corticosteroids

MOA

• mimics endogenous glucocorticoid hormones by binding to intracellular glucocorticoid receptors and altering gene transcription and ultimately protein synthesis.

• this turns OFF the production and release of cytokines (IL-1, TNF-alpha, etc), COX, and phospholipase A2, and decreases the expression of adhesion molecules.

corticosteroids

physiologic effects

1. block inflammation
2. reduce leukocyte migration
3. reduce macrophage activation
4. inhibit APC function
5. inhibit T cell proliferation and activation
6. indirectly inhibit B cell proliferation and activation

corticosteroids

therapeutic applications

1. inflammation/inflammatory disorders
2. allergies
3. autoimmune dz
4. prevention of transplant rejection

corticosteroids

adverse effects

1. pt. may become immunocompromised
2. bone loss
3. diabetes
4. weight gain
5. skin/eye effects
6. in general, Cushing's yndrome-like symptoms

cytotoxic and antiproliferative drugs

general MOA

azathioprine

Class and MOA

• a cytotoxic/anti-proliferative drug

• inhibits the enzyme required for synthesis of purine bases (adenine and guanine)

methotrexate

Class and MOA

• a cytotoxic/anti-proliferative drug

• inhibits the enzyme required for synthesis of thymidine and purine bases

mycophenolate mofetil

Class and MOA

• a cytotoxic/anti-proliferative drug

• inhibits the de novo (new, as opposed to recycled through the salvage pathway) synthesis of guanine bases

• lymphocytes are more dependent on de novo synthesis than other types of cells, so this drug is slightly more specific for lymphocytes than other drugs

cyclosphosphamide

Class and MOA

• a cytotoxic/anti-proliferative drug

• alkylating agent (when it comes into contact with cell macromolecules, it reacts with them and essentially add itself onto the macromolecule)
• DNA becomes cross-linked
• prevents cells from dividing
• prevents gene transcription

chlorambucil

Class and MOA

• a cytotoxic/anti-proliferative drug

• alkylating agent (when it comes into contact with cell macromolecules, it reacts with them and essentially add itself onto the macromolecule)
• DNA becomes cross-linked
• prevents cells from dividing
• prevents gene transcription

cytotoxic/anti-proliferative drug

physiologic effects

cytotoxic/anti-proliferative drug

therapeutic applications

1. autoimmune dz
2. severe inflammatory conditions
3. prevent organ transplant rejection
4. (chemotherapy, at higher doses than for immune suppression)

cytotoxic/anti-proliferative drug

adverse effects

1. pt is immunocompromised
2. kills other rapidly-dividing cells
1. bone marrow/HSC leading to anemia, thrombocytopenia, and leukocytopenia
3. can cause cancer through cell damage and subsequent mutation

cytostatic drugs

MOA

• do not kill cells, just holds them in stasis
• primarily target T cells
• to block
• proliferation
• development of effector function (blocks differentiation into TH and CTL)
• by
• binding “immunophilins” (cyclophilin and FKBP) - don’t worry about what these really are
• interfering with intracellular signaling cascades

cytostatic drugs

AKA

1. calicneurin inhibitors
2. MTOR inhibitors
3. immunophilin ligands
4. T cell inhibitors
5. proliferation signal inhibitors

cyclosporine A

MOA

1. CSA binds immunophilin cyclophilin
2. CSA-cyclophilin complex binds calcineurin
3. Ca2+ cannot bind to calcineurin
4. NFAT is not activated
5. DNA is not transcribed
6. IL-2 is not synthesized
7. T-cell is not activated

1. MHC-Ag complex on APC stimulates T cell receptors
2. This causes an increase in intracellular Ca2+
3. Ca2+ binds and activates calcineurin
4. Calcineurin activates a transcription factor called NFAT (nuclear factor of activated T cell)
5. NFAT travels to the nucleus where it binds to DNA and changes gene transcription
6. IL-2 is turned on/transcribed by the action of NFAT

cyclosporine A

Effects

1. T cell never makes IL-2 and are therefore never activated
2. other cytokines, proteins, and immune cells are missing or nonfunctional
3. macrophage and B cell function is indirectly inhibited, since T cells aren't working

