1.
 Immunomodulators are medications used to help,
regulate or normalize the immune system
 Immunomodulators or biological-response modifiers
include both immunostimulatory and
immunosuppressive agents

2.
 Glucocorticoids
 Calcineurin Inhibitors: Cyclosporine,Tacrolimus
 Proliferation signal inhibitors (PSIs): Sirolimus,
Everolimus,Temsirolimus, Zotarolimus
 Cytotoxic Agents:
 Alkylating agents: Cyclophosphamide, vinca alkaloids
 Antimetabolites: Azathioprine, methotrexate,
Mycophenolate mofetil, Leflunomide,Teriflunomide

3.
 Others: Hydroxychloroquine,Thalidomide
 IMiDs: Lenalidomide, Pomalidomide
 Sphingosine-1-Phosphate Receptor Modulators:
 Fingolimod, siponimod, ozanimod, and ponesimod.
 Immunosuppressive antibodies: Antilymphocyte &
Antithymocyte Antibodies
 Immune Globulin Intravenous (IGIV)- Hyperimmune
immunoglobulins

4.
 Inhibitors of Immune CellAdhesion & Activation
 Anti-LFA-1/LFA3 Mabs:
Efalizumab,Alefacept
 α-4 integrin inhibitor: Natalizumab
 Tolerogens or Inhibitors of Immune Cell
Costimulation:
 Anti-CD80 &Anti CD86 Mabs: Abatacept

5.
 CTLA-4 inhibitors: Ipilimumab
 PD-1 inhibitor: Nivolumab
 Miscellaneous: Rho (D) Immune Globulin
 Immunostimulants: Bacillus Calmette-Guerin
(BCG), Levamisole,Thalidomide
 Recombinant Cytokines

6.
 Lympholytic property- Glucocorticoids size
& lymphoid content of the LN & spleen
 Interfere with the cell cycle of activated
lymphoid cells (CMI is more affected than
humoral immunity)
 Use: Immunosuppressant & anti-
inflammatory agent majority of conditions

7.
 It is a peptide antibiotic - act at an early stage
in the antigen receptor induced differentiation
ofT-cells & blocks their activation
 It selectively suppress CMI
 It is free of toxic effects on bone marrow & RE
system

8.
 May be given IV or PO; bioavailability is low
 Metabolized in the liver by CYP3A4 & excreted
in bile
 Plasma t1/2 is biphasic 4-6 hr & 12-18 hr
 Interactions:All nephrotoxic drugs enhance the
toxicity
 Failure of immunosuppression with inducers
 Hyperkalemia with potassium supplements

9.
 Standard drug for the transplantation of
kidney, pancreas, liver, & cardiac
transplantation
 Cyclosporine+ methotrexate- prophylactic
regimen in prevention of GVHD after
allogeneic stem cell transplantation

10.
 Autoimmune disorders, including uveitis, RA,
psoriasis & asthma
 Ophthalmic solution- Severe dry eye syndrome &
ocular GVHD
 A/E: Nephrotoxicity, 7 H, altered mental status,
seizures, OI’s
 Lymphoma & some cancers

11.
Hypertension
Hyperglycemia
Hepatic dysfunction
Hyperuricemia
Hyperkalemia
Hirsutism
Hyperplasia of gums

12.
 Macrolide antibiotic produced by Streptomyces
tsukubaensis
 On a weight basis it is 10-100 times more
potent than cyclosporine in inhibiting immune
responses
 It has same M.O.A instead of cyclophilin it
binds to FKBP-12 inhibit calcineurin

13.
 It is valuable in liver transplantation because
its absorption is not dependent on bile
 It is considered as standard prophylactic
agent ( with mtx or MMF ) in GVHD
 It is also suitable for suppressing acute
rejection that has set in

14.
Rejection type Hyperacute Acute Chronic
Mechanism Preformed recipient
antibodies react with
donor antigen &
activate complement
Cellular- Donor
antigen activates
recipientT cells
Humoral: Recipient
generates antibody
response to donor
antigen
Both humoral &
cellular in nature--
Chronic inflammation
caused by the
response of activated
T cells to donor
Antigen)
Time course Minutes to hours Weeks to months Months to years
Mode of damage Antibody-
dependent, cell-
mediated
cytotoxicity or
through activation of
the complement
cascade
CytotoxicT cell
mediated interstitial
& vascular damage
H- Antibody
directed against
endothelial cells
(Acute vascular
rejection)
ActivatedT cells
release cytokines i.e.
recruit macrophages
into the graft (chronic
inflammation i.e.
leads to intimal
proliferation of the
vasculature & scarring
of the graft tissue).
How suppressed Matching donor &
recipient blood types
Immunosuppression Cannot be suppressed
(Major cause of graft
loss)

15.
Cyclosporine acts by
decreasing the production of:
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16.
 GVHD is a major complication of allogeneic
bone marrow or stem cell transplantation
 Occurs when transplanted immune cells attack
the cells of the recipient.
 GVHD ranges from mild to life-threatening
 Ameliorated by removingT cells from the donor
bone marrow before transplantation

