2.

13 IMMUNOPHARMACOLOGY PHARMACOLOGY
 

Dr.  Angeles  D.  Marbella  |  October  18,  2018  

TRANS  GROUP:  Valdez,  Valencia,  Valenzuela,  Vea   LE  2  TRANS  13  
TRANS  HEADS:  Tagorda  
 
OUTLINE   •   Due  to  breakdown  of  self-­tolerance  
  3.   Isoimmune  diseases  
  •   Also  known  as  Alloimmunity  is  an  immune  response  to  
I.   INTRODUCTION  
nonself  antigens  from  members  of  the  same  species,  which  
A.   Classification  of  Immunopharmacologic  Drugs  
B.   Uses  of  Immunosuppression   are  called  alloantigens  or  isoantigens.    
C.   Signals  for  T-­cell  Activation   4.   Prevention  of  cell  proliferation  
II.   CLASSIFICATION  OF  IMMUNOSUPPRESIVE  AGENTS    
A.   Corticosteroids   C.   Signals  for  T-­cell  Activation  
B.   Calcineurin  Inhibitors  
 
C.   Cytotoxic  Agents  
D.   Proliferative  Signal  Inhibitors   1.   SIGNAL  1:  Engagement  of  antigen  to  T-­cell  receptor  by  the  
E.   Biologicals  (Ab)   MHC  peptide  complex  
III.   IMMUNOSUPPRESSION  IN  RENAL  TRANSPLANTATION   2.   SIGNAL  2:  Binding  of  co-­stimulatory  molecules,  CD80  &  
A.   IS  Renal  Transplantation   CD86  on  dendritic  cells  (APC)  to  CD28  on  t-­cell  
B.   Hydroxychloroquine   3.   SIGNAL  3:  Engagement  of  cytokines  to  specific  receptors  on  
IV.    Monoclonal  Antibodies   T-­cell  surface  
A.   Anti-­Tumor  Mabs  
•   RESULT:  Clonal  proliferation  of  t-­cells  
B.   Immune  Checkpoint  Inhibitor  Mabs  
C.   Mabs  and  Fusion  Proteins   •   TREATMENT:  targeted  therapy  on  specific  receptors  on  t-­cell  
V.   Overview  of  the  Mechanisms  of  Pharmacologic   surface  
Immunosuppression    
VI.   Immunomodulators  
A.   Levamisole  
B.   Thalidomide  
C.   BCG  
D.   Cytokines  
1.   Hematopoietic  growth  factors  
2.   Interferons  
3.   Interleukin-­2  
4.   Therapeutic  antibodies  
 
 
LEARNING  OBJECTIVES  
 
1.   Explain   the   mechanism   of   action,   the   PK   and   PD   for   most   commonly  
used  immunosuppressive  agents  
2.   Identify  major  side  effects  and  toxicities  
3.   Identify  the  uses/indication  for  immunosuppressants  
 
LEGEND  
 

Remember   Lecturer   Book   Prev.  Trans   Notes  

G U & 4 !
   
I.  INTRODUCTION  
A.   Classification  of  Immunopharmacologic  Drugs  
1.   Immunosuppresants  –  ê  immune  response  
2.   Imuunomodulators  –  é  immune  response  
3.   Immunologicals  
 
B.   Uses  of  Immunosuppressants    
1.   Organ  transplantation   Figure  1.  T-­cell  activation  
•   Terminologies:    
o   Autograft  –  within  own  body   •   DEVELOPMENT  OF  DIFFERENT  IMMUNOSUPPRESANTS:    
o   Isograft  –  between  twins   o   1950’s  –  used  radiation  on  organ  transplants  between  twins  
o   Allograft  –  same  species   o   1960’s  –  use  of  steroids    
o   Xenograft  –  different  species   o   1970’s  –  use  of  Azathioprine  
•   Can  be  done  on  almost  all  organs.  Most  commonly   o   1980’s  –  discovery  of  Cyclosporine,  which  revolutionized  
transplanted  is  the  kidney  (you  add  a  3rd  kidney)   organ  transplantation;;  introduction  of  CYA  improved  
success  
•   Used  to  prevent  immune  attack  on  transplanted  organ  
o   2000’s  –  targeted  therapy  on  specific  antibodies,  CD  25  &  
•   History:  
CD22  
o   1954  –  1st  kidney  transplant  of  Herrick  twins  
o   1959  –  started  transplanting  non-­identical  HLA  
individuals  
o   1962  –  1st  diseased  donor  organ  
2.   Autoimmune  diseases  
•   Host  immune  system  attacks  own  tissues,  mistaking  self-­
antigens  as  foreign  antigens  

LE  2  TRANS  13   1 of 10
        2.14  IMMUNOPHARMACOLOGY    
 
B.   PHARMACOLOGIC  EFFECT  
Adaptive  immune  response  
•   T-­cells  (Cell-­mediated)  
o   Lyse  and  induce  the  redistribution  of  lymphocytes  
o   Inhibits  T  cells  from  making  IL-­2  
o   Activation  of  cytotoxic  T-­lymphocytes  is  inhibited  
o   Pro-­inflammatory   cytokines   (Il-­1   and   IL-­6)   are  
downregulated  
•   B-­cells  (Humoral)  
o   Curtail   activation   of   NF-­KB   (Nuclear   Factor   –   kappa  
enhancer  of  B-­cells)  
Innate  immune  response  
•   Neutrophils   and   monocytes   displays   poor   chemotaxis   and  
decreased  lysosomal  enzyme  release  
  OTHERS:  Regulates  the  transcription  of  numerous  other  genes  
Figure  2.  Development  of  Different  Immunosupressants    
 
II.  CLASSIFICATION  OF  IMMUNOSUPPRESSIVE  AGENTS  
1.   Corticosteroids  
2.   Calcineurin  inhibitors  
3.   Cytotoxic  agents  (Mycophenolate  mofetil)  
4.   Proliferative  signal  inhibitors  
5.   Biologicals  (Antibodies)  
 
A.   Corticosteroids  
•   G Cornerstone   in   immunologic   regimens   in   renal  
transplantation  and  autoimmune  diseases  

A.   MECHANISM  OF  ACTION  

1.   Glucocorticoid   (S)   is   released   by   corticosteroid   binding  
globulin   (CBG)   and   combines   with   receptor   (R)   in   the  
cytoplasm.    
2.   Binding   induces   conformational   change   in   R   releasing   Figure  4.  Pharmacological  effects  of  glucocorticoids  in  inflammatory  
HSP90   cells  and  structural  cells.    
3.   Activated  steroid-­R  dimer  enters  the  nucleus  and  binds  with    
glucocorticoid  response  element  (GRE)   •   Effect   on   inflammatory   cells   –   Usually   decrease   in  
4.   U Inhibit   mRNA   synthesis   and   further   protein   numbers  
synthesis  so  your  production  of  cells  are  diminished     o   Decrease  number  of  lymphocytes  eosinophils  
  o   Decrease  in  cytokines  
o   Decrease  action  of  macrophages  and  
o   Decrease  number  of  dendritic  cells  
o   Increase  WBC  count  in  CBC    

