Pharm Immunomodulating Drugs

Answer: C
(Koda-Kimble, pp 35-35, Dipiro, pp 745)
Several patients who receive an initial immunosuppressant therapy with cyclosporine are converted to
tacrolimus ether because of persistent drug reactions or of a poor response, like in the present case.
Tacrolimus has a mechanism of action very close to that of cyclosporine. Nevertheless patient survival
rates exceeding 80% have been reported in liver transplant patients who were converted from
cyclosporine to tacrolimus because of failure of cyclosporine therapy.
A, B, D, E) These drugs are not immunosuppressants.

Answer: B
(Hardman, pp 1471, Katzung, pp 944)
Azathioprine is an immunosuppressant agent often used in organ transplantation to prevent rejection. It
is a prodrug that is converted in the body to mercaptopurine, an antimetabolite anticancer drug that
blocks purine synthesis. This leads to cytotoxicity mainly towards cells with a high turnover rate which
include T and B lymphocytes. The proliferation of these lymphocytes is inhibited and this explains why
most antimetabolite anticancer drugs do have immunosuppressant actions. Azathioprine, however,
appears to be a more effective immunosuppressant than mercaptopurine itself. The basis for this
superiority is unknown.
A) Azathioprine has no blocking activity on receptors of TNT-Alpha
C) Antigen presentation by different antigen presenting cells is an early step in the adaptive immune
response. This step is not inhibited by azathioprine.
D, E) These two actions would actually increase, not decrease, the immunological defense of the body.

Answer: C
(Hardman, pp 1466, Koda-Kimble, pp 35-8)
Cyclosporine has a very selective inhibitory effect on T helper cells, suppressing the early cellular
response to antigenic stimuli. The drug binds to a T-helper cell cytoplasmic cyclophilin and the complex
then binds to calcineurin (a phosphatase) and inhibits its action. This inhibition is thought to prevent
activation of nuclear factors involved in the gene transcription of interleukin-2 and other cytokines. Since
interleukin-2 is needed for T-cell activation and proliferation, these T cell functions are suppressed.
A, B, D, E) These cells are not direct targets for cyclosporine.

Answer: B
(Koda-Kimble, pp 35-23, )
Immunosuppressive therapy is given aggressively during the early transplant period because the risk of
organ rejection is greater at this time. Azathioprine with prednisone were associated with a 50% organ
survival rate. When cyclosporine was added, more than 80% rate of organ survival was obtained.
A) Aldesleukin is an immunostimulant drugs and therefore its use would be irrational in this setting.
C) Triamcinolone is a synthetic glucocorticoid. The combined use of prednisone and triamcinolone (two
different glucocorticoids with equivalent effects) is superfluous.
D, E) Infliximab and etanercept are immunosuppressant drugs that neutralize TNF-alpha. They are used
only in selected autoimmune diseases (Crohn’s disease, rheumatoid arthritis).

Answer: A
(Hardman, pp 1478, Craig, pp 652)
Aldesleukin is an immunostimulant drug with a mechanism of action essentially identical to that of
interleukin-2. Aldesleukin activates interleukin-2 receptors expressed on T helper cells and stimulates a
cytokine cascade involving various interferons, interleukins and tumor necrosis factors. In this way it
induces proliferation of B and T cells (including cytotoxic T cells) and activation of natural killer cells and
lymphokine-activated killer cells. The drug is indicated for the adjunctive treatment of renal cell
carcinoma and malignant melanoma. The mechanism of antitumor activity is unknown but is probably
related to the activation of cytotoxic T cells. Aldesleukin is associated with serious cardiovascular, renal
and CNS toxicity and therefore extensive monitoring is required during therapy.
B, C, D, E) All these actions would lead to immunosuppressant, not immunostimulant, effects.

Answer: C
( Dipiro, pp 1023, Lane pp 1476)
Interferon beta-1b is a cytokine produced by various cells including fibroblasts and macrophages. Like
other interferons it has antiviral, immunomodulating and antiproliferative activities. Interferon beta-1b
was the first agent shown to have an effect on the course of multiple sclerosis. The exact mechanism of
its action is still unknown but it is likely related to its immunomodulating properties, including the down
regulation of the expression of class II major histocompatibility complex and of interferon gamma. It is
thought that interferon gamma is a major factor responsible for triggering the autoimmune reaction
leading to multiple sclerosis. It stimulates cytotoxic T cells and induces macrophages to produce
proteinases that degrade the myelin sheath around the spinal cord.
A, B, D, E) These drugs are not recombinant cytokines.

