Lecture 11:

Immunomodulators &
Anti- Neoplastics

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A. Anti-Neoplastic Drugs
*Carcinogenesis includes: 1. Initiation 2. Promotion 3. Progression
Either Benign or Malignant

*Types: 1. Solid tumor : a. Carcinoma (epithelial cells) → lung, colon & breast.
b. Sarcoma (connective tissues) → bones & muscles.

2. Hematological : leukemia (myeloid & lymphoid).

*Phases of Cell Cycle:

1. M Mitosis (2 Mitotic spindle formation

daughter cells): ttt: Vinca & Taxanes
2.G1 : Formation of RNA & protein starts to form
DNA. ttt: Asparginase
3. S : Where DNA synthesis & replication occurs.
ttt: Antimetabolites.
4. G2 Synthesis of cellular components required
premitotic & for mitosis.*Topoisomerase I&II are
postsynthetic : produced to prepare to duplicate cell.
ttt: Bleomycin & Etoposide
5. G0 Resting Recruitment where cells no division & not
phase: sensitive to chemotherapy.

*Chemotherapeutic agents:
1. Phase Specific: Against tumor with high growth fraction
*M: Vinca & Taxanes.
*G1: Asparginase & prednisone.
*S: antimetabolite
*G2: Bleomycin & Etoposide.
2. Phase non specific: Don't require cell to be in specific phase.
e.g. Alkylating agent & antitumor
3. Cell cycle non specific : Effective in all phases.
e.g. Carmustine, Lomustine & radiation.

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A. Anti-Cancer Drugs" Cytotoxic antineoplastics":

I. Alkylating agents: *Bifunctional Alkylating agents

* Interfere with cellular replication by forming cross-linkages between DNA strands.
1. Nitrogen 1.Cyclophosphami myelosuppression , alopecia, anorexia, haemorrhagic cystitis(Occurs as a
mustard: de & ifosfamide result of accumulation of active metabolites acrolein in the bladder); nasal
congestion (with rapid injection)
2. Melphalan Amenorrhea& decreased spermatogenesis
3. Chlorambucil Common: myelosuppression.
Infrequent: abdominal discomfort, diarrhea.
2. Ethylenimines: Thiotepa Common: myelosuppression
High dose: oral mucositis, forgetfulness, confusion, somnolence
Infrequent: dysuria, urinary retention, haemorrhagic cystitis
(intravesical administration), alopecia, pain at injection site
High dose: hyperpigmentation, elevation of hepatic aminotransferases
and bilirubin, SIADH
3. Carmustine Hepatotoxicity, hyperuricemia & pulmonary fibrosis.
Nitrosureas Lomustine Nephrotoxicity & alopecia.
Streptozosin Nephrotoxicity & hepatotoxicity.
4. Alkyl sulfonates: Busulfan Gynecomastia, anhydrosis, generalized skin pigmentation &
pulmonary fibrosis.
5. Triazenes: dacarbazine Fever, malaise & Myalgia.
monofunctional Alkylating agent
6.Fotemustine Common
myelosuppression , reversible rises in liver enzymes (aminotransferases,
ALP) and bilirubin, phlebitis, reversible neurological toxicity
(disturbance of consciousness, paraesthesia, loss of taste)
7. Procarbazine Common: myelosuppression, anorexia, neurotoxicity
Infrequent or rare: diarrhea, oral mucositis, alopecia, skin reactions
(eg rash, itch, and hyperpigmentation), pulmonary fibrosis,
pneumonitis, haemolysis, hepatic dysfunction, fever, myalgia,
arthralgia, nystagmus, diplopia, orthostatic hypotension, T.C.
8. Temozolomide Common: myelosuppression, headache, fatigue, dyspnea, fever, pain,
malaise, weight loss, rigors
First dose in gliomas: neurological disturbance including weakness,
dysphasia, headache, confusion, seizure and obtundation
Rare: allergic Rx e.g. Stevens-Johnson synd.