 
Note:  U Paradoxical  effect  on  WBC  Count  
•   If   glucocorticoids   are   immunosuppressants,   you   might  
expect  the  drug  to  decrease  WBC  count  
•   HOWEVER,   the   WBC   count   will   usually   INCREASE  
(Leukocytosis)   which   is   due   to   an   INCREASE   IN  
NEUTROPHIL  (Segmenters)  
•   De-­margination   of   neutrophils  →  neutrophils  detach  from  
endothelial  lining  and  become  available  in  the  blood  stream  
•   Steroids   also   diminishes   migration   of   neutrophils   to  
target  tissues  making  them  more  available  in  blood  stream  
•   EXAMPLE:   Patients   in   steroids   after   weeks   if   you   repeat  
CBC,   WBC   count   will   be   as   high   as   30,000   with   92%  
  segmenters  but  patient  is  NORMAL  with  no  fever  and  other  
Figure  3.  Mechanism  of  action  of  glucocorticoids.  
  symptoms  →  NOT  AN  INFECTION  
 
& KATZUNG   MOA:   Interfere   with   cell   cycle   of   active   lymphoid  
cells,  cytotoxic  to  certain  subset  of  T-­cells  –  however  some  say  it    
is   due   to   their   ability   to   modify   cellular   functions   rather   than   to   •   Effect  on  structural  cells  
direct  cytotoxicity.  Humoral  immunity  (antibodies)  are  less  affected   o   Epithelial:  Decrease  in  release  of  cytokines  and  mediators  
but   primary   antibody   response   can   be   diminished   also,   with   o   Endothelial:  Decrease  leakiness  of  capillaries  
continued  use,  previously  established  antibody  responses  are  also   o   Airway   smooth   muscle:   Increase   B2-­Receptor   activity  
decreased.     (Vasodilation)  and  decrease  cytokine  production  
  o   Mucous  glands:  decrease  secretion  
  →  Effects  on  Airway  smooth  muscle  and  Mucus  glands  explain  
  why  steroids  are  important  in  controlling  Asthma  U  
   
   
   
   
LE  2  TRANS  13   2 of 10
        2.14  IMMUNOPHARMACOLOGY    
 
Table  1.  Comparison  of  Systemic  Adrenocorticosteroids    
Anti-­ Na-­ •   Complications   of   Chronic   Use   (Not   sure   why   Ma’am  
Equivalent  
Compound   inflammatory   retaining   separated  chronic  from  long  term  use)  
dose  
potency   potency   o   Suppression  of  HPA  Axis  
Hydrocortisone   1   1   20mg   §   You  are  giving  exogenous  steroids  
Cortisone   0.8   0.8   25mg   §   No  endogenous  production  due  to  feedback  mechanism  
Deoxycorticosterone   0   100   -­   §   G If   your   patients   are   in   prolonged   steroid   use,   you  
Aldosterone   0   3000   -­   have    to  taper  the  doses  gradually    
Prednisone   4   0.8   5mg  
-   G   Give   time   for   the   adrenal   glands   to   produce   the  
Methylprednisolone   5   0   4mg  
endogenous  steroids  (Ma’am  said  remember  this)  
Triamcinolone   5   0   4mg  
o   Patients  that  are  considered  not  suppressed:  
Dexamethasone   30   0   0.75  
§   Any   patient   who   has   received   any   non-­parenteral   dose  
 
of  GC  for  less  than  3  weeks  
Emphasized  in  the  table    
§   Patients   treated   with   alternate   day   steroids   at  
•   U Dexamethasone  –  highest  anti-­inflammatory  property     physiologic  doses  
•   U Followed  by  methylprednisolone     o   Patients  that  are  suppressed:  
o   Although  in  the  table  it’s  the  same  as  triamcinolone     §   Anyone   who   has   received   more   than   20mg   of  
•   U The  lowest  is  the  Hydrocortisone     prednisone  a  day  for  more  than  3  weeks  
o   U Lowest  because  it  is  in  the  endogenous  form   §   Any  patient  who  has  clinical  Cushing’s  syndrome  (since  
o   Although   in   the   table   cortisone   to   aldosterone   have   lower   patient   already   manifested   symptoms   of   prolonged   use  
potency     of  steroids)  
   
C.   PHARMACOKINETICS   •   Minimizing  GC(Glucocorticoids  aka  steroids)  side-­effects  
•   50  –  90%  Bioavailability     o   Exercise  programs  
•   Absorption:  delayed  by  food   o   Ca2+and  vitamin  supplements  (Vitamin  D,  Bisphosphonates)  
o   U Notorious  for  inducing  peptic  ulcer  disease     o   Estrogen  therapy  for  menopausal  women  
o   Usually  given  with  food  to  avoid  side  effects  of  hyperacidity   §   Estrogen   is   also   an   exogenous   steroid   by   why   should  
o   Prevent  side  effects  of  hyperacidity     we   administer   estrogen   concomitantly   with   GC?   Mainly  
•   Peak  plasma  levels:  30-­100  min  after  drug  intake   because  it  protects  menopausal  women  from  bone  loss  
•   Half-­life  is  3  hours   –  hence  Calcium  and  Vitamin  D  are  given.  
•   Metabolism  in  the  liver   o   Alternate  day  steroid  (Patients  receive  entire  total  dose  that  
•   Excretion  in  the  kidney     would   be   given   for   2   days.   Example:   You   need   2   grams  
•   All  forms  are  bioequivalent   daily,  take  4  grams  for  today,  don’t  take  the  next  day,  then  
•   Prednisone  is  NOT  yet  the  active  form   take  another  4  grams)  
o   It  is  converted  to  Prednisolone  in  the  liver  for  it  to  be  active    
o   TIP:  “-­solone”  means  activated  form   E.   CLINICAL  USE  OF  STEROIDS  
•   Clearance  decreases  with  age  varies  with  time  of  day   •   Rheumatoid  and  other  arthritides  
o   Best  time  to  give  steroids  is  in  the  morning  because  the  is   •   SLE,  systemic  dermatomyositis  
the  time  for  peak  steroid  excretion.  Administration  is  in  sync   •   Psoriasis  and  other  skin  conditions  
with  the  physiologic  body  processes  for  lesser  side  effects   •   Asthma  and  other  allergic  disease  
  •   Inflammatory  renal  diseases  
D.   SIDE  EFFECTS   •   Inflammatory  ophthalmic  disease  
  •   Autoimmune  hematological  disorders  
•   Acute  exacerbation  of  Multiple  Sclerosis  
 
