active form accumulates within the cell and acts as a false metabolite interacting
directly in the production of nucleotides, by binding the structure which is being formed. The
activated drug also interacts with essential coenzymes and impairs the DNA and RNA
production. For this reason the drug is known to inhibit the cell cycle S phase. The drug
mechanism of action causes death in cells with high mitotic rate such as immune cells, cells of
the gastrointestinal tract and cancer cells. However lymphocytes represent the most affected
group by the drug, since there is no alternative pathway for the nucleotide synthesis in these
cells (Pascal Frei, 2013), (A. Patel and A. Swerlick, 2006).
Another action mechanism of the drug is by the active form (6-TG) binding to Rac1
protein. This protein is involved in signal transduction promoted by CD28 co-stimulatory
molecule in T cells. T cells to be activated needs more than antigen recognition, they also
Dudley, L., Lan, Y. and Pekka, K.
Rapamycin-induced insulin resistance is mediated by mTORC2 loss and
uncoupled from
longevity
In-text: (Dudley, Lan and Pekka, 2012)
Bibliography: Dudley, L., Lan, Y. and Pekka, K. (2012). Rapamycin-induced insulin
resistance is mediated by mTORC2 loss and uncoupled from longevity.
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Glander, P., Hambach, P. and Liefeldt, L.
Inosine 5'-monophosphate dehydrogenase activi... [Clin Chim Acta. 2012] - PubMed - NCBI
In-text: (Glander, Hambach and Liefeldt, 2011)
Bibliography: Glander, P., Hambach, P. and Liefeldt, L. (2011). Inosine 5'-monophosphate
dehydrogenase activi... [Clin Chim Acta. 2012] - PubMed - NCBI. [online] Ncbi.nlm.nih.gov.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/21889500 [Accessed 16 Aug. 2014].
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Hall and Tilby
Mechanisms of action of, and modes of resistance t... [Blood Rev. 1992] - PubMed -
NCBI
In-text: (Hall and Tilby, 1992)
Bibliography: Hall, and Tilby, (1992). Mechanisms of action of, and modes of resistance
t...
[Blood Rev. 1992] - PubMed - NCBI. [online] Ncbi.nlm.nih.gov. Available at: http://
www.ncbi.nlm.nih.gov/pubmed/1422285 [Accessed 15 Aug.
2014].
Shile, H., Bjornsti, M. and Houghton, P.
Rapamycins, mechanism of action and cellular resistance
In-text: (Shile, Bjornsti and Houghton, 2003)
Bibliography: Shile, H., Bjornsti, M. and Houghton, P. (2003). Rapamycins, mechanism of
action and cellular resistance. [Accessed 17 Aug. 2014].