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 II. Platinum compounds:→ Carboplatin Cisplatin Oxaliplatin
M.O.A: Pt. compounds are activated within the cell by displacement of chloride ions, leaving +ve charged
molecules→ reacts with DNA.→DNA replication, transcription & cell division are inhibited including
apoptosis.(Cell cycle non specific).
*Comparative information
Cisplatin is more emetogenic and nephrotoxic, and causes more neuropathy (often irreversible) than carboplatin.
Carboplatin causes more severe myelosuppression than cisplatin, with pronounced effects on platelets.
Cisplatin cannot be used if CrCl <40 mL/minute, but carboplatin can be used if CrCl >20 mL/minute.

III. Anthracyclines: Daunorubicin Doxorubicin Epirubicin

Idarubicin Mitozantrone (anthracenedione)
M.O.A: (Cell cycle nonspecific). Inhibit DNA and RNA synthesis by intercalation of DNA base pairs and
prevent DNA repair by inhibiting topoisomerase II. Free radical production may also contribute to cytotoxicity.
Precautions: anthracyclines increase radiation toxicity (eg skin reactions, mucositis).
S.E: *Cardiac toxicity * Extravasation
*Hepatic toxicity Dose reduction required in moderate-to-severe hepatic impairment.

IV. Antimetabolites:
1. Folic acid antagonists
Methotrexate *M.O.A: Folic acid antagonist. Inhibits DNA synthesis and cell replication by competitively
inhibiting the conversion of folic acid to folinic acid, with cytotoxic, immunosuppressive and
anti-inflammatory action.
*S.E: Nephrotoxicity & hepatic dysfunction→ dose related & minimized by Leucoverin
(Folinic acid).
Pemetrexed *M.O.A: Inhibits key folate-dependent enzymes necessary for the synthesis of purine and
thymidine nucleotides essential for cell replication.
Raltitrexed *M.O.A: Folate analogue which directly inhibits thymidylate synthetase. This interferes with
thymidylic acid formation and in turn with the synthesis of DNA.
2. Purine antagonists
Cladribine *M.O.A: inhibits DNA repair and synthesis, particularly in lymphocytes and monocytes.
S.E: Jaundice, hepatotoxicity & anorexia
Fludarabine *M.O.A: inhibits DNA synthesis & induces apoptosis, & reduces RNA & protein synthesis.
*S.E: Myelosuppression & Neurotoxicity
Mercaptopurine *M.O.A: Impairs cellular proliferation through interference with purine synthesis. Active
6-MP metabolite of azathioprine. Cross-resistance with thioguanine occurs.
*Interaction with Allopurinol: Allopurinol reduces mercaptopurine metabolism, ↑the risk
of severe bone marrow toxicity. Reduce mercaptopurine dose to one-quarter to one-third.
*S.E: Jaundice, hepatotoxicity & anorexia.
Thioguanine *M.O.A: Purine antimetabolite with activity similar to mercaptopurine; cross resistance
6-TG with mercaptopurine occurs.
*S.E: Myelosupression & hepatotoxicity.
3. Pyrimidine antagonists
Capecitabine *M.O.A: Non-cytotoxic pro-drug of fluorouracil. Converted to fluorouracil by a 3-step
conversion process in which the final step is more active in malignant than normal cells.
*S.E: Diarrhea & cardiotoxicity
Cytarabine *M.O.A: Pyrimidine antimetabolite chemically related to gemcitabine. Cytarabine is converted
intracellularly to a nucleotide which inhibits DNA synthesis.
*S.E: Fever, hepatic dysfunction

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Fluorouracil *M.O.A: Pyrimidine antimetabolite which, following intracellular conversion to active
5-FU metabolites interferes with DNA and RNA synthesis.
*S.E: hand-foot syndrome (more common with continuous infusion), Hyperpigmentation, nail
disorders, weakness & malaise.
Gemcitabine *M.O.A: Pyrimidine antimetabolite chemically related to cytarabine. Gemcitabine is
metabolized intracellularly to active nucleosides which inhibit DNA synthesis & induce
apoptosis.
*S.E: Pulmonary toxicity & myelosuppression, ↑in hepatic enzymes and bilirubin
4. Others
Hydroxyurea *M.O.A: Interfers with the conversion of ribonucleotides to deoxyribonucleotides.
S.E: Myelosuppression, haemolysis, oral mucositis, nausea, vomiting, anorexia, constipation,
diarrhoea, maculopapular rash, facial erythema, itch