B.   Calcineurin  Inhibitors  (CnI)  
•   U You  only  need  to  remember  2:  
o   Cyclosporin  A  (CsA)  
§   from  fungus  Tolypocladium  inflatum  
§   & Treatment   of   Graft   vs   Host   transplantation   (mainly  
Renal  transplant)  and  Autoimmune  disorders  
o   Tacrolimus  (TAC)  
§   macrolide  antibiotic  from  Streptomyces  tsukubaensis  
§   Same   indication   as   Cyclosporin   but   is   also   used   for  
  organ  and  stem    cell  transplantation  
Figure  5.  Cushing  Syndrome  that  may  be  a  side  effect  of  steroid  use  
  §   & Standard   prophylactic   agent   for   graft   versus   host  
Table  2.  Immediate  and  Long-­term  effects  of  Cushing  Syndrome   disease  
Immediate  effects   Long  term  effects   §   50-­100x  more  potent  than  CsA.  (& 10-­100x)  Main  diff.  
Peptic  ulcer  disease   Osteoporosis   between  CsA  and  TAC  
Cushingoid  features   Growth  retardation    
A.   MECHANISM  OF  ACTION  
Weight  gain   Skin  atrophy  
1.   Both   are   structurally   related   but   binds   to   different   intracellular  
(prolonged  use)  
mediators  
Hypertension  and  Hyperlipidemia   Avascular  necrosis  
•   CsA  binds  to  Cyclophilin  (CpN)  
(10-­15%  with  high  
doses)   •   TAC  binds  to  FK-­Binding  Protein  12  (FKBP-­12)  
Diabetes  (5  –  10%;;  transient)   2.   Both  have  the  same  inhibitory  target  →  Calcineurin  
3.   Block   the   intracellular   T-­cell   signal   responsible   for   cytokine  
Cataracts  (10%  with  high  doses)  
production  
Acne,  hirsutism  
Mood  changes/  Psychiatric  disturbances  
Infection   (Susceptible  to  opportunistic  inf.  –  
viral  /fungal.  Why?  Immunocompromised)  
LE  2  TRANS  13   3 of 10
        2.14  IMMUNOPHARMACOLOGY    
 
§   Hypertension  and  Hyperlipidemia  
o   Hepatic  
§   Increased  bilirubin  –  cholestasis  
§   Increase   hepatic   enzymes   from   centroacinar  
degeneration  of  hepatocytes  
o   Neurologic  
§   Tremors  
§   Nausea  
§   Anorexia  
o   Epithelial  
§   Hirsutism  –  increase  hair  growth    
§   Gingival   Hypertrophy   (ppt;;   in   recordings   she   said  
hyperplasia)  
o   Immunologic  
  §   Infections  
Figure  6.  U Cyclosporine  A  (CsA)  binds  to  cyclophilin  intracellularly   §   Malignancies  
(CpN)  and  Tacrolimus  (FK-­506  old  name)  binds  to  FKBP-­12  →  Both  
 
inhibit  the  activation  of  calcineurin  (CaN)  →  inhibit  the  
dephosphorylation  of  nuclear  factor  of  activated  T-­Cell  (NF-­ATc)  →     •   TACROLIMUS  
activation  and  proliferation  of  gene  will  not  push  through  U     o   Table  below  compares  CsA  and  TAC  based  on  incidence  of  
(manufacturing  and  cloning  of  the  T-­cell  4)     diabetes  
  o   KEY  FINDING:  TAC  has  a  higher  incidence  of  new  onset  
B.   PHARMACOKINETICS   diabetes  →  metabolic  effect    
CYCLOSPORIN  A  
•   2  forms:   Table  4.  Studies  comparing  CsA  and  TAC  for  DM  Incidence.  
o   Sandimmune  –  oil  based,  100mg/ml   Definition  of  Glucose  
o   Neoral   –   microemulsion   formulation   (gel   like     TAC   CsA  
Intolerance  
preparation)   US  Kidney  Trial   New  Onset  DM    
20%   4%  
•   Oral  Bioavailability:  30-­45%   (Pirsch)   (>30  days  of  Insulin)  
•   Food  tend  to  enhance  absorption  of  CyA   European  Kidney   New  Onset  DM  (>30  days  of  
8%   2%  
•   Narrow  therapeutic  index   Trial   Insulin)  
o   U Can  be  toxic    thus  a  need  to  monitor  blood  levels     US  Liver  Trial   Hyperglycemia   47%   38%  
  European  Trial   All  cases  of  DM   15%   9%  
TACROLIMUS   5-­
Miller  et  al.  2000   New  Onset  DM   N/a  
•   Oral  capsule:  5mg,  1  mg,  0.5mg,  administered  2x  a  day   19%  
•   Absorbed  in  the  small  intestine   Ahsan  et  al.  2001   New  Onset  DM   6%   4%  
•   Oral  bioavailability:  25%    
•   Excretion:  bile,  minimal  renal  excretion   •   COMPARISON  OF  ADVERSE  EFFECTS    
o   CsA  is  more  causative  for  hypertension  and  hyperuricemia,  
•   Not  significantly  dialyzed  
  hypercholesterolemia.   More   causative   of   gum   hypertrophy,  
C.   DRUG  INTERACTIONS   and  hirsutism  
CYCLOSPORIN  A   o   TAC   has   more   effects   on   the   pancreas.   May   also   exhibit  
Neurotoxicity,  Hairloss,  and  GI  side  effects.  
•   CYP  Inducers:  Decrease  CsA  levels  
 
•   CYP  Inhibitors:  Increase  CsA  levels   Table  5.  Comparison  of  AE  between  CsA  and  TAC.  
o   U Clinical   –   if   you   want   to   be   economical,   you   can   give   Adverse  Effect   CsA   TAC  
combination   of   CsA   with   CYP   inhibitors   but   monitor   with   Nephrotoxicity   +   +  
blood  levels     Hyperkalemia   +   +  
•   Nephrotoxic  drugs:  Nephrotoxic  Synergy   Hypomagnesemia   +   +  
 
Hypertension  and  Na  Retention   ++   +  
Table  3.  Drug  Interactions  of  CsA  
Hyperuricemia   ++   +  
Nephrotoxic  
Decreased  CsA   Increased  CsA   Pancreatic  Islet  Toxicity  (Glucose  Intolerance)   +   ++  
Synergy  
levels   levels   Neurotoxicity   +   ++  
(Nephrotoxic  
(CYP  Inducers)   (CYP  Inhibitors)  
drugs)   Hirsutism   +   -­  
Carbamazepine   Diltiazem   Acyclovir   Gum  Hypertrophy   +   -­  
Phenobarbital   Erythromycin   Aminoglycosides   Hypercholesterolemia   +   -­  
Phenytoin   Fluconazole   Amphotericin  B   Hair  Loss   -­   +  
Rifampin   Itraconazole   Furosemide   GI  Side  Effects   -­   +  
Rifabutin   Ketoconazole   Ganciclovir    
Nafcillin   Metoclopramide   H-­2  Antagonists   C.   Cytotoxic  Agents  
Octreotide   Methylprednisolone   Melphalan  
U I  will  not  discuss  this  in  detail.  More  of  this  will  be  discussed  in  
Ticlopidine   Nicardipine   NSAIDs  
Orlistat   Verapamil   TMP/SMX   cancer   chemotherapy.   I   will   just   discuss   mycophenolate  
St.  John’s  Wort   Grapefruit  Juice   Vancomycin   mofetil  (MMM)  
  Protease  Inhibitors      
  Sirolimus     •   Classifications  
    o   Antimetabolite  
D.   ADVERSE  EFFECTS   §   Azathioprine  
•   CYCLOSPORIN  A   §   Methotrexate  
o   Renal   §   Mycophenolate  Mofetil  (MMM)  
§   Nephrotoxicity   –   Isometric   Vacuolization   and   Interstitial   §   Leflunomide  
Fibrosis   o   Alkylating  agent  
§   Hyperkalemia  and  Hyperuricemia   §   Cyclophosphamide  

