Vaccines Modulates [Ab] Cancer treatment Overcoming immunosuppressed states

_Used for:_ Transplantation Autoimmune diseases Allergies

_Used in combo w/ other immunosuppressants for:_ Solid organ transplantation Hematopoietic stem cell transplantation Certain autoimmune diseases RA SLE Attenuate allergic reactions

Cytotoxic agent Folate derivative ⊗ several enzymes responsible for nucleotide synthesis Used for immunosuppresion but not transplantation RA Psoriasis

Cytotoxic agent Alkylates DNA and RNA ⇒ cross-linking of strands ⊗ Protein synthesis Used for immunosuppression but not transplantation Cancers SLE

Exam 2: Immunopharmacology Flashcards by Quynh Tran

Immunopharmacological agents act to…

mobilize and/or modify the immune system

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Immune Mobilization

Vaccines
- Modulates [Ab]
Cancer treatment
Overcoming immunosuppressed states

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Immune Suppression

Used for:

Transplantation
Autoimmune diseases
Allergies

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Immunopharmacologic

Targets

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Glucocorticoid

Actions

Functions by inhibiting gene expression.

Immunosuppressive
- ⊗ activation of innate and adaptive immune cells
  - T-cells more affected
  - ↓ 1° Ab responses
  - ↓ 2° Ab responses w/ prolonged use
Anti-inflammatory
- ⊗ Expression of inflammatory mediators
  - TNF & interleukins
- ⊗ Phospholipase A₂
  - ↓ Eicosanoid production

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Glucocorticoid

Adverse Effects

Adrenal suppression ⇒ taper therapy to avoid adrenal crisis
Cushingoid reactions ⇒ having the constellation of signs and symptoms caused by excess cortisol
Mood swings
Diabetes
↓ resistance to infections
Osteoporosis
Cataracts
Weight gain
HTN

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Prednisone

Used in combo w/ other immunosuppressants for:

Solid organ transplantation
Hematopoietic stem cell transplantation
Certain autoimmune diseases
- RA
- SLE
Attenuate allergic reactions

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Azathioprine ⇒ Mercaptopurine

Actions

Cytotoxic agent

Azathioprine (pro-drug) ⇒ Mercaptopurine (anti-metabolite)
- Converted non-enzymatically in tissues by rxn with sulfhydryls
- Slow release favors immunosuppressive activity
Mercaptopurine interfers with purine nucleic acid synthesis
- Required for lymphoid cell proliferation
Uses:
- Kidney transplantation
- Autoimmune diseases

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Azathioprine ⇒ Mercaptopurine

Adverse Effects

Low doses
- Bone marrow suppression
  - Leukopenia
- Rash
High doses
- GI disturbances
- Hepatotoxicity

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Azathioprine/Mercaptopurine interacts with…

Allopurinol

(Xanthine oxidase inhibitor)

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Mycophenolate mofetil (MMF)

Actions

“Mycophenolic acid”

Cytotoxic agent

Inhibits inosine monophosphate dehydrogenase II (IMPDHII)
- Isoform expressed in lymphocytes
  - Less toxic to other cells
- Rate limiting step in guanosine synthesis
  - Blocks de novo purine synthesis
Cytostatic and can cause apoptosis in lymphocytes
Uses:
- Kidney transplant
  - More effect than Azathioprine in preventing rejection
  - Prevents chronic rejection in animal models
- Autoimmune diseases

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Mycophenolate mofetil (MMF)

Adverse Effects

GI disturbances
Headache
HTN

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Methotrexate

Cytotoxic agent

Folate derivative
⊗ several enzymes responsible for nucleotide synthesis
Used for immunosuppresion but not transplantation
- RA
- Psoriasis

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Cyclophosphamide

Cytotoxic agent

Alkylates DNA and RNA ⇒ cross-linking of strands
- ⊗ Protein synthesis
Used for immunosuppression but not transplantation
- Cancers
- SLE

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Cyclosporine (Cyclosporin A)