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V. Plant products:
1. Podophyllotoxin: *M.O.A: Inhibit topoisomerase II resulting in DNA strand breaks and inhibition of cell division
Etoposide in the late S and G2 phases of the cell cycle.
Teniposide *S.E: Common: myelosuppression, alopecia, nausea, vomiting, oral mucositis, diarrhoea,
hypersensitivity reactions
Infrequent: hypotension (with rapid infusion), peripheral neuropathy
Rare: rash, urticaria 2ry malignancies.
2. Vinca Alkaloids: *M.O.A: Bind to tubulin inhibiting its polymerisation and microtubule formation;
Vinblastine results in mitotic arrest in metaphase. Cell cycle specific for M phase.
Vincristine *S.E: Common: nausea, vomiting, oral mucositis, alopecia
Vinorelbine Rare: acute shortness of breath and bronchospasm (may be progressive)
VI. Taxanes:
Docetaxel *M.O.A: Promote assembly of tubulin into stable non-functional microtubules, and
inhibit disassembly, arresting cell cycles in late G2and M phase.
*Uses: or ovarian cancer, breast cancer, non–small-cell lung cancer, AIDS-related
Paclitaxel Kaposi’s sarcoma, cervical cancer, germ cell cancer, endometrial cancer.
*S.E: Common: hypersensitivity, elevated liver enzymes, bradycardia, ECG abnormalities,
hypotension Rare: cardiac conduction abnormalities
VII. Topoisomerase I inhibitors:
Irinotecan *M.O.A : Inhibit the enzyme topoisomerase I, thereby interfering with coiling and uncoiling of
Topotecan DNA during replication which inhibits nucleic acid synthesis. Actions are specific for S-phase.
*S.E: 1. common: myelosuppression, infection, nausea, vomiting, anorexia, weakness, alopecia,
dyspnoea, cough, raised liver enzymes and bilirubin.
2. rare: extravasation reaction (mild for topotecan), allergy
VII. Other cytotoxic antineoplastics:→antibiotics
1.Dactinomycin *M.O.A: Complexes with DNA interfering with DNA-dependent RNA synthesis; also
(actinomycin D) has immunosuppressant properties.
*S.E: common: myelosuppression (below), nausea, vomiting, oral mucositis,
oesophagitis, pharyngitis, diarrhoea, fever, malaise, myalgia, alopecia, rash, acne
Rare: anaphylaxis, hepatotoxicity, hepatic sinusoidal obstruction syndrome (common
in Wilms’ tumor).
2.Bleomycin M.O.A: Inhibits DNA and to a lesser extent RNA synthesis, produces single and
‫يقطع تقطيع‬ double strand breaks in DNA possibly by free radical formation.
*S.E: Pulmonary toxicity, acute allergic Rx, vesiculation & ulceration.
Infrequent: Raynaud’s phenomenon.
3.Bortezomib *M.O.A: Reversibly inhibits the 26S proteasome (which degrades intracellular proteins
including those involved in cell cycle control and growth) impairing cell growth
leading to apoptosis.
*S.E: Peripheral neuropathy—may worsen.
Thrombocytopenia—increases the risk of severe thrombocytopenia with bortezomib.
Hypotension or fainting—bortezomib may worsen hypotension; use with caution.
Dehydration—may worsen; correct before treatment. Dehydration may also worsen
hypotension. Heart failure—may worsen.
4. Gemtuzumab
Indications: According to specialist protocol for CD33-positive acute myeloid
ozogamicin
leukaemia
5. Mitomycin *M.O.A: Reduced to active metabolite which cross links DNA, inhibits DNA, RNA
and protein synthesis and may have an effect via free radical production.
*S.E:1. Common: myelosuppression, nausea, vomiting, anorexia, oral mucositis,
alopecia, increased serum creatinine.
2. Rare: haemolytic uraemic syndrome, pulmonary toxicity (dyspnoea, non-productive
cough, pulmonary infiltrates), rash