LE  2  TRANS  13   4 of 10
        2.14  IMMUNOPHARMACOLOGY    
 
  o   Sirolimus  binds  to  FKBP-­12  (similar  to  Tacrolimus)  and  the  
MYCOPHENOLATE  MOFETIL   complex   binds   and   inhibits   kinase   mTOR   (mammalian  
-­   Potent  cytostatic  effects  on  T  &  B  lymphocytes   target  of  Rapamycin)  
-­   Inhibits  Ab  production  by  B  lymphocytes   (Sirolimus   –   inhibits   mTOR;;   Tacrolimus   –   inhibits  
-­   Inhibits   T-­cell   proliferation   after   mitogen   and   allogenic   calcineurin)  
stimulation    
-­   Prevents   glycosylation   of   adhesion   proteins   (inhibits  
recruitment  of  lymphocytes  to  inflammatory  foci)  
 
Clinical  use  
•   Prevention  of  organ  rejection  
•   Autoimmune  Diseases  
•   & First   line   drug   for   preventing   or   reducing   chronic  
allograft  vasculopathy  in  cardiac  transplant  recipients  
 
A.   MECHANISM  OF  ACTION  
•   Reversibly   inhibits   inosine   monophosphate  
dehydrogenase  (IMPDH)  
•   IMPDH  is  the  rate  limiting  enzyme  in  the  de-­novo  synthesis    
Figure  7.  Distinction  of  CsA,  TAC,  with  Sirolimus  based  on  MoA.  
of  purine  building  block  of  DNA  (guanine  &  adenine)  
 
•   IMPDH  prevents  the  conversion  of  Inosine  monophosphate   CsA  vs  TAC  vs  Sirolimus  
to  Xanthine  Monophosphate   Binding  proteins:  Cyclophilin  and  FKBP12  
•   Prevent  proliferation  of  both  T  &  (B  cells  →  Inhibit  antibody   Effector  proteins:  Calcineurin  and  mTOR  
production)   1.   Calcineurin   is   a   key   enzyme   in   cell   cycle   progression  
  from  Go  to  G1  (CsA  and  TAC:  Inhibit  IL-­2  Message)  
B.   PHARMACOKINETICS   2.   mTOR  is  a  key  enzyme  in  cell  cycle  progression  from  G1  
•   Rapidly   absorbed   and   hydrolyzed   to   Mycophenolic   Acid   to  S  phase  (Sirolimus:  Inhibit  IL-­2  Response)  
(MPA),   the   active   immunosuppressive   moiety,   in   the    
liver,  peak  level  1-­2hrs   B.   PHARMACOKINETICS  
o   MMM   is   not   yet   active.   It   must   be   converted   to   •   Sirolimus  
mycophenolic  acid  and  conjugated  with  glucuronic  acid   o   1mg  or  2  mg  capsule  
in  the  liver  to  become  mycophenolic  acid  glucoronate   o   Peak:  1-­2hours  
•   Bioavailability  of  capsule  form:  90%,  T1/2:  12  hrs   o   T1/2:   62   hours     (U MAIN   DIFFERENCE:   Sirolimus   has   a  
•   1  gm  BID  dose  is  recommended   longer  half-­life)  
•   May   be   adjusted   based   on   tolerance:   GI/hematologic   •   Everolimus  (NOT  DISCUSSED)  
Adverse  effects   o   Similar  to  sirolimus  but  with  shorter  T1/2  
•   G MMF  is  not  co-­administered  with  azathioprine     o   T1/2:  23  hours  
o   U They  are  both  antimetabolites  and  they  act  on  the  cell    
cycle  purine  synthesis   •   Both  metabolized  by  Cyp3A  and  P  glycoprotein  
•   Not  dialyzed   o   Has  interactions  with  drug  inhibitors  and  inducers  
  •   Excretion:  Renal  minimal  
C.   ADVERSE  EFFECTS   •   Target  trough(minimum  concentration):  5-­15  ng/dL  
•   Gastrointestinal  disturbances   •   Should  be  given  4  hrs  after  the  CsA  dose  
o   Nausea  and  Vomiting    
o   Diarrhea   C.   ADVERSE  EVENTS  
o   Dyspepsia   •   Hyperglycemia  
•   Suppression  of  Bone  Marrow   •   Hypercholesterolemia  
o   Leukopenia  (Decrease  WBC  count)   •   Lymphocoele  
o   Thrombocytopenia  (Decrease  Platelet  Count)   •   U G Impaired  wound  healing    
  o   Not   part   of   regimen   in   post   kidney   transplant   since   wound  
G IF  YOU  ARE  ASKED:  Which  of  the  ff  drugs  is  most  likely  taken  
healing  is  impaired  
when  there  is  a  decrease  in  WBC  Count  →  MMF  has  this  effect     o   May   be   given   after   a   month   or   2,   after   the   wound   has  
  healed  
•   Enteric-­Coated   Mycophenolic   Sodium   (   EC-­MS   )   •   Impaired  renal  function  –  U be  wary  of  this  effect  
“Myfortic”  
•   Blood  effects:  cytopenia,  thrombocytopenia,  anemia  
o   Same  therapeutic  activity  w/  MMF  
 
o   Less  GI  Adverse  Effects  
D.   OTHER  EFFECTS  
 
•   Oncologic   effect   (anti-­neoplastic)t:   anti-­angiogenesis,   arrests  
D.   Proliferative  Signal  Inhibitors  
malignant  cell  growth  in  G1  –S  phase  
•   Sirolimus  (Rapamycin  or  Rapammune)   •   Also  given  for  patients  with  malignancies  
•   Everolimus    
•   Temsirolimus   E.   Biologicals  (Antibodies)  
 
•   Two  Types:  Polyclonal  or  Monoclonal  
A.   MECHANISM  OF  ACTION  
A.   Polyclonal  Antibodies  
•   SIROLIMUS  (SRL)    aka  (Rapamycin  or  Rapammune)  
•   Contains   antibodies   with   multiple   distinct   antigen   combining  
o   Note:   Only   drug   in   this   class   discussed   in   lecture   for  
sites  
MoA  is  Sirolimus  
o   Only  2%  of  antibodies  produced  are  specific  to  immunizing  
o   Isolated  from  Streptomyces  hygroscopicus  
antigen  
o   Structurally  similar  to  tacrolimus  (TAC)  
•   Purified   Ig   preparation   from   animals   after   immunization   with  
o   27x  more  potent  than  TAC  
human  thymocytes  or  lymphocytes  