Answer: B
(Katzung, pp 946, Koda-Kimble, pp 46-11)
Since the woman was Rho(D) negative and her husband was Rho(D) positive, the baby had 100%
chance (if the father was homozygous) or 50% chance (if the father was heterozygous) of being Rho(D)
positive. If a Rho(D) negative mother caries a Rho(D) positive fetus she will produce antibodies against
Rho(D) positive erythrocytes if these erythrocytes leak into the maternal circulation. This can occur
during pregnancy and the risk of this fetomaternal hemorrhage increases as the pregnancy progresses.
The risk is the highest during delivery. In subsequent pregnancies these maternal antibodies are
transferred to the fetus leading to the development of hemolytic disease in the new born
(erythroblastosis fetalis).
When the Rho(D) immune globulin is given to the mother within 72 hours after the delivery, it destroys
the Rho(D) positive fetal cells in the maternal bloodstream before she has an opportunity to make her
own antibodies, so preventing erythroblastosis fetalis in subsequent pregnancies. This is an example of
passive immunization.
A) Placental crossing of Rho(D) positive erythrocytes in subsequent pregnancies of course is not
prevented, and therefore the mother must receive the Rho(D) immune globulin after each delivery to
prevent sensitization (it should be remembered that .passive immunization lasts for the life time of the
administered antibodies. The half-life of Rho(D) immune globulin is 20-25 days).
C) The drug actually prevents the hemolytic disease of the newborn, not of the mother.
D) The production of fetal erythrocytes Rho(D) positive is genetically determined.
E) Rho(D) antibodies are produced by the mother, not by the fetus.

Answer: C
(Katzung, pp 941, Koda-Kimble, pp 35-8)
Antibiotics endowed with immunostimulant properties include cyclosporine, tacrolimus and sirolimus.
They interfere with T cell function by binding to immunophilins, small intracellular proteins that play a key
role in T cell response to receptor activation and to cytokines. Cyclosporine (a macrolide antibiotic) binds
to cyclophilin, tacrolimus and sirolimus bind to FK-binding proteins. The tacrolimus-protein complex
binds to calcineurin, a cytoplasmic phosphatase, and inhibits its action. Since calcineurin regulates the
ability of a nuclear factor of activated T cells to translocate to the nucleus and increase the production of
interleukin-2, this production is suppressed.
A) Azithromycin is a macrolide antibiotic with antibacterial activity. It is devoid of immunosuppressant
properties.
B) Azathioprine is a cytotoxic drug with immunosuppressant properties.
C) Cyclosporine also inhibits calcineurin actions but it binds to cyclophilin, not to a FK-binding protein.
E) Tobramycin is an aminoglycoside antibiotic devoid of immunosuppressant properties.

Answer: A
(Koda-Kimble, pp 92-24, Dipiro, pp 2440)
The patient most likely suffered from chronic graft versus host disease (GVHD) which occurs in up to
70% of allogeneic bone marrow transplanted patients. The most important risk factor for developing
chronic GVHD is a prior diagnosis of acute GVHD. The mainstay of therapy of GVHD is long-term
immunosuppressive therapy. Prednisone, azathioprine and cyclosporine have emerged as the most
commonly used agents with the best efficacy. The combination of cyclosporine and prednisone has
resulted in higher survival when compared with prednisone or cyclosporine alone.
B, C, D, E) Erythromycin, doxorubicin, and vinblastine are not immunosuppressant drugs.

Answer: E
(Hardman, pp 1474, Koda-Kimble, pp 35-9)
Muromonab-CD3 is a monoclonal antibody against CD3 molecules present on the surface of human
thymocytes and mature T cells. CD3 molecules are necessary for a signal to be transduced to the
cytoplasm after the T cell receptor binds to the antigen
The drug binds and neutralizes the CD3 protein receptor complex, so causing the death of T cells
Muromonab-CD3 is used in renal allograft rejection, especially when the rejection is resistant to
corticosteroid treatment.
A) Muromonab-CD3has negligible effects on B cells.
B) This is actually the mechanism of action of azathioprine
C) This is actually the mechanism of action of cyclosporine and tacrolimus.
D) Stimulation of the synthesis of interleukin -1 would cause an immunostimulant, not an
immunosuppressant ,effect.