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VIII. Hormones:
A. Direct destruction of lymphocytes & provides symptomatic relief of the
Corticosteroids: complications of neoplastic diseases.
B. Estrogens: ttt of testosterone dependant cancers (prostatic cancer), these agents produce
1. Diethyl Stilbesterol: chemical castration.
2. Estramusine: Pro-drug site specific Alkylating agent for estrogen dependant cancers.
C. Androgens &
anabolic
steroids: To treat estrogen dependant cancers.
Fluoxymesterone
Testolactone
Nandrolon
D. Progestins:
1. Megestrol→ Endometrial & breast
2. Medroxy-
progesterone→ For endometrial & renal carcinoma.
IX. Anti- hormones:
a. Anti-androgens: *M.O.A: competitively inhibit the binding of androgen at androgen receptors.
Nonsteroidal: *Cyproterone (a steroidal anti-androgen) also inhibits oestrogen, progestin,
1. Bicalutamide mineralocorticoid and glucocorticoid receptors resulting in decreased production of
2.Flutamide testosterone. Nonsteroidal anti-androgens do not suppress androgen production and
3. Nilutamide may even increase testosterone concentration.
*Uses: Prostate cancer.
Steroidal:
Cyproterone
b. Aromatase *M.O.A: Aromatase enzymes (in fat, liver, muscle and breast tissue of
inhibitors: postmenopausal women) convert circulating androstenedione and testosterone to
Anastrozole oestriol and oestradiol. Aromatase inhibitors reduce tissue oestrogen concentration.
Exemestane *Uses: Hormone receptor-positive breast cancer in postmenopausal women
Letrozole
c. Gonadotrophin- *M.O.A: GnRH initially stimulates synthesis of FSH and LH transiently increasing
releasing hormone serum testosterone in males or serum oestrogen in females. Continuous
(Gn-RH) agonists: administration of GnRH agonists inhibits gonadotrophin production, suppressing
Goserelin ovarian and testicular steroidogenesis and inhibiting the growth of certain hormone-
Leuprorelin dependent tumours.
Triptorelin *Uses : Prostate cancer Breast cancer
d. Selective *M.O.A: Compete with oestrogen for receptor sites in breast tissue (anti-
oestrogen oestrogenic effect) inhibiting tumor growth. Also have oestrogen agonist activity on
receptor endometrium, bone and lipids.
modulators: Suppression of other growth factors and cytokines may occur.
Tamoxifen *Uses : Hormone receptor-positive breast cancer
Toremifene
e. Other hormonal: *M.O.A: Competitively binds to oestrogen receptors resulting in their down-
Fulvestrant regulation. Inhibits the growth of oestrogen receptor-positive tumours.
*Uses : locally advanced or metastatic breast cancer in postmenopausal

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 B. Drugs used with antineoplastics:
1. Colony stimulating factors:
Ancestim *M.O.A: Ancestim is a recombinant stem cell factor which stimulates the growth of
Filgrastim primitive progenitors which then can mature into any blood cell type including
Lenograstim neutrophils and mast cells.
Filgrastim, pegfilgrastim and lenograstim are granulocyte colony stimulating factors
(G-CSF) which stimulate production and differentiation of neutrophils from blood
precursor cells.
*Uses: Chemotherapy-induced neutropenia (G-CSF)
Drug-induced neutropenia (G-CSF) Severe chronic neutropenia (G-CSF)
Autologous and allogeneic bone marrow transplantation (G-CSF)
Stem cell mobilization for autologous transplantation (ancestim with G-CSF)
*Precautions:
Treatment with chemotherapy—do not administer for 24 hours before (14 days before for
pegfilgrastim), or until 24 hours after, chemotherapy as rapidly dividing cells are more
sensitive to myelosuppressive chemotherapy.
Autoimmune and inflammatory conditions—may be exacerbated.
Cardiac disease—risk of arrhythmia.
2. Other drugs used with antineoplastics:
Amifostine *M.O.A: Pro-drug is activated to a free sulfhydryl (thiol) metabolite; its higher
concentration in normal cells than cancer cells may explain the selective protection of
normal cells from toxic effects of antineoplastics and radiation.
*Uses: Reduction of neutropenia-related risk of infection due to DNA-binding
antineoplastics, eg alkylating agents, platinum compounds
Reduction of acute and cumulative nephrotoxicity due to cisplatin
Reduction of xerostomia due to radiotherapy alone for head and neck cancer
Aprepitant & *M.O.A: Antagonize substance P/neurokinin 1 receptors.
Fosaprepitant *Uses: Prevention of nausea and vomiting associated with highly or moderately emetogenic
chemotherapy.
Calcium *M.O.A: 1. Bypasses inhibition of dihydrofolate reductase by folic acid antagonists, eg
folinate: Also methotrexate (folinic acid rescue) reducing their toxicity. Competes for cellular uptake
known as with methotrexate.
calcium
leucovorin, 2. Enhances the inhibition of thymidylate synthetase by fluorouracil, increasing its
folinic acid. cytotoxicity.
*Uses: Acute methotrexate overdose. Rescue treatment after methotrexate chemotherapy
To enhance cytotoxicity of fluorouracil
To reduce incidence of bone marrow suppression with long term pyrimethamine therapy
Mesna *M.O.A: Contains free sulfhydryl (thiol) groups which interact with urotoxic metabolites,
including acrolein, of ifosfamide and cyclophosphamide and reduce the incidence of
haemorrhagic cystitis and haematuria. Enhances urinary excretion of cysteine which may
increase uroprotective effect.
*Uses: ↓& prevention of haemorrhagic cystitis and haematuria caused by
cyclophosphamide or ifosfamide
Palifermin To decrease severity of oral mucositis in patients with haematological malignancies
receiving myelotoxic therapy requiring haemopoietic stem cell support
Rasburicase ttt & prophylaxis of acute hyperuricaemia associated with tumour lysis in haematological
malignancy