LE  2  TRANS  13   5 of 10
        2.14  IMMUNOPHARMACOLOGY    
 
•   Usually  given  as  induction  therapy  for  kidney  transplantation   I.  T-­CELL  DIRECTED  ANTIBODIES  (MUROMONAB  OKT3)  
o   Induction   therapy   –   first   phase   of   treatment   for   multiple    MECHANISM  OF  ACTION    
myeloma   to   reduce   number   of   plasma   cells   in   the   bone   •   The  first  therapeutic  monoclonal  antibody  
marrow  and  the  protein  that  they  secrete.   o   Antibody  directed  specifically  against  the  CD3   receptor   on  
•   Anti-­Thymocyte  Globulin  or  ATG   T  cells  
o   & Antiserum   is   usually   obtained   by   immunization   of   o   Effective  in  preventing  and  treating  rejection  
horses,  sheep,  or  rabbits,  with  human  lymphoid  cells   o   Significant  Side  effects:  
§   Rabbit  ATG  (rATG)  –  from  rabbit   §   G Cytokine   release   syndrome   –   results   from   the  
§   Equine  ATG  (eATG)  –  from  horses   release   of   cytokines   from   cells   targeted   by   the  
  antibody  
-­   First  Dose  effect  
-­   Fever,  chills,  rigors,  “Shake  and  Bake”  
-­   Pulmonary  Edema  
§   Sensitization  
§   Risk   of   serious   infections   and   cancer   (due   to  
immunosuppression)  
•   Manufactured  via  Hybridoma  Technology  

 
Figure  8.  Polyclonal  Antibody  Manufacturing.  U  Thymocyte,  
lymphoblast,  or  thoracic  duct  lymphocyte  from  humans  are  injected  to  
animals.  After  some  time,  serum  will  be  pooled  and  unwanted  Ab  are  
removed.  Sterilization  is  done  to  remove  unwanted  antibodies.  
Stabilizers  are  added  and  sample  is  tested  for  microbial  presence.  
Afterwards  they  are  stored  in  ampules  
 
 MECHANISM  OF  ACTION  (ATG)  
o   Inhibit  and  suppress  T-­cell  mediated  immune  response  
§   Depletion  of  circulating  T-­cells  
§   Modulation  of  cell  surface  receptor  molecules    
§   Induction  of  anergy   Figure  9.  Hybridoma  Technology  in  Mab  Manufacturing.  UThe  antigen  
o   Absence   of   normal   immune   response   to   an   is  injected  in  a  mouse  and  the  mouse  produces  (Ab-­producing  plasma  
allergen  or  antigen   cells).  These  cells  are  fused  to  preformed  cancerous  plasma  cells  and  
§   Apoptosis  of  activated  T-­cells   form  hybridomas.  These  cells  (hybidromas)  are  cultured  and  clones  will  
o   Side  Effects   be  chosen  and  tested  for  the  desired  Ab.  Hybridomas  can  be  
§   75  %  -­  infusion  related  reactions  (e.g.  fever,  chills)   proliferated  by  injecting  it  in  another  mouse  OR  the  desired  clones  are  
§   40  %  -­  formation  of  anti–antibodies   frozen  and  eventually  processed.  Very  expensive  
o   Impairs  the  function  of  introduced  antibodies    
§   20  –50  %  -­  leukopenia   II.  IL-­2  RECEPTOR  ANTAGONISTS  
§   6%  -­  serum  sickness   •   Directs   against   IL-­2   receptor   alpha   chain   antigen   (CD25)  
  expressed  on  T-­lymphocyte  surface  
Table  6.  Comparison  of  Polyclonal  Antibodies    
  ATGAM   THYMOGLOBULIN   Table  7.  Chimeric  mAb  vs.  Humanized  mAb  
Removing  borders  is     Chimeric  mAb   Humanized  mAb  
Dose   15  mg/kg/day   75%  human   90%  human  
suggested   Composition  
Shading  rows  with  gray  is   25%  murine  protein   10%  murine  protein  
Regimen   5  -­14  days   Well-­tolerated,  but  
suggested  
Efficacy   ++  Monitor  CD2/3     may  cause  
Side  effects   Well-­tolerated  
Fever,  chills,  serum   Fever  chills,  low  plts,  low   hypersensitivity  rxn  
Safety   (foreign  substance)  
sickness   WBC  
Predictable  suppression  of  T   Example   Basiliximab   Dacilizumab    
Benefits   Comfort  level   •   TIP:    (-­Ximab:  MiXture  –  chimeric)  ;;  (-­Zumab:  HumaniZed)  
cells  better  tolerated  
CRS  –  premed  required;;    
CRS  –  premed  required;;  
Risks   slow  infusion;;  similar  rates  of    
slow  infusion  
infection/malig    
UThey  are  mostly  the  same.  Not  elaborated  in  the  lecture.    
   
B.   Monoclonal   Antibodies   (categorized   under   antibodies   but    
will  have  a  separate  section  later  for  thorough  discussion)    
•   Ab  derived  from  a  single   clone   that   is  active  against  a  single    
antigen    
o   T-­cell  directed  antibodies  –  Muromonab  CD3  (OKT3)      
o   IL-­2  receptor  antagonists      
   
   
   