17.
 Other uses: FistulatingCrohn’s disease,
 Topically:Atopic dermatitis & Psoriasis
 Hypertension, hirsutism, gum hyperplasia &
hyperuricemia are less marked than CSA
 Tacrolimus is more likely to precipitate
diabetes, cause neurotoxicity, alopecia &
diarrhea. Dose-limiting toxicity is renal

18.
 Sirolimus binds the circulating immunophilin
FK506-binding protein 12 → an active
complex i.e. inhibits the kinase activity of
mTOR (mammalian target of rapamycin)
 Blockade of mTOR – inhibition of interleukin
drivenT-cell proliferation
 t1/2 of sirolimus is- 60 hrs & i.e. of everolimus
is 43 hrs

19.
 To prevent rejection of solid organ allografts
 Prophylaxis & as therapy for steroid-refractory
acute & chronic GVHD in hematopoietic stem
cell transplant recipients
 Sirolimus eluting coronary stents
 Topically –in dermatological disorders & in
combination with cyclosporine in uveoretinitis

20.
 Prophylaxis of liver & kidney transplant
rejection
 Others: Cardiac stents
 Advanced renal cell cancer, hormone receptor-
positive Her-2 negative advanced breast cancer
 Pancreatic neuroendocrine tumours

21.
 Myelosuppression (esp. thrombocytopenia)
 Hepatotoxicity, diarrhea, headache,
hypertriglyceridemia & pneumonitis
 ↑ use in stem cell transplantation regimens
with tacrolimus has revealed an ↑ incidence
of HUS

22.
 Azathioprine : is a prodrug that is converted
first to 6-mercaptopurine (6-MP) & then to the
corresponding nucleotide, thioinosinic acid
 They inhibit de novo purine synthesis & cause
damage to DNA
 Cellular immunity as well as primary &
secondary serum antibody responses can be
blocked

23.
 Azathioprine is well absorbed PO & is
metabolized primarily 6-MP, XO splits much
of the active material to 6-thiouric acid
 Much of the drug’s inactivation depends on
XO , patients who are also receiving
allopurinol for control of hyperuricemia
should have azathioprine dose-↓ ½ to 1/3

24.
 Uses: Maintaining renal allografts
 Management of acute glomerulonephritis & in
the renal component of SLE
 RA, Crohn’s disease & MS
 Prednisone-resistant antibody-mediated ITP &
AIHA
 A/E: BM suppression, skin rash, fever, nausea,
vomiting, diarrhoea & hepatic dysfunction

25.
 Inhibiting DHFRase & thymidylate synthase
 It markedly depresses cytokine production &
cellular immunity & has anti-inflammatory
property
 Uses: Autoimmune diseases like rapidly
progressive RA, MG, psoriasis, uveitis etc.

26.
 Semisynthetic derivative of mycophenolic
acid, isolated from - mold Penicillium glaucus
 M.O.A: MPA, a selective, noncompetitive,
reversible inhibitor of inosine monophosphate
dehydrogenase (IMPDH) an important
enzyme in the de novo pathway of guanine
nucleotide synthesis

27.
 MMF undergoes rapid & complete metabolism
to MPA after PO or IV administration
 The t1/2 of MPA is ~16 hours
 Uses: For prophylaxis of transplant rejection, in
combination with glucocorticoids & a
calcineurin inhibitor
 Prophylaxis & Rx of both acute & chronic GVHD
in hematopoietic stem cell transplant patients

28.
 Prevention of chronic allograft vasculopathy in
cardiac transplant recipients
 New applications: Lupus nephritis, RA, IBD, &
some dermatological disorders
 A/E: GI disturbances, headache, hypertension
 Reversible myelosuppression (Neutropenia)
 Predisposition for infections, esp.CMV

29.
 Leflunomide: It is a prodrug of teriflunomide
 Dihydroorotate dehydrogenase

30.
 It inhibitsTNF-α, reduces phagocytosis by
neutrophils, ↑ production of IL-10, alters
adhesion molecule expression & ↑ CMI
 Uses: Multiple myeloma- at initial diagnosis or
relapsed-refractory disease with dexamethasone
 GVHD, ENL, Skin manifestations of SLE

31.
 A/E: Peripheral neuropathy, constipation, rash,
fatigue, hypothyroidism, & ↑ risk of DVT
 Immunomodulatory derivatives of thalidomide
(IMiD’s):
 Lenalidomide- MDS with 5q deletion, primary
and relapse/refractory myeloma
 Pomalidomide- Relapse or refractory MM

32.
 Polyclonal: IGIV, Rho(D) Immune globulin
micro-dose, hyperimmune immunoglobulins
 Monoclonal antibodies:
 Muromonab-CD3: It is murine MAB against CD
3 glycoprotein expressed near to theTCR on
helperT cells
 It obstructs approach of the MHCII-antigen
complex to theT-cell receptor

33.
 Acute renal allograft rejection & steroid
resistant acute cardiac & hepatic transplant
rejection
 A/E: Initial doses are associated with cytokine
release syndrome with flu like symptoms
 Occasionally aseptic meningitis, intragraft
thrombosis, pulmonary edema, seizures &
shock like state is produced
 Rx- High dose corticosteroid pretreatment