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 C. Immunosuppressive Drugs: → Prophylaxis &
ttt of Graft rejection
*Selective inhibitors of Cytokine production & function.

A. Calcineurin inhibitors:
*M.OA: They bind to intracellular R cyclophilin→ makes complex which inhibits Calcineurin (is an
intracellular phosphatase which activates IL2).
*Inhibition of Calcineurin→ inhibition of IL2 synthesis→ inhibition of T-cell activation in early stage of
immune response to foreign antigen such as graft.
1. Cyclosporin: *S.E:* Nephrotoxicity [major S.E] *Neurotoxicity & hepatotoxicity (common).
binds to cyclophilin *HTN, Hypokalemia. *Hirsutism & Gum hyperplasia.
2. Tacrolimus: binds S.E: *Nephrotoxicity *Neurotoxicity & drug induced IDDM (common).
to FKBP-12 N.B.: Neurotoxicity is more common with Tacrolimus than Cyclosporin in form
of headache, tremors & seizures.
*Notes:
1. Although they can be used alone for graft rejection, they are more effective when used with
glucocorticoid.
2.Cyclosporin is used as alternative to methotrexate for ttt of severe active rheumatoid arthritis &
psoriasis.
3.Tacrolimus is (10-100) more potent than Cyclosporin.
*D.I: 1. Drugs that stimulate their metabolism (stimulate cyp450) → antiepileptic drugs (phenytoin,
Phenobarbital, CBZ), Rifampin or Isoniazide
2. Drugs that inhibit metabolism (inhibit cyp450) → azole antifungal, Erythromycin & CCBs (verapamil,
Diltiazem).
3. Inhibition of GI cyp450 (grape fruit juice) so avoid it.
4. Avoid sun exposure, wear protective clothing and use sunscreen.
5. If you forget to take a dose at the usual time take it as soon as you remember. If it is almost time for
your next dose, skip the dose you missed. Take your next dose (normal amount) at the usual time.

