``` Prodrug Converted to 6-MP by HGPRT Inhibits de novo purine synthesis Incorporated into DNA & causes SSB base mispairing  apoptosis Inhibits CD28 co-stimulation ```

Lecture #2 - Immunomodulation Flashcards by M G

Glucocorticoids

MOA

Immunosuppression
To Prevent graft rejection
To prevent GvHD
Treatment of  Cytokine-
      release Syndrome
Treatment of a wide variety 
      of autoimmune and inflammatory
     diseases e.g. RA, SLE, asthma etc

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Glucocorticoids

Many Adverse effects
Hyperglycemia
Hypertension
Hyperlipidemia
Obesity
Diabetes
Poor wound healing
Mania &amp; Psychosis
increased Risk infections

Glucocorticoid dose should be
gradually educed to minimize
adverse effects

Glucocorticoids should not
be withdrawn abruptly

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Glucocorticoids (prednisone/prednisolone)

Clinical Uses

Immunosuppression
To Prevent graft rejection
To prevent GvHD
Treatment of  Cytokine- release Syndrome
Treatment of a wide variety of autoimmune and inflammatory diseases e.g. RA, SLE, asthma etc

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Azathioprine

MOA

Prodrug
Converted to 6-MP by HGPRT
Inhibits de novo purine synthesis
Incorporated into DNA &amp; causes SSB
     base mispairing  apoptosis
Inhibits CD28 co-stimulation

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Azathioprine

Adverse

Leukopenia/thrombocytopenia
Hepatotoxicity
increased Risk infections
increased Risk malignancy

Interacts with anti-gout drugs
Allopurinol & Febuxostat
Leading to increased [Azathioprine] increased toxicity

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Azathioprine

interactions?

Interacts with anti-gout drugs
Allopurinol & Febuxostat
Leading to increased [Azathioprine] increased toxicity

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Azathoprine

Clinical use

Immunosuppression
To Prevent graft rejection
To prevent GvHD
Treatment of autoimmune 
      diseases

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Mycophenolate
Mofetil

MOA

Prodrug
Converted to mycophenolic acid
Inhibits inosine monophosphate
dehydrogenase II (IMPDH2
- selectively expressed in lymphocytes)
- Inhibition of purine nucleotide synthesis
- no salvage pathway in lymphocytes

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Mycophenolate
Mofetil

Adverse

Leukopenia/anemia
Teratogenic (Male/Female)
increased Risk infections
increased Risk malignancy
RARE- Risk of Progressive multifocal 
        leukoencepalopathy (PML)
- Fatal viral disease caused by 
	   reactivation of JC virus

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Mycophenolate
Mofetil

clinical use
contraindications?

Immunosuppression
To Prevent graft rejection
To prevent GvHD
Treatment of autoimmune 
      diseases

Contraindicated in pregnancy,
Women who wish to become
pregnant, and men who wish
to become fathers

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What are the 2 calcineurin inhibitors?

Cyclosporine

Tacrolimus

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Cyclosporine
Tacrolimus

drug class

MOA

calcineurin inhibitors

Cyclosporin and tacrolimus bind
cyclophilin and FKBP, respectively to form inhibitory complexes
Cyclophilin/cyclosporin and
FKBP/tacrolimis complexes inhibit the calcium-regulated phosphatase, calcineurin

Inhibition of calcineurin inhibits the activation of the NFAT transcription factor, which is involved in regulating the expression of IL-2 and multiple other immunoregulatory genes
Potently inhibit the T cell immune response by inhibiting Signal 1

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What are the 2 main Adverse effects of Cyclosporine & tacrolimus

some others?

Nephrotoxicity****
Hypertension***

Neurotoxicity/Tremor
Glucose intolerance (T>C)
Hyperlipidemia (C>T)
Hypertrichosis (C)
Alopecia (T)
increased Risk infections
increased Risk malignancy

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Cyclosporine
Tacrolimus

metabolized by what?

How do inducers and inhibitors effect them?

Metabolized by CYP3A4
Many drug interactions
3A4 inhibitors promote 
-increased drug levels 
INCREASED risk of toxicity

3A4 inducers promote
DECREASED Drug levels
INCREASED risk graft rejection

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Cyclosporine
Tacrolimus

clinical use

Immunosuppression
To prevent graft rejection
To prevent GvHD
Treatment of autoimmune 
        diseases

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What are the 2 mTOR inhibitors?

mTor Inhibitors

Sirolimus
Everolimus

Immunosuppression
To prevent graft rejection
           - NOT LUNG
           - NOT LIVER
To prevent GvHD
Included in arterial stents to
       inhibit restenosis

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what 2 drugs cannot be used for lung or liver graft rejection?

sirolimus, everolimus

MOA

Drugs form complex with FBKP
FKBP/drug complexs inhibits
IL-2 mediated activation of mTor kinase
(T cell signal 2)
Inhibits IL-2 stimulated protein synthesis,
Cell proliferation and survival

sirolimus, everolimus

adverse effects

Hypertriglyceridemia
Hypercholesterolemia
increased Lung disease
increased Risk of diabetes
Anemia, thrombocytopenia, 
       &amp; leukopenia
DEcreased Wound healing
Teratogenic
increased Risk infections
increased Risk malignancy

sirolimus, everolimus

contraindications? MAIN?

Metabolized by CYP3A4
Many drug interactions

Contraindicated in:
     - Pregnancy
NOT RECOMMENDED
     - Lung transplantation
       (risk anastomotic dehiscence)
     - Liver transplantation
       (risk hepatic artery thrombosis)

What drugs are contraindicated in pregnancy?

sirolimus
everolimus
Mycophenolate
Mofetil
methotrexate
cyclophasphomide
Chlorambucil

Rabbit
anti-thymocyte
globulin

MOA

ADVERSE (2 main!)

Rabbit polyclonal antibodies specific
For human lymphocytes
Depletes lymphocytes from blood

Cytokine release syndrome
Leukopenia

Alemtuzamab

MOA

adverse (3 MAIN)

Binds to CD52 expressed on T cells, B cells, macrophages,
NK cells & granulocytes
Depletes cells from blood by
Ab-mediated lysis

Cytokine release syndrome
Leukopenia
Can take > 1 yr for immune system to recover

What 2 drugs can cause cytokine release syndrome

Alemtuzamab

Rabbit
anti-thymocyte
globulin

IVIG Clinical MOA

1. Prevention of hemolytic disease of the newborn in inewborns born To Rh- females 2. Purified Ig to Rh (D) antigen Given to Rh- mother at 28 weeks & 72 hr post pregnancy to deplete any fetal RBC in maternal blood to prevent the mother from generating an immune response to fetal RBC

Hyperimmune Ig Clinical MOA

1.To provide rapid specific antibody immunity to specific viruses and/or toxins 2.Purified Ig to specific antigens purified from healthy volunteers Given IV to patient in order to promote clearance of virus/toxin

Ipilimumab CLinical MOA ADVERSE

1.Treatment of late stage melanoma 2. Antibody specific for CTLA4 Antagonizes the negative regulatory CTLA4 protein responsible for downregulating activated T cells Enhances T cell responses 3. Potential for RARE autoimmune response (can be fatal)

Pembrolizumab/Nivolumab Clinical MOA

1.Treatment of late stage melanoma 2. Antibody specific for the PD1 protein, which is a negative regulatory receptor expressed on activated T cells that is responsible for downregulating T cell responses The PD1 ligand PD-L1 is expressed on tumor cells- this is a mechanism for tumor cells to avoid the immune response Antibody drugs block PD1/PD1-L1 interactions blocking the inhibitory signal and leading to enhanced tumor immune responses

Methotrexate Clinical MOA

1. Treatment of autoimmune disease - especially Rheumatoid arthritis 2.Inhibition of dihydrofolate reductase to inhibit lymphocyte proliferation Indirect mechanism of immunosuppression

Methotrexate adverse