• wide range of possible applications for this drug

tacrolimus

MOA

1. tacrolimus binds immunophilin FKBP
2. tacrolimus-FKBP complex binds calcineurin
3. Ca2+ cannot bind to calcineurin
4. NFAT is not activated
5. DNA is not transcribed
6. IL-2 is not synthesized
7. T cells are never activated

sirolimus (Rapamycin)

MOA

1. sirolimus binds to FKBP
2. inhibits MTOR (mammalian target of Rapamycin)
3. since MTOR is incapacitated, signal generated by IL-2 at the IL-2 receptor is blocked

sirolimus (Rapamycin)

Effects

1. T cells cannot proliferate
2. binding of MTOR also inhibits
1. B cells
2. other immune cells

• NOTE: MTOR is often inappropriately activated in some cancers

calicneurin and MTOR inhibitors

Therapeutic Uses

1. prevent graft rejection
2. severe autoimmune Dz
3. asthma
4. arthritis
5. skin Dz
6. etc.

calicneurin and MTOR inhibitors

Benefits

1. more specific for the immune cells than CS/GC or cytotoxic/anti-proliferative drugs
2. innate immune system remains largely functional

calicneurin and MTOR inhibitors

Disadvantages and ADRs

1. still somewhat immunocompromised (but less so than other drugs)
2. ADRs seen most commonly with CSA and tacrolimus
1. nephrotoxicity (bad since these drugs are mostly used to prevent kidney transplant rejection)
2. HTN
3. hyperglycemia
4. hirsutism
3. ADRs seen most commonly with sirolimus
1. hepatotoxicity

Biologics

Used to Prevent Transplant Rejection

1. muromonab
2. antithymocyte globulin
3. basiliximab

Biologics

Used for Autoimmune Dz and other HS Responses

Drugs the Block/Bind TNF-alpha

1. etanercept
2. infliximab
3. adalimumab
4. certolizumab pegol

Biologics

Used for Autoimmune Dz and other HS Responses

Drugs the Block the Action of

other Inflammatory Cytokines

1. anakinra
2. toclizumab

Biologics

Used for Autoimmune Dz and other HS Responses

Drugs that Target APC-T cell Interaction

1. abatacept
2. alefacept

Biologics

Used for Autoimmune Dz and other HS Responses

Drugs that Target Immune Cell Trafficking

1. natalizumab
2. fingolimod

Biologics

Used for Autoimmune Dz and other HS Responses

Drugs that Target/Kill B cells

Biologics

Used for Autoimmune Dz and other HS Responses

Drugs that Target IgE

Biologics

Used for Autoimmune Dz and other HS Responses

Drugs that Target are Recombinant Cytokines

Biologics

Types

1. monoclonal antibodies (usually end in -mab)
2. soluble receptors/fusion proteins (usually end in -cept)
3. naturally-occurring receptor antagonists
4. recombinant cytokines

muromonab

Form and MOA

FORM: mouse mAb

MOA:

1. mAb binds CD3 on T cells
2. tags and flags the T cell, i.e. opsonizes it
3. macrophages eat the T cell

murmonab

Disadvantages

fully-mouse Ab

can lead to the development of HAMAs

(human anti-monoclonal antibodies)

muromonab

Advantage

antithymocyte globulin

Form and MOA

FORM: polyclonal horse or rabbit antibodies that recognize human thymocytes

NOTE: heterologous hyperimmune serum

MOA:

1. drug binds T cells
2. kills them
1. by fixing complement
2. opsonizing
3. and stimulating ADCC
3. possible HAMA response

basiliximab

Form and MOA

FORM: chimeric mAb

MOA:

1. basiliximab binds IL-2R-alpha (aka CD25)
2. blocks signaling of IL-2 through the IL-2R

basiliximab

Effects

• prevents the T cell from binding IL-2
• proliferation/differentiation of the T cell is blocked
• doesn't actually kill the T cell

muromonab

Therapeutic Applications

1. prevention of transplant rejection
2. other uses that differ from antithymocyte globulin and basiliximab

antithymocyte globulin

Therapeutic Applications

1. prevention of transplant rejection
2. other uses that differ from antithymocyte globulin and basiliximab

basiliximab

Therapeutic Applications

1. prevention of transplant rejection
2. other uses that differ from antithymocyte globulin and basiliximab

Drugs Used for Autoimmune Diseases

and Other Hypersensitivity Responses

1. etanercept
2. infliximab
3. adalimumab
4. certolizumab pegol
5. anakinra
6. toclizumab
7. abatacept
8. alefacept
9. natalizumab
10. fingolimod
11. rituximab
12. omalizumab
13. interferon beta

FORM: SR/FP (2 molecules of TNF receptor fused to the Ig constant region)

MOA: blocks TNF (acts like a sponge to sop it up)

DISADVANTAGES:

1. leaves pt immunocompromised
2. very costly to manufacture
   

FORM: chimeric mAb

MOA: recognizes, binds, and blocks TNF-alpha

FORM: human mAb

MOA: binds TNF-alpha, blocking its function

FORM: pegylated fab fragment of monoclonal Ab against TNF-alpha

NOTE: pegylation (w/ polyethylene glycol)

1. improves stability
2. protects against enzymatic degradation
3. slows clearance
4. thereby increasing drug half-life
   

MOA: small fab fragments bind TNF-alpha

FORM: recombinant form of naturally occurring IL-1 receptor antagonist (NOT mAb)

MOA: binds IL-1R, blocking the binding of IL-1 (therefore, no activation of macrophages, chondrocytes, etc.)

FORM: humanized mAb

MOA: binds IL-6R, blocking the binding of IL-6 (therefore the cell never gets activated)

FORM: SR/FP CTLA-4 bound to the Fc portion of a mAb

MOA:

1. abatacept binds a CD80/86 receptor on the APC
2. prevents this CD80/86 receptor from binding CD28 on the T cell, which would normally activate it
3. allows another CD80/86 receptor to bind CTLA-4 on the T cell receptor, which normally prevents T cell activation
4. therefore, this drug not only prevents activation, it promotes it by blocking signal T in T cell activation
   

USE: rheumatoid arthritis

FORM: FP/SR, an adhesion molecule plus Fc portion

MOA: alefacept binds adhesion molecule on T cell receptor and prevents APC cell from binding T cell (therefore signals 1 and 2 are never delivered)

FORM: humanized mAb

MOA: natalizumab binds a unique adhesion molecule on T cells that normally allows the T cell to traverse the BBB (therefore activated T cells cannot enter the brain and cause damage)

USE: multiple sclerosis, Crohn's Dz

FORM: fungal metabolite

MOA: binds S1P trafficking receptors on lymphocytes, holding them in the lymph nodes (therefore they cannot reach the brain)

USE: less expensive multiple sclerosis Tx

FORM: chimeric mAb

MOA: rituximab binds CD20 on B cells, acting like an antibody (kills B cell) (therefore immune response caused by the B cell never happen)

FORM: humanized mAb

MOA: omalizumab recognizes and binds the Fc portion of IgE antibodies, blocking the activation of mast cells and subsequent release of mast cells

USE: moderate-to-severe allergic asthma

FORM: recombinant cytokine

MOA: inhibits T cell cytokines that normally stimulate inflammation

USE: multiple sclerosis

Immune Macromolecules

Other Therapeutic Uses

1. enhance immune responses
2. kill cancer cells
3. treat osteoporosis
4. etc...

Immunoglobulin Drugs

That Provide Passive Immunity