B. Sirolimus &Everolimus "Rapamycin- SRL"→ mTOR Inhibitors

*M.O.A: Sirolimus inhibits mTOR (mammalian target of Rapamycin) → inhibition of T- cell activation in
late stage of immune response to foreign antigen such as graft.
*N.B: Sirolimus doesn't owe its effect to lowering IL2 production rather to inhibiting the cellular
responses to IL-2.
S.E: *Hyperlipidemia (major S.E).
*Leukopenia, thrombocytopenia & GI S.E.
* N.B: 1. Sirolimus+ Cyclosporin→ synergism (&↑↑ toxicity).
2. Sirolimus + Tacrolimus→ synergism (&↓↓ toxicity).
3. Sirolimus has anti-proliferative action so SRL- coated stents inserted in cardiac vasculature
inhibit restenosis of blood vessels by reducing proliferation of endothelial cells.
C. Antimetabolites:
*M.O.A: they inhibit purine synthesis→ inhibit DNA & RNA synthesis in immune cells.
1. Azathioprine: *S.E: Bone marrow suppression (leukopenia & thrombocytopenia).
D.I: Azathioprine is converted to 6-MP in the body so it interacts with
Allopurinol.
2. Mycophenolate S.E:1. Bone marrow suppression (leukopenia & thrombocytopenia). 2. GI S.E
mofetil: *D.I: With Antacids containing Al, Mg or Cholestyramine→↓ absorption.
3. Methotrexate: Prevents graft rejection in bone marrow transplant.

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D. Adrenocorticosteroids : e.g. prednisone & methyl prednisolone.
*M.O.A: They↓↓ T-lymphocytes either by destruction or redistribution.

E. Antibodies :
1. Muromonab CD3 *M.O.A: It binds to CD3 region of T-Cells→ lose antigen recognition function →
can't initiate rejection process.
*S.E: 1. "Cytokine release syndrome"→severe flu-like symptoms (fever, chills,
nausea& vomiting) so it requires premedication with acetaminophen,
diphenhydramine & corticosteroids.
2. CNS S.E→ so C.I in epilepsy.
2. Basiliximab & *M.O.A: They block IL2 receptor.
Daclizumab *S.E: Only GIT disorders.
3. Antithymocyte *M.O.A: destruction of T-lymphocytes.
globulins: *S.E: 1. Profound immunosuppression (leukopenia & thrombocytopenia).
2. Fever & chills.
*N.B: Basiliximab & Daclizumab are used for prophylaxis of acute rejection in renal transplantation
while Muromonab is used for ttt of acute rejection of renal transplantation.

**Complications of immunosuppression:
1. Infection: *Trimethoprim/Sulfamethoxazole→ ↓ Pneumocystis crainii & UTI.
*Acyclovir 800 mg qid→ ↓ cytomegalovirus (CMV) infection.
* Nystatin or Clotrimazole→ reduce oral candidiasis.
2. ↑ risk of malignancy .
3. HTN : (Cyclosporin, Tacrolimus & steroids) → ttt Diuretics & CCBs.

**Immunosuppressive drugs: →↑↑ risk of malignancies→ what

types?
1. Cancers that are common in general population:
e.g. lung, breast, colon→ aren't increased among transplant patients.
2. ↑ Cancers that are uncommon among general population :
e.g. *Lymphomas.
*Squamous cell carcinoma of lip & skin.
*Kaposi's sarcoma & other sarcoma.

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D. Immunology:
*Immunology: it is a study of a specific mechanism by which living tissues act to
foreign biological bodies (including M.O) to develop immunity or resistance.
*The immune system can be classified into two major components:

1. Humoral Immunity "antibody mediated 2. Cellular immunity "cell mediated

immunity": immunity":
*carried out by Antibodies circulating in blood.
*Carried out by T-lymphocytes.
*When an antigen enters into the body→ lymphocytes
*It occurs at cellular level, especially when antige
initiate the chain of reactions which release antibodies.
are inside host cells & not accessible by circulatin
antibodies.
*Immune system of humans normally consists of the following
cells:

B-Lymphocytes T-Lymphocytes Natural killer Macrophages

cells (NK)
1. They develop from
1. The outer lymphoid *They are large *Monocytes develop from
Lymphoid stem cells in
stem cells migrate from lymphocytes. myeloid stem cells.
adult bone marrow.the bone marrow to *They mature from *When monocytes
2. Following thymus, where they turn lymphoid stem cells in migrate from bone
maturation they to T-lymphocytes (t-cells) bone marrow. marrow into the blood &
migrate to Lymphoid
2. They live in thymus *They comprise 15% of from blood to tissues→
tissues, lymph nodes,
for a prolonged period & blood lymphocytes. mature to macrophages
spleen, adenoids & its
do not require constant *They kill foreign cells, (big eaters).
associated lymphoid
replacement. virus infected cells & *They are divided into:
tissues. When Ag 3. They account for 75% tumor cells. 1. Fixed macrophages:→
invades the body, B-
of Lymphocytes remain stationary in
lymphocytes secretes
circulating in blood & tissues.
Ab. are divided into: 2. Wondering
3. They account for up
1. Helper T-cells (TH): macrophages:→ normal
to 5% of lymphocytes
stimulates B cells & circulating in blood but
circulating in themacrophages. enter tissues when M.O
blood. 2. Cytotoxic T-cells (TC): are present.
kills infected cells.
*Classes of Immunoglobulins:

Ig A: Ig D: Ig E: Ig G: Ig M:
Represents 10% <1% of <1%, known as 70% of 20%
immunoglobulines Reagin. immunoglobulines
& 20% of plasma
proteins.
*inhibits M.O *serves as antigen *has an important *provides *1st Ig produced in
from binding or R in early stages role in fighting antibody response to immune
adhering to of immune against helminthes protection to system.
tissues. response. & is ↑ in asthma & developing fetus. *1st Ig to be produced
hay fever. by fetus.
Not cross Not cross Not cross placenta Crosses placenta Not cross placenta
placenta placenta
In external blood Found in serum. In body fluids &
secretions e.g. beneath skin &
tears, colostrum, mucosa.
saliva & urine.

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**Hypersensitivity Reactions are classified into: "EXAM"

1.Type I: 2. Type II: 3. Type III: 4. Type IV:

"Immediate Cytotoxic Immune complex Cell mediated/
hypersensitivity/ hypersensitivity hypersensitivity Delayed hypersensitivity
Anaphylaxis Rx
Due to Ig E secretions. Due to Ig M & Ig G Due to ↑ load of Ag or Due to prolonged
secretions. ↓ production of Ab. immune response.
*T-cells plays an
important role.
After stimulation Ig E Ig M or Ig G binds to Ig M + Antigen→ T-cells mediated →
binds to Fe receptors on antigen on cell surface Ig G cytokines release
mast cells & basophiles. → activates compliment complex in (accumulates) →
system→ destruct cells. circulation activates macrophages.
→activates
complement → attracts
granulocytes→
Lytic cells.
Rapid (within mins.) Hours Delayed type (1-2 days).
e.g. Anaphylactic shock e.g. Autoimmune e.g. Serum sickness e.g. Tuberculin like Rx
disease:
1. Antagonistic
autoantibodies:
Myasthenia gravis.
2. Agonistic
autoantibodies e.g.
Grave's disease.

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E. Vaccination:
A. Passive Vaccination: accomplished by administration of purified &
concentrated antibody solution [antitoxin] derived from humans or animals that have
been actively immunized against a living antigen.
*Protection depends on the serum half life of injected antibody & usually limited to
several few weeks or several few months.
*Preparations: Standard human serum immune globulin for I.M vaccination [IG
IM].
Characteristics: 1- immunity lasts for 1-2 months.
2. Consists of gamma globulin [16-17%]
3. Skin test shouldn't be performed before injecting IG → WHY?
Because intradermal injection of  globulin will cause a localized
inflammation which may be incorrectly interpreted as +ve reaction so it's better to have
Epinephrine available to combat any occasional sensitivity reaction.
*Put (T) or (F): 1) Immune serum globulin is usually administered I.M (T)
2) Botulism antitoxin is used to produce active immunity (F)
passive immunity ‫ ده معناه‬antitoxin ‫لما االقي كلمة‬
*Choose:
1. The route of administration of antitoxins in the prophylactic ttt of tetanus would be
……….. [I.M, IV, SC, either S.C or I.M]→ WHY?
*For therapeutic effect antitoxins are usually taken I.M or I.V
* For prophylaxis they are taken I.M or S.C why?→ Due to slow release from S.C route.
*Examples of passive vaccines "Hepatitis B immunoglobulin"→ taken I.M & stored in
refrigerator.