LE  2  TRANS  13   6 of 10
        2.14  IMMUNOPHARMACOLOGY    
 
Table  8.  IL-­2  receptor  competitive  antagonists   •   Humanized  mAb  
Agent   Target   MOA   •   Cell  lysis  and  long  lasting  depletion  
Targets:  Binds  to  and   •   Therapeutic  uses:  
CD  25  (IL-­2   blocks  IL-­2  receptor  on  T-­
Basiliximab   o   Induction  of  immunosuppression  
receptor  α   cells  
Daclizumab   o   Acute  rejection  in  kidney  transplant  
chain)   Result:  Inhibit  IL-­2  induced  
T-­cell  activation     •   Not  for  maintenance  therapy  
Targets:  Receptors  on  T  &   •   Minimal  side  effects  
B  cells,  monocytes,    
Alemtuzumab   CD52   macrophages  &  NK  cells   D.   Rituximab  (ANTI-­  CD20)  
Result:  cell  lysis  and  long-­ •   Anti-­B  cell  
lasting  depletion   •   Chimeric   Mab   approved   for   treatment   of   refractory   non-­
Targets:  B  cells     Hodgkin’s  lymphoma  
Ritumixab   CD20   Result:  B  cell  lysis  and  
•   Specific  for  CD20  markers  on  B  cell  
depletion    
•   Mediates  cell  lysis  and  depletion  
Target:  complement  C5  
protein   •   Therapeutic  uses:  
Complement   Result:  inhibit  cleavage  to   o   Treatment  of  refractory  non-­Hodgkin’s  lymphoma  
Eculizumab   o   Treatment   of   Post-­Transplant   Lymphoproliferative  
protein  C5   C5a  &  C5b,  prevent  
terminal  complement   Diseases  (PTLD)  
complex  C5b-­9   o   Treatment  and  prophylaxis  of  Ab-­mediated  rejection  
  o   Limited  evidence  for  kidney  transplant  
A.   Dacilizumab  (Zenapax®)  U4    
E.   Eculizumab  (Recombinant  Humanized  mAb)  U4  
•   90%  human,  10%  murine  protein  (mouse)  
•   inhibition   of   critical   cellular   immune   response   involved   in   •   Anti-­tumor  monoclonal  antibodies  
allograft  rejection   •   Binds  to  complement  protein  C5,  inhibiting  cleavage  to  C5a  &  
•   Therapeutic  use:   C5b  
o   Prophylaxis  for  acute  organ  rejection  in  kidney  transplant   •   Prevent  generation  of  terminal  complement  complex  C5b-­9  
patients    
•   Adverse  reactions:   Table  9.  Summary  of  Sites  of  Action  of  Selective  Immunosuppressants  
o   GIT  disorders  (67%)   on  T-­cell  activation  
o   CMV  infections  (16%)   Drug   Site  of  Action  
Glucocorticoid  response  element  in  DNA  
•   Dose:     Glucocorticoids  
(regulate  gene  transcription)  
o   1  mg/kg  in  50  mL  0.9%  NSS  IV  for  15  min  given  24  hrs  
T-­cell  receptor  complex  (block  Ag  
before  transplant   Muromonab-­CD3  
recognition)  
o   Subsequent  doses  every  14  days,  for  5  doses   Cyclosporine/Tacrolimus   Calcinuerin  (inhibit  phosphatase  activity)    
  Azathioprine   DNA  (false  nucleotide  incorporation)  
B.   Baciliximab  (Simulect®)  U4   Inosine  monophosphate  dehydrogenase  
MMF  
•   75%  human,  25%  murine  protein  (mouse)   (inhibits  activity)  
•   used  more  than  Daclizumab   IL-­2  receptor  (block  IL-­2  mediated  T-­cell  
Diclizumab/Basilizumab  
•   prevents  T-­cell  proliferation   activation)  
•   Therapeautic  use:   Protein  kinase  involved  in  cell  cycle  
Sirolimus  
o   Prophylaxis  for  acute  organ  rejection   progression  (mTOR)  (inhibits  activity)  
o   De  novo  renal  transplantation   U Memorize  table.  
•   Adverse  reactions:    
o   Well-­tolerated   F.   Other  immunosuppressant:  Hydroxychloroquine  
o   Some  reports  of  hypersensitivity   •   Anti-­malarial  agent  
•   Dose:  40mg  given  in  2doses  (20mg  each)   •   Suppresses  intracellular  antigen  processing  and  loading  of  
o   1st  Dose:  20  mg  given  2  hrs  before  transplant   peptides  onto  MHC  class  II  molecules  by  increasing  the  pH  
o   2nd  Dose:  20  mg  given  4  days  after  transplantRitumixab   of  lysosomal  and  endosomal  compartments,  thereby  
•   Anti-­tumor  monoclonal  antibodies   decreasing  T-­cell  activation  
•   For  CD20  markerks  on  B  cell  (anti-­B  cell)   •   Indication  for  SLE:  U preventing  activation  of  flares  in  SLE  
•   Chimeric  mAb   patients.  
•   Mediates  cell  lysis  and  depletion    
•   Therapeutic  uses:   III.   IMMUNOSUPPRESSION  IN  RENAL  
o   Refractory  non-­Hodgkin’s  lymphome   TRANSPLANTATION  
o   Post-­transplant  lymphoproliferative  diseases  (PTLD)   Immunosuppression  in  Renal  Transplantation  
o   Treatment  &  prophylaxis  of  Ab-­mediated  rejection   U We   don’t   only   give   one   immunosuppressant   in   kidney  
o   Limited  evidence  for  kidney  transplant   transplantation.   We   usually   give   a   combination   and   the   usual  
  are  the  CnI,  Steroids,  and  Anti-­metabolites  (not  yet  discussed)  
C.   Alemtuzumab  (CAMPATH  1H)  U4   •   Cnl/Steroids/  Anti-­metabolites  (not  yet  discussed)  
•   Humanized   Mab   directed   against   CD52   receptor   on   T-­cells,   •   CsA/  MMF/  Steroids  
B-­cells,  monocytes,  macrophages,  and  NK  cells  >>  cell  lysis   •   TAC/  MMF/  Steroids  
and  long-­lasting  depletion   •   CsA/SRL/  Steroids  
•   Used   for   induction   of   immunosuppression   and   treatment   of   •   TAC  /SRL/  Steroids  
acute  rejection  in  renal  transplantation   o   90-­95%  1-­year  graft  survival  
•   NOT  for  maintenance  therapy   o   10-­20%  incidence  of  acute  rejection  
•   Reports  as  induction  in  adult  kidney  transplant   •   Antibodies  –  further  decrease  incidence  of  acute  rejection  
•   Anti-­tumor  monoclonal  antibodies    
•   For   CD52   receptor   on   T-­cells,   B   cells,   monocytes,  
macrophages,  and  NK  cells  

LE  2  TRANS  13   7 of 10
        2.14  IMMUNOPHARMACOLOGY    
 
B.   IMMUNE  CHECKPOINT  INHIBITOR  MAbs  
U    Indication:  Cancer  therapy  
 
Table  11.  Immune  Checkpoint  Inhibitor  Mabs  
 
MAbs   Target   Disease  
 
Ipilimumab   CTLA-­4   Metastatic  melanoma  
Nivolumab   PD-­1   Hodgkin’s  
Pembrolizumab   Lymphoma,  RCC,  
Atezolimumab   NSCLC,  melanoma,  
HIV  tumors,  Bladder  
Cancer  
Panitumab   IgG2  kappa  light   EGFR  expressing  
  chain  Mab         metastatic  colorectal  
Figure  10.    One  year  renal  graft  survival  with  different  
CA  
immunosuppressive  agents.  Note  the  advent  of  immunosuppressive  
Pertuzumab   IgG1  Mab   HER2/neu  +  breast  
agents.  There  is  a  decrease  in  the  incidence  of  acute  rejection  
CA  
 
Ofatumumab   IgG1  against   CLL  
 
CD20  
IV.   MONOCLONAL  ANTIBODIES  (MAbs)  
 
U DON’T  NEED  TO  KNOW  EVERYTHING,  DIFFERENT  MABS  
C.   MAbs  AND  FUSION  PROTEINS  (USED  AS  
ARE  USED  IN  DIFFERENT  SUBSPECIALTIES.  JUST  BE   IMMUNOMODULATORY  AND  ANTI-­INFLAMMATORY  AGENTS)  
FAMILIAR  WITH  THE  DRUGS!  (AKA  DON’T  STUDY  
U ACCORDING  TO  MA’AM,  NO  NEED  TO  MEMORIZE  
ANYMORE.  JOKE)  
    Indication:  Psoriasis,  Rheumatoid  arthritis  ,  SLE,  Crohn’s  
disease/Inflammatory  bowel  disease  
A.   ANTI-­TUMOR  Mabs  
 