Answer: B
(Hardman, pp 1471, Koda-Kimble, pp 35-7)
Mycophenolate mofetil is a prodrug which is biotransformed into mycophenolic acid.
This active metabolite inhibits inosine monophosphate dehydrogenase, an enzyme involved in the de
novo pathway of purine biosynthesis. However, unlike azathioprine, it does not inhibit enzymes involved
in the salvage pathway of purine or pyrimidine biosynthesis and, therefore, it selectively inhibit the
proliferation of lymphocytes (including B and T lymphocytes) because these cells lack the enzymes of
the alternative salvage pathway. Because of this, mycophenolate mofetil is cytotoxic only for
lymphocytes, whereas azathioprine is cytotoxic for all rapidly growing cells. This explains why the drug
has significantly less adverse effects than azathioprine.
A) The immunosuppressant activity of mycophenolate and azathioprine is roughly the same since both
drugs are able to kill B and T lymphocytes.
C) Graft versus host disease is a disease that occurs after stem cell transplantation, not after solid organ
transplantation.
D) Mycophenolate mofetil has negligible effects on macrophages since these cells can utilize the
salvage pathway for purine biosynthesis.
E) Mycophenolate mofetil has no effect on antigen presenting cells.

Answer: D
(Lane, pp 1497, Hardman, pp 1661)
Myasthenia gravis is an acquired autoimmune disease characterized by exercise-induced muscle fatigue
that resolve after rest. The pathogenesis is due to antibody mediated destruction of Nm receptor sites.
The initiating event leading to antibody production is unknown. The present patient most likely
developed a myasthenic crisis (edrophonium improved muscle strength), which may be precipitated by
infection but also can occur without apparent cause. Myasthenic crisis requires intensive management
which include selected anticholinesterase drugs (like neostigmine), and immunosuppressive treatment
with glucocorticoids and cyclosporine. The immunosuppressant effect of glucocorticoids is likely due to
multiple mechanisms of action. Especially important in this regard is the inhibition of T cells activation
(due to inhibition of synthesis of interleukin-1) and of T cell proliferation (due to inhibition of synthesis of
interleukin-2)
A, B) Glucocorticoids have no effect on plasma cholinesterase or on nicotinic receptors.
C, E) Glucocorticoids actually decrease the synthesis of these interleukins (see answer above)

Answer: B
(Koda-Kimble, pp 44-3, Katzung, pp 651)
The sings and symptoms of the patients strongly indicate that she is affected by lupus erythematosus In
fact the patient shows five of the 11 sings and symptoms most often associated with this disease (malar
butterfly erythema, arthritis, oral ulcers, renal disorder, nuclear antibodies). According to the American
College of Rheumatology the diagnosis of lupus erythematosus is made when the patient has 4 or more
of these 11 signs and symptoms.
The cause of lupus erythematosus is unknown but it is thought to involve autoimmune mechanisms.
Therefore the therapy almost always includes corticosteroids that are especially valuable for the more
severe and life threatening manifestations of the disease. Since in the present case there are sings of
renal insufficiency (see creatinine and BUN values) steroid therapy is strongly indicated.
A) Infliximab is currently approved for use in rheumatoid arthritis and Crohn’s disease.
C, D, E) These are immunostimulant drugs and therefore are would be contraindicated in autoimmune
disease.

Answer: D
(Hardman, pp 1471, Koda-Kimble, pp 35-6)
The profound leukopenia and thrombocytopenia exhibited by the patient strongly suggest bone marrow
suppression. Transplanted patients always receive immunosuppressive therapy to prevent organ
rejection. Cyclosporine, azathioprine and a glucocorticoid are the drugs most frequently used for this
purpose. Azathioprine is a prodrug that is converted in the body to mercaptopurine, an antimetabolite
anticancer drug. It is therefore a cytotoxic agent that can cause significant myelosuppression.
A) Cyclosporine is the drug most frequently given for immunosuppression in transplanted patients, but it
does not cause myelosuppression.
B, C) These drugs are often given to heart transplanted patients to increase cardiac output and renal
blood flow but they do not cause myelosuppression
E) Fluorouracil is an anticancer drug that is not used for immunosuppression.

Answer: B
(Hardman, pp 1469, Koda-Kimble, pp 35-14)
The lab exams strongly suggest that the patient is suffering from renal insufficiency. Nephrotoxicity is
the most common adverse effect of cyclosporine, occurring in up to 80% of treated patients. The
pathophysiology of this adverse effect is still uncertain.
A, C, D, E) These drugs have a negligible risk of nephrotoxicity

Answer: AB
(Hardman, pp 1475, Koda-Kimble, pp 43-5)
Etanercept and infliximab are drugs that are able to neutralize TNF-alpha. Etanercept is a recombinant
form of the TNF receptor, infliximab is a monoclonal antibody against TNF-alpha. Both drugs bind to
TNF-alpha with high affinity and specificity, so inhibiting its actions. TNF-alpha is produced by
macrophages and activated T cells and plays a central part in the immune and inflammatory response.
Both drugs are used mainly in severe rheumatoid arthritis.
C) Muromonab CD3 is a monoclonal antibody against the CD3 antigen present on the surface of human
thymocytes and mature T cells.
D) Tacrolimus is an immunosuppressant antibiotic that acts by inhibiting calcineurin.
E) Aldesleukin is an immunostimulant drug.