Actions

Inhibition of lymphocyte signaling

Decapeptide that binds cyclophilic
Complex inhibits Calcineurin
- Ca²⁺/calmodulin-dependent protein phosphatase
- Normally dephosphorylates cytoplasmic transcription factors that controls IL-2 gene
Highly selective action in inhibiting activation of T cells
- Esp. T_h cells
Uses:
- Organ transplantation
  - Renal, heart, liver, bone marrow, lung, pancreas
  - Proactively & graft-vs-host reactions
- Psoriasis
- RA
- Rare autoimmune diseases refractive to other treatments
Often used in combo with other immunosuppressants ⇒ ↓ effective dose & ↓ adverse effects
- Corticosteroids
- Rapamycin

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Cyclosporine

Adverse Effects

Nephrotoxicity
- Dose-related
- Caused by vasoconstriction
- Important to monitor drug levels & creatinine clearance
Neurotoxicity
- Paresthesia, tremor, seizures
Hepatotoxicity
HTN
HLD

Cyclosporine

Metabolism

Metabolized by cytochrome p450

Interpatient variability in response
Potential for drug interactions

Tacrolimus (FK506)

Actions

Inhibition of lymphocyte signaling

Macrolide abx with immunosuppressive properties
Similar to cyclosporine but 10-100x more potent
Binds to FK-binding proteins (FKBP)
Complex:
- Inhibits calcineurin
- Inhibits IL-3, IL-4, IFN-γ, and TNF-α
Uses:
- 2nd line med after standard therapy fails
  - Organ transplants
  - Autoimmune diseases
- Standard prophylactic agent used in combo for graft-vs-host
- Topical prep available
  - Atopic dermatitis
  - Psoriasis

Tacrolimus (FK506)

Adverse Effects

Similar to cyclosporin but more severe.

Higher potency and solubility.

Nephrotoxicity
Neurotoxicity
Hepatotoxicity
HTN
HLD

Sirolimus (Rapamycin)

Actions

Inhibition of lymphocyte signaling.

Macrolide abx w/ immunosuppresive activity
Binds to FK-binding proteins (FKBP)
Mechanism:
- Inhibits molecular target of rapamycin (mTOR)
  - mTOR normally phosphorylates
    - p70 S6 kinase
      - Involved in protein synthesis
    - PHAS-1
      - ℗ results in release of initiation factor involved in translation
- Results in inhibition of IL-2 stimulated protein synthesis
- Arrests lymphocytes in G1 phase
Used alone or in combo with other immunosuppressants for solid organ transplant
Sirolimus-eluting stents
- Inhibits proliferation of smooth muscle cells

Sirolimus (Rapamycin)

Adverse Effects

HLD
Leukopenia
Thrombocytopenia
Hepatotoxicity
NOT nephrotoxic alone
- Cyclosporine + sirolimus ⇒ more impaired renal function
  - Likely d/t pharmacokinetic interaction where sirolimus ↑ [cyclosporine]
- Sirolimus + glucocorticoids + mycophenolate used instead for pts with or high risk for calcineurin inhibitor associated nephrotoxicity

Sirolimus (Rapamycin) is metabolized by…

cytochrome p450

Potential for drug interactions.

OKT3

Actions

“Muromonab-CD3”

Selective depletion of T cells

Monoclonal Ab against CD3 on T-cells
- Mouse Ab so body can make Ab against it
Depletes T cells through Ab activation of complement
Uses:
- Preparation for transplant
- Prevent acute rejection
  - Renal, liver, heart
- Suppresses T-cell mediated responses against transplants
- Deplete T-cells from donor bone marrow prior to transplant

OKT3

Adverse Effects

Profound but transient immunosuppression
Can sometimes activate T cells ⇒ Cytokine release syndrome
- Occurs if T cells release cytokines before being eliminated
- Usually occurs after first few doses
- See fever, myalgia, nausea, diarrhea