&  KATZUNG   Table  12.  Mabs  and  Fusion  Proteins  (used  as  Immunomodulatory  and  
1.   Alemtuzumab   Anti-­inflammatory  Agents)  
2.   Bevacizumab   MAbs   Target   Disease  
3.   Cetximab    
4.   Ofatumumab   Adalimumab   TNF  a   Rheumatoid  arthritis  
5.   Panitumumab   Certolizumab   Psoriatic  arthritis  
6.   Rituximab   pegol   Ankylosing  spondylitis  
7.   Trastuzumab   Etanercept   Crohn’s  diseases  
8.   Eculizumab  (Recombinant  Humanized  Mab)     Golimumab   Ulcerative  colitis  
•   humanized   IgG   monoclonal   antibody   that   binds   the   infliximab  
C5   complement   component,   inhibiting   its   cleavage   Abatacept   CTLA-­4   RA  
into  C5a  and  C5b  thereby  inhibiting  the  terminal  pore-­   KT  
forming  lytic  activity  of  complement.  &   Anakinra   IL-­1   RA  
Rilonacept   IL-­1R1  
•   Approved   for   patients   with   paroxysmal   nocturnal  
Ixekizumab   IL-­17   Plaque  psoriasis  
hemoglobinuria   (PNH)   and   atypical   hemolytic   uremic  
Secukinumab  
syndrome  (aHUS).  
Brodalimab  
•   Reduces  the  need  for  red  blood  cell  transfusions.  &   Reslizumab   IL-­5   Severe  eosinophilic  
  Mepolizumab   asthma  
Table  10.  Anti-­Tumor  Mabs  4&   Siltuxomab   IL-­6   Casilieman’s  disease  
Drug   Description   Use   (HIV    )  
Tocilizumab   Humanized  IgG1    
Bevacizumab   Anti-­VEGF  (anti   Metastatic  CA   IL-­6  
vascular  endothelial   Basiliximab   CD25  (IL2  receptor   KT  
growth  factor)   a)  
Ranibizumab   VEGF-­A  antagonist   Age-­related  macular   Belimumab   B  cell  activating   SLE  
degeneration   factor  
Pegaptanib   RNA  aptamer   Macular   Canakinumab   IL-­1b   CAPS  (cryopyrin  
directed  against   degeneration   associated  periodic  
VEGF-­165   syndromes)  
Cetuximab   Anti  EGFR   Metastatic  wild  type   Natalizumab   Humanized  IgG1   MS  
Kras  colon  cancer   binds  to  a4  subunit   Crohn’s  disease  
Gemtuzumab   Anti  CD33;;   AML   of  a4  b1  of  
withdrawn  due  to   leucocytes  
deaths   Omalizumab   Anti-­IgE   Allergic  asthma  
Panitumumab   Anti  CD20   Lymphoma,    
leukemia,  transplant    
rejection,    
autoimmune    
disorders    
Trastuzumab   Anti-­HER-­2/neu   HER  2+  breast  CA    
   
   
   
   
   
   

LE  2  TRANS  13   8 of 10
        2.14  IMMUNOPHARMACOLOGY    
 
V.   OVERVIEW  OF  THE  MECHANISMS  OF   Peripheral  neuropathy,  constipation,  rash,  fatigue  
o  
PHARMACOLOGIC  IMMUNOSUPPRESION   Hypothyroidism  
o  
  Increased  risk  for  DVT  (deep  vein  thrombosis)  
o  
  IMids   (immunomodulatory   drugs)   analogue:   Lenalidomide,  
o  
Pomalidomide  
 
C.   Bacillus  Calmette-­Guerin  (BCG)  
•   Live  attenuated  culture  of  Mycobacterium  bovis      
•   Induces  a  granulomatous  reaction  at  site  of  administration  
•   Indications:  
o   CA  in  situ  of  urinary  bladder  
o   Prophylaxis   of   primary   and   recurrent   papillary   tumors  
after  transurethral  resection  
 
D.   Recombinant  Cytokines    
1.   Hematopoietic  growth  factors  
•   Erythropoietin  
o   Hormone   produced   by   the   kidneys   that  
stimulate  bone  marrow  for  RBC  production  
o   Therapeutic  use:  Iatrogenic  anemia  
•   G-­CSF,  GM-­CSF  
o   Glycoprotein   produced   by   recombinant   DNA  
technology  
o   Increase  WBCs  of  patient  with  cytopenia  due  to  
chemotherapy  
o   Therapeutic  use:  leukopenia  
•   U After  chemotherapy,  when  all  the  blood  cells  are  down  
and  low,  these  drugs  can  be  given  to  increase  the  count.  
   
Figure  11.  Sites  of  immunosuppressant  action  
  2.   Interferon  
1.   Nuclear  Region     •   Consists   of   recombinant   DNA   products   that   are  
o   Inhibition   of   gene   expression   to   mediate   available  for  IM,  SQ,  IV,  and  intralesional  route  
inflammatory  response.  MRNA  transcription   •   Biologic   activity:   Mimics   those   of   the   naturally  
o   U Corticosteroids   occurring   endogenous   molecules   that   are   produced  
2.   Clonal  expansion  of  cells     and  secreted  by  WBC  in  response  to  viral  infections  and  
o   Depletion  of  expanding  lymphocyte  population     for  immunologic  activation  
o   Hallmark  of  immune  response  4   •   Three  forms:  INF-­α2b,  INF-­β,  INF-­γ  
o   U Corticosteroids,  CnI   •   Adverse  effects:  
3.   CnI  (location  of  CnI  >>  orange  arrow)   o   Common:   (First   dose   effect)   fever,   transient  
a.   U  CnI   will  inactivate  NFAT.  Therefore,   forward   skin   rash,   flu-­like   symptoms,   bone   marrow  
action  in  nucleus  will  not  anymore  proceed.   suppression  
4.   Release  of  cytokines   o   Rare:   Urticaria,   angioedema,  
a.   Corticosteroids   bronchoconstriction,  anaphylaxis  
5.   Different  cell  surface  receptors   o   Neuropsychiatric   symptoms   and   depression  
a.   U MAbs     (30%)  
   
VI.  IMMUNOMODULATORS   Table  13.  Differences  between  IFN-­α-­2b  and  β-­1a  
•   It  boost  our  immune  systemU   IFN-­α-­2b   IFN-­β-­1a  
•   Agents   that   stimulate   hematopoietic   recovery   in   patients    
suffering  from  cytopenia  resulting  from  disease  of  therapy   •   Obtained  from  E.  coli  
•   Has  antiviral  and  
  •   Indications:  Chronic  
immunomodulatory  effect  
A.   Levamisole   Hepatitis  B  and  C,  Melanoma,  
•   Indication:  Multiple  Sclerosis  
Follicular  lymphoma  and  
•   Originally  synthesized  as  anti-­helminthic   Kaposi’s  sarcoma  
 