B. Active vaccination: accomplished by administration of antigens

designed to stimulate immune system for specific immune response. The response
generates antibodies, activated T-cells & specific memory. Protection through memory
varies but immunity is long lasting.
*Types:
1. Live attenuated vaccine: consists of whole organisms usually virus that are
attenuated to reduce their pathogenicity.
e.g. MMR [Measles, Mumps & Rubella]: for persons 15 months & older, & at age of 1
year (if high risk).
2. Killed inactivated vaccines.
3. Toxoids:
characteristics:1. Detoxified toxins with antigenic characteristics.
2. Available in ppt or absorbed form.
3. Produce active immunity.
*Put (T) or (F):
1. Toxoids produce permanent immunity (F) → WHY?
The duration of memory varies with each vaccine & booster. Vaccination is often
necessary.
e.g. Tetanus toxoid should be administered as routine booster about every 10 years or as
a boaster in the management of minor clean wounds, not more frequently than every 6
years.
2. Most active vaccines are taken once in life (F).
They are taken by a series of vaccination + boosters.
e.g. Diphtheria & tetanus toxoid & pertussis vaccine [DTP]: they are intended for
administration to infants by a series of 4 injections [ baby is 6 weeks -2 months of age
then 2 additional injections are given 6 weeks intervals]→ if needed booster injection

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may be given.
N.B: DTP must never be given for children > 6 years→ WHY?
Because serious reactions may occur.

4. Subunit vaccine: it is a protein or glycoprotein of an organism that is produced

by recombinant DNA technology.
e.g. 1. HBV vaccine.
2. Lyme disease vaccine [Lymerix ®]:
a .Vaccine taken I.M in delloid muscle.
b. Vaccine is approximately 80% effective.
N.B: Several vaccines & toxoids are precipitated & adsorbed onto Aluminum hydroxide
or aluminum phosphate→ WHY?
→ To cause slow release of antigen so ↑ antigenicity of the vaccine.

Notes: 1. The usual storage conditions for biological is in re frigerator [2-80C].

N.B: Small pox vaccine must be stored at 0 0C [frozen].
2. e.g. of Viral infections: [influenza, measles, mumps, hepatitis & rabie s].
3. e.g. of Bacterial infections: [Cholera, plague, pertussis, T.B & typhoid fever].

**Different diseases & their vaccines:

Disease Vaccine Dosing
Measles Live virus Age 15 months & booster at 11-12 years
Mumps Live virus Age 15 months & booster at 11-12 years.
Rubella Live virus Age 15 months & booster at 11-12 years.
Diphtheria Toxoid Age 2, 4 & 6 months; 1.5 & 4-6 years.
Tetanus Toxoid Age 2, 4 & 6 months; 1.5 & 4-6 years.
Pertussis Toxoid Age 2, 4 & 6 months; 1.5 & 4-6 years.
Hepatitis B Viral antigen fragments Birth, ages 2 & 6 months
Poliomyelitis Live virus Age 2, 4 & 6 months; 1.5 & 4-6 years.

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**Skin susceptibility tests:
1. Schick's test:→ it is used to determine susceptibility to Diphtheria.
*Test: Diphtheria toxin for Schick test is injected intradermally [0.1 ml] into forearm →
if +ve reaction→ redness at injection site in 24-36 hours & persists for 4-5 days.

2. Tuberculin tests:
Tuberculin: is a solution of soluble products of tubercle bacillus that is used as
diagnostic aid for exposure to the bacillus.
*Two tests:
a. Mantoux test: intradermal injection of purified protein derivative [PPD] of
tuberculin
*Strength of Tuberculin used: 1. Intermediate strength PPD [5u/0.1] ml
2. For individuals suspected of being highly sensitive [1u]
3. For people who didn't react to previous injections of
either 1 or 5u [250 u].
b. Multiple puncture method [Tine test]: *Tuberculin syringes:
1. 1 ml with 0.05 ml accuracy.
2. Despite their name, they are suitable for measuring small volume of any liquid
e.g. Insulin.
*Put (T) or (F): Toxins are used for active immunization (F).
They are used primarily as diagnostic aid to determine the state of immunity
e.g. Diphtheria toxin.

***BCG Vaccine [Bacillus Chalmette- Guerin]:

1. Used for immunization against T.B
2. Used as immune-stimulant in cancer chemotherapy.
M.O.A: Macrophage activation so entrance killing activity.

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