``` Renal toxicity Hepatic toxicity GI toxicity Lung disease BM suppression Neurotoxicity teratogenic ``` **Contraindicated in pregnancy

Cyclophosphamide Clinical MOA

1.To Prevent graft rejection To prevent GvHD Treatment of severe cases of autoimmune disease 2. Alkylation chemotherapeutic agent Crosslinks DNA, RNA & proteins Inhibits cell proliferation Promotes apoptosis

Cyclophosphamide adverse

``` BM suppression GI toxicity increased Risk infections increased Risk malignancy Teratogenic (Male/Female) ``` Contraindicated in pregnancy, Women who wish to become pregnant, and men who wish to become fathers

Chlorambucil MOA Clinical

1. Alkylation chemotherapeutic agent Crosslinks DNA, RNA & proteins Inhibits cell proliferation Promotes apoptosis 2.Sometimes used in the treatment of severe autoimmune diseases

Chlorambucil adverse contrindication

``` BM suppression GI toxicity increased Risk infections increased Risk malignancy Teratogenic (Male/Female) ```

Fingolimod Clinical MOA

Treatment of Relapsing-Remitting Multiple sclerosis Sphingosine analog Binds to S1P receptor to promote sequestration of lymphocytes in the lymph node, thereby preventing lymphocyte entry to CNS

What are the 4 drugs used in the tx of MS?

1. fingolimod 2. natalizumab 3. interferon beta 4. glatiramer acetate

fingolimod adverse effects (2 serious, 2 others)

Bradyarrhythmia Atrioventricular block increased Risk VZV infection (potentially fatal) increased Risk malignancy

Natalizumab MOA CLINICAL

1. Binds alpha4 integrin adhesion molecule Prevents entry of lymphocytes into the CNS 2.Treatment of Relapsing-Remitting Multiple sclerosis

Natalizumab ADVERSE

INCREASED risk of PML- especially if: - prior use of immunosuppression - seropositive for JC virus - chronic treatment

Interferon Beta MOA CLINICAL

``` 1. Activates IFN beta receptors Alters expression of pro-inflammatory gene expression Inhibits entry of inflammatory cells into CNS ``` 2.Treatment of Relapsing-Remitting Multiple sclerosis

Glatiramer Acetate MOA Clinical

1. Polymer of 4 amino acids found in MBP Production of specific suppressor T cells that suppress inflammation in the CNS 2.Treatment of Relapsing-Remitting Multiple sclerosis