•   Restores   depressed   immune   function   of   B-­   lymphocytes,   T-­  
lymphocytes,  monocytes  and  macrophages    
•   Indication:  Colon  CA  Duke’s  Stage  C,  adjuvant  5-­FU   3.   Interleukin-­2  
  •   T-­cell  growth  factor  in  1976  
B.   Thalidomide   •   Stimulates  growth  of  T-­lymphocytes  from  normal  human  
•   Known  for  severe,  life  threatening  birth  defects   BM  
o   Banned  before,  for  use  as  an  abortifacient   •   Indications:  Metastatic  renal  cell  CA  
•   Inhibits   TNF-­α,   reduces   phagocytosis   by   neutrophils,   •   Adverse  effects:  
increases   production   of   IL-­10,   alters   adhesion   molecule   o   Hypotension  
expression  and  enhances  cell-­mediated  immunity   o   Major  organ  failure  
•   Indication:   o   Fatal  systemic  capillary  leak  
o   Erythema  Nodosum  leprosum   •   Others:  U GOOD  TO  KNOW  
o   Multiple  myeloma   o   Dimethyl  fumarate  (DMF)  –  flushing  
o   Rheumatoid  arthritis   o   Glatiramer  acetate  –  skin  hypersensitivity  
o   Lupus     o   Fingolimod  hydrochloride  (FH)  –  cardiac  toxicity  
•   Adverse  effects:   o   Approved   for   treatment   of   relapsing-­remitting  
o   Teratogenesis  (phocomelia)   multiple  sclerosis  

LE  2  TRANS  13   9 of 10
        2.14  IMMUNOPHARMACOLOGY    
 
  o   Respiratory  Syncitial  Virus  (RSV)  
4.   Therapeutic  antibodies   immuneglobulin  (IV)  
a.   Intravenous  Immunoglobulin  (IVIG)  (Polyclonal)    
•   Prepared   by   cold   ethanol   fractionation   of  
plasma  from  multiple  donors  (10,000  to  60,000  
donors)  followed  by  processes  that  remove  Ab  
aggregates   and   inactivate   potential   viral  
pathogens  
•   Supplied  as  5%  or  10%  Protein  solution  
•   95-­99%  of  IVIG  is  IgG  with  traces  of  IgA,  IgM  
•   MOA:    
o   Reduction  of  T-­helper  cells   Figure  12.  Balance  on  immunosupression  
o   Increase  of  regulatory  T  cells    
o   Decreased  spontaneous  IgG   Ex:  U Organ  Transplantation    
production   o   Reduced  immunosuppressant,  there  will  be  rejection.    
o   Fc  receptor  blockade   o   Increase  immunosuppressant  too  much,  then  infections  
o   Increased  Ab  catabolism   will  come  out.  
o   Idiotypic-­anti-­idiotypic   interaction   with   U  “BALANCED  IMMUNOSUPPRESSION  IS  THE  GOAL  TO  
pathologic  antibodies   ATTAIN  DESIRED  AFFECT  FREE  FROM  SIDE  EFFECTS!”  
•   Uses:    
o   U Useful   for   neurologic   symptoms,   TEST  YOUR  KNOWLEDGE  
even  in  immunodeficient  patients    
§   Encephalitis   1.   The  correct  immunosuppressant  and  intracellular  
§   Multiple  sclerosis   mediators/receptors  combination  is:    
o   U Immune   replacement   for   primary   A.   Cyclosporine:  Calcineurin  
immunodeficiency  diseases   B.   Sirolimus:  mTOR  
o   U Immunomodulation  for:   C.   Tacrolimus:  FKBP12  
§   Autoimmune   TTP   D.   Evermolimus:  Cyclophilin  
(thrombotic    
thrombocytopenic  purpura)   2.   Which  of  the  following  biologicals  is  correctly  matched  with  its  
§   Toxic  epidermal  necrolysis   target  antigen?  
§   Kawasaki  disease  to  prevent    
formation   of   cardiac   A.   Daclizumab  -­  CD  20  
aneurysm   B.   Rituximab  -­  CD  52  
§   HIV,  bone  marrow  transplant   C.   Alemtuzumab  -­  CD  25  
•   Adverse  effects:   D.   Eculizumab  -­  C5  
o   Infections    
o   Formation  of  immune  complexes   3.   The  attending  medical  doctor  of  Tara  decided  to  give  her  
o   Flushing   something  to  boost  her  immune  system  as  treatment  for  her  
o   Headache   hepatitis  B  infection.  Which  of  the  following  drugs  should  be  
o   Nausea  and  vomiting   given?  
o   Myalgias   A.   Rabbit  anti-­thymocyte  globulin  
o   Aseptic  meningitis  (rare)   B.   Interferon  
o   Pre-­treatment:   Aspirin,   C.   Mycophenolate  mofetil  
Acetaminophen,   Diphenhydramine,   D.   Prednisone  
Hydrocortisone   (U Given   in   order   to      
prevent  reactions  to  IVIG)   4.   A  25-­year  old  post  kidney  transplant  patient  on  follow-­up  
  presented  with  decreased  WBC  and  platelet  counts.  Which  of  
b.   Polyclonal  antibody  (directed  against  cells)   the  following  drugs  is  most  likely  causing  these?    
•   RhD  Immunoglobulin    
o   Human   IgG   globulin   solution   A.   Prednisone    
containing   an   enriched   fraction   of   Ab   B.   Mycophenolate  mofetil    
against  the  D  blood  group  Ag   C.   Tacrolimus    
o   Given   after   first   pregnancy   of   Rh   (-­)   D.   Cyclosporine  A  
mother   within   72   hours   of   birth   of   an    
Rh  (+)  baby   5.   Increased  susceptibility  to  infection  in  patients  on  prolonged  
  steroid  use  is  mainly  due  to  this  pharmacologic  effect:  
c.   Hyperimmune   globulins   (Polyclonal   and    
monoclonal)  for  infectious  disease   A.   Regulation  of  transcription  of  genes    
•   Specific   immuneglobulins   also   called   B.   Lysis  and  redistribution  of  induced  lymphocytes    
“hyperimmune  globulins”   C.   Poor  chemotaxis  of  neutrophils  and  macrophages  
•   Prepared   from   select   donors   who   have   high   D.    Inhibition  of  cytotoxic  T-­cell  activation  
titers   of   the   desired   Ab,   either   naturally    
acquired  or  simulated  through  immunization   REFERENCES  
 
•   Hyperimmune  globulins:  
1.   Lecture  Presentation    
o   Hep  B  immunoglobulin  
2.   Notes  
o   Rabies  immunoglobulin  
3.   2020  Trans  
o   Tetanus  immunoglobulin  
4.   Katzung  
o   Varicella  immunoglobulin  
 
o   Cytomegalovirus  (CMV)   Answers:  1)  C  2)D  3)B  4)B  5)C  (2020A  Anek)  
immuneglobulin  (IV)    
 
LE  2  TRANS  13   10 of 10