**ATG** (Anti-thymocyte Ab) or **ALG** (Anti-lymphocyte Ab)

**Selective Depletion of T cells** * **Polyclonal Ab against whole human lymphocytes** * Made by injecting rabbits or larger animals * **Targets many epitopes** * **Act on long-lived peripheral lymphocytes** * Little effect on B cells * **Similar uses to OKT3** * Preparation for transplantation * Acute rejection * Preparing donor bone marrow * Similar side effects to OKT3 but much broader immunosuppresion b/c polyclonal

Anti-CD25 mAb | (Daclizumab)

Selective depletion of T-cells * **Humanized Ab against CD25** ⇒ α-subunit of IL-2 receptor * Only expressed on activated T-cells * **Used for induction** * **Used in combo to prevent rejection**

Organ Transplantation Treatment Summary

Host vs graft reactions: 1. **Preparation (induction)** ⇒ several days - 1 week before * _Immunosuppressive regimen_ * **Daclizumab, ATG, or anti-CD3** 2. **Hyperacute rejection** ⇒ mins - hours * Cannot be stopped by immunosuppressive drugs 3. **Acute rejection** ⇒ weeks to months * Generally treated with _combo of immunosuppressive drugs_ * **Calcineurin inhibitor** ⇒ cyclosporine or tacrolimus * **Cell cycle inhibitor** ⇒ Mycophenolate mofetil or sirolimus * **± Steroids** 4. **Chronic rejection** ⇒ months - years * Cannot be stopped by immunosuppressive drugs

Graft vs Host Disease

**Major complication of bone marrow and stem cell transplantation** * Transplanted immune cells attack host cells * **Start w/ high dose steroids** * Add drugs: * **Cytotoxic agents** * Mycophenolate mofetil * **Inhibition of lymphocyte signaling** * Tacrolimus * Daclizumab * **Inhibit cell cycle** * Sirolimus

**Immune checkpoint signals** used to...

inhibit the immune response

Checkpoint Inhibitors

* **Block immune checkpoint signals** * **Facilitates ability of immune system to attack tumors** * Consists of: * CTLA-4 blockade * PD-1 blockade

CTLA-4 Blockade

* **Cytotoxic T-lymphocyte associated antigen 4 (CTLA-4)** * Expressed on surface of activated T-cells * Competes with CD28 for binding of B7 on APC * Prevents co-stimulation of T cells * **Modulatory mechanism where CTLA-4 attenuates activation of the T-cell** * Block CTLA-4 wiith **Ipilimumab** * T-cell remains active * Enhances immune response to cancer * ↑ immune response ⇒ immune-related adverse events common

PD-1 Blockade

* **T-cells express programed cell death protein (PD-1)** * Probes cells for PD-L1 * **Cells with PD-L1 avoids attack** * e.g. human cells * Some cancers express PD-L1 * **Nivolumab** and **Pembrolizumab** * **Humanized monoclonal Ab against PD-1** * Block interaction with PD-L1 * Inhibits the inhibition of T-cell proliferation and cytokine production * **Anti-tumor immune response allowed to proceed** * Recommended for **unresectable or metastatic melanoma** that _has not responded to ipilimumab/other first line treatments_ * PD-1 blockade more focused @ level of the tumor * **More favorable adverse effect profile**

Immunoglobulin Preparations

* IV-IG * Rho Immunoglobulin * Hyperimmune immunoglobulin

Immune Globulin Intravenous | (IV-IG)

* Preparation of **immunoglobulin** pooled from _large population of donors_ ⇒ normalized serum * Used @ _low doses_ in **humoral deficiency** * Used @ _high doses_ * Severe asthma * Some autoimmune disorders * Kawasaki syndrome

Rho Immunoglobulin | (Rhogam)

* **Human IgG against Rho(D) Ag of RBC** * Prevents sensitization of Rh^⊖mother * Administered to mother within 24-72 hours after birth of Rh^⊕ infant

Hyperimmune Immunoglobulin

* Made from pools of selected human or animal donors w/ **high titer to particular Ag** * Ex. cytomegalovirus or respiratory syncytial virus