3 signals necessary for a dendritic cell to activate a T-cell
1) MHC from dendritic cell -> TCR on T-cell 2) CD80/86 (B7) from dendritic cell -> CD28 on T-cell 3) IL-2 from dendritic cell -> IL-2R on T-cell drives T-cell proliferation and more IL-2 production.
What role do the dendritic cells play in maintaining tolerance?
They are constantly sampling self around them, presenting self to T-cells without CD80/86 (B7) and making those T-cells become anergic. Conversely, when a dendritic cell samples its environment in the setting of infection, trauma or ischemia (danger signals), TLR activation upregulates B7 expression and then the T-cells can be activated against antigen.
What are the two immune reactions we are trying to avoid when doing organ transplantation?
Host vs. graft disease: donor APCs can stimulate activation of host T-cells and the host’s APCs can sample the allograft and activate T-cells to destroy the donated tissue. Graft vs. host disease: donor T-cells attack systemic tissue of its new host.
How does the peptide cyclosporin A work?
It binds to TCR protein cyclophilin -> inhibits activation of calcineurin -> NFAT dephosphorylation inhibited b/c calcineurin is inactive -> Phosphorylated NFAT is unable to migrate into T-cell nucleus and induce transcription of cytokine genes (including IL-2)
What is cyclosporin A used for?
Prevent rejection of solid organ transplants and graft vs. host disease, typically in conjunction with corticosteroids. Also used to treat RA and psoriasis.
Most serious adverse effects of cyclosporin A
Nephrotoxicity, hepatotoxicity, lymphoma and infection.
Why is cyclosporin A dosing difficult?
It’s hydrophobic, is not absorbed well when taken orally and is thus variable for each patient. Also, it is metabolized by CYP3A4, resulting in changing in concentration based on what other drugs patients are taking.
How does the macrolide lactone tacrolimus work?
It binds FK binding protein 12 in the T-cell -> inhibits calcineurin phosphatase activity -> prevents NFAT from getting into the nucleus and activating transcription of cytokine genes
What is tacrolimus used for?
Preventing acute rejection of solid organ allografts. Note that this is more potent than cyclosporin A and used more often. Also used for dry eye (restasis) and atopic dermatitis (protopic).
Side effects of tacrolimus
Nephrotoxicity, diabetes, hypertension and lymphoma.
How does sirolimus (rapamycin) work?
It binds FK binding protein 12 -> inhibits mTOR which is normally activated by IL-2 -> mTOR can no longer direct protein synthesis and cell cycle progression in T-cells.
What is sirolimus used for?
Prevention of renal allograft rejection to avoid cyclosporine nephrotoxicity. Also coating cardiac stents with sirolimus prevents re-stenosing of arteries. Note that it is contraindicated for liver and lung transplants.
Toxicities of sirolimus?
Pancytopenia, hyperlipidemia and HTN
How do mycophenolate mofetil (MMF) and azathioprine work?
MMF is hydrolyzed by liver esterase’s to MPA -> MPA inhibits inosine monophosphate dehydrogenase -> de novo purine synthesis is inhibited -> rapidly turning over T-cells can no longer divide due to decreased purine biosynthesis. Azathioprine is metabolized to 6-mercaptopurine -> 6-mercaptopurine disrupts de novo purine synthesis and inhibits DNA transcription.
What are mycophenolate mofetil (MMF) and azathioprine used for?
MMF = kidney and liver transplants in patients who experience calcineurin inhibitor nephrotoxicity. Azathioprine = used in combination with prednisone and calcineurin inhibitors to prevent organ rejection and to treat rheumatoid arthritis.
Side effects of MMF and azathioprine
GI distress, leukopenia and increased infection
How do the 1st line drugs for rheumatoid arthritis work?
Methotrexate = Inhibits dihydrofolate reductase -> inhibits lymphocyte proliferation by reducing nucleoside biosynthesis. Inhibits AICAR transformylase -> release of excess anti-inflammatory molecule adenosine. Leflunamide = metabolized in liver -> inhibits pyrimidine biosynthesis -> reduced lymphocyte proliferation. Note that these are DMARDs.
Aside from 1st line drugs like MTX and leflunamide, what other DMARDs are used to treat rheumatoid arthritis?
Gold compounds = might inhibit induction of IL-1 and TNF. Chloroquines = decrease T-cell activation by limiting lysosomal processing and antigen presentation. D-penicillamine = prevents IL-1 and collagen maturation (metal chelator). Sulfasalazine = scavenges ROS produced by neutrophils. Note that standard practice = combining 2+ DMARDs with MTX.
Most DMARDs are slow onset and take 3-6 months to work. Which one can you use for rapid onset?
How does tofacitinib work?
Block JAK autophosphorylation -> cytokine (IL-2, IL-4, IFN-gamma, IL-6) signaling cannot use JAK/STAT pathway -> Differentiation of T-cells to Th1, Th2 and Th17 inhibited -> pro-inflammatory molecule production inhibited
When do you use tofacitinib?
RA patients where MTX didn’t work
Side effects of tofacitinib
Increased infection, pancytopenia, malignancy
Monoclonal antibody nomenclature
Mouse = omab. Chimeric = ximab. Humanized = zumab. Human = umab.
How does muromonab work?
It is an anti-CD3 antibody that blocks engagement of the TCR.
What is muromonab used for?
Reversal of heart, liver and kidney allograft rejection
Side effects of muromonab?
Non-specific T-cell activation and cytokine release syndrome. Hypersensitivity reaction b/c it is a mouse antibody.
How do daclizumab and basiliximab work?
They are anti-CD25 alpha chain antibodies that inhibit the IL-2 receptor (CD25) and thus inhibit T-cell proliferation.
What are daclizumab and basiliximab used for?
Used in combo with cyclosporine, prednisone and azathioprine in renal and cardiac transplantation.
Side effects of daclizumab and basiliximab?
Acute hypersensitivity reactions can occur with basiliximab
How do abatacept and belatacept work?
It is CTLA4 attached to IgG Fc domain. CTLA4 binds CD80/CD86 (B7) on APCs with a higher affinity than CD28. This prevents their binding to T-cell CD28 and activation of T-cells.