Answer: CF
(Hardman, pp 1470, Koda-Kimble, pp 35-8)
Sirolimus is an antibiotic that, like tacrolimus, binds to a FK-binding protein. The sirolimus-protein
complex binds to mammalian kinase, an enzyme which is essential for cell-cycle progression, resulting
in cell-cycle arrest in the late G1-phase
. Daclizumab is a monoclonal antibody against the interleukin-2 receptors present on the surface of T
cells. The drug prevents the il-2 mediated T cell activation events (e.g. activation of CD4 T helper cells).
A) Glucocorticoids, not tacrolimus, increase the catabolism of IgG antibodies.
B) Azathioprine is an immunosuppressant drug. Stimulation of interleukin-2 synthesis would cause
immunostimulant effects.
D) Mycophenolate mofetil, not cyclophosphamide, inhibits inosine monophosphate dehydrogenase.
E) Cyclosporine and tacrolimus, not muromonab-CD3, inhibit calcineurin

Answer: ABD
(Hardman, pp 1464, Craig, pp 658)
Inhibition of the immune response is more likely to occur if the immunosuppressant drugs are given
before, rather than after, the exposure to the antigen. This explains why intensive immunotherapy is
given just before a solid organ transplant. Unfortunately almost always the immune disease is treated
when it is clinically evident, that is when the exposure to the antigen has already occurred.
Primary immune responses (i.e. antigen recognition, cell proliferation, lymphokine synthesis, etc.) are
most sensitive to immunosuppressant drugs. On the contrary the secondary immune response (i.e. the
response generated by memory B cells when they re-encounter the antigen) is not much affected by
immunosuppressant drugs.
Since many anticancer drugs are cytotoxic, they can also kill the cells that mediate the immune
response, and therefore several anticancer drugs do have immunosuppressant effects. Among these
only three (cyclophosphamide, methotrexate and the prodrug azathioprine) have been consistently used
clinically as immunosuppressants. When anticancer drugs are used for immunosuppression they are
given continuously (not in cycles) and the doses are generally lower than those employed in anticancer
therapy C) .Antigen presenting cells take up the antigens and subject them to proteolytic degradation.
These events are called antigen processing. and are required because, although B cell antigen
receptors bind directly to antigen, T cell antigen receptors only recognize processed antigens. This very
early step of immune response is not affected by immunosuppressant drugs.
E) The toxicity of the immunosuppressant drugs is high and death due to immunosuppressant therapy
have been reported.

Answer: BC
(Koda-Kimble, pp 35-5, 35-26, Craig, pp 658)
Since immunosuppressant drugs impair the adaptive immune system the risk of infections becomes
substantial (for example infection is the leading cause of death in the first 60 days after lung
transplantation).
Moreover therapies with these drugs require lifelong use, so exposing the patient to increased risk of
some cancers, mainly lymphomas. The overall prevalence of malignancies in the transplantation
population averages about 6% and the risk of cancer increases with time after a transplantation.
Transplanted patients are 100 times more likely to have cancer that the general population.
The frequency of the other listed disorders is increased with some immunosuppressant agents, but not
with others. Specifically:
A, D) Kidney failure and neurologic disorders are often caused by cyclosporine and tacrolimus.
E) Myelosuppression is significant with cytotoxic drugs and mycophenolic acid.
F) Hepatotoxicity can occur with cyclosporine and azathioprine but hepatic failure is extremely rare.

Answer: BFG
(Hardman, pp 1661, Koda-Kimble, pp 35-7)
Most actions of glucocorticoids on leucocytes and macrophages can impair immunity. Especially
important in this regard are:
-The inhibition of macrophage-mediated production of interleukin-1 and interleukin-6 (this inhibition in
turn decreases T cells activation and impairs B cell proliferation).
-The inhibition of T cell-mediated production of interleukin-2 (this inhibition in turn decreases T cells
proliferation and impairs the activation of NK cells).
-The direct lympholythic effect on certain subset of T cells (including cytotoxic T cells)
The inhibition of other interleukins by glucocorticoids (IL-6, IL-12) also impairs immunity.
The antiinflammatory effect of glucocorticoids (due to decreased synthesis of prostaglandins,
leukotrienes, PAF, TNF, histamine, kinins and interferon gamma) also exerts an indirect
immunosuppressant effect, since it modifies tissue injury from immune responses.
A) Glucocorticoids actually stimulate the catabolism of IgG.
C, D) These actions would stimulate, not inhibit, the immune response.
E) Glucocorticoids actually inhibit phospholipase A2.