As indicated in the article "Translational Research in Inflammatory Bowel Disease," the key to putting immunological diseases into remission lies in the restoration of the delicate balance of the immune system. Both Crohn's Disease (CD) and Ulcerative Collatis (UC) are diseases that arise when the immuno-scales are skewed. Patients with CD often display a Th-1 cytokine profile, implying hyperactivity of Th-1 mediated immunity. UC patients commonly show a Th-2 cytokine profile, implying a Th-2 mediated response. In real life, though, it is not as black and white as that. There is a lot of gray when looking at these diseases and it is because of the interrelatedness of the T-cell mediated immunity. While seemingly bad, all of the interconnectedness actually allows a lot of opportunity for intervention. Some of the proposed treatments for CD and UC include:
1. Blocking downstream effects such as cytokines
2. Inhibiting the T-cell
3. Inhibiting the migration of immune cells
1. Infliximab
Infliximab is a monoclonal antibody to TNF-a. TNF-a is a Th1-mediated cytokine. Based on the information, one would assume that Infliximab would be particularly useful for patients with CD. Interestingly enough, Infliximab also has its successes with the remission of UC. This effect reinforces the interconnectedness of T-cell mediated immunity. In a randomized trial for remission of Crohn's Disease upon 1 treatment of Infliximab, it was found that patients who have initial decline in disease will be likely to continue disease remission with continued Infliximab treatment. A study of Infliximab and UC patients showed that moderate to severe UC could be sent into remission with treatments of Infliximab. Results showed showed that 44-45% of patients treated with infliximab for a year maintained a response to the medication, compared with 21% of patients who were treated with placebo medication. At 2 months, the response was 61-69% for patients treated with infliximab, and 31% for those who were treated with placebo.
There is similar success with anti-cytokine drugs for INF-g and IL-12. Based on our knowledge of these cytokines, what are the advantages to developing drugs like these? What are the disadvantages?
2. Visilizumab
Visilizumab is a drug that binds the CD3 receptor on activated T cells without affecting the resting T cells. The current trials with this drug are being used in the more severe cases of IBD. More specifically, Visilizumab is an IgG2 non FcGR. This receptor is expressed on >95% of circulating, resting T cells and on activating T cells that are actively involved in inflamed tissues. The company, BioPharma, which produces the drug, has also produced similar versions of this drug that have been used for imaging lymphocytes, type 1 diabetes, and multiple myeloma. (, , , respectively)
PDL BioPharma's "Nuvion" is currently in its Phase 2/3 clinical trials and is used in patients with steroid-resistance UC and CD. Knowing that the drug is an immunosuppresant, what complications can arise from this drug? Does the benefit outweigh the cost?
3. Natalizumab
Natalizumab is an anti-adhesion monoclonal antibody drug. It is an anti alpha-4 integrin, a cellular adhesion molecule. Alpha-4 integrin is required for white blood cells to move in to organs. It is believed that Natalizumab blocks this interaction, preventing white blood cells from leaving the blood stream. The drug Natalizumab has historically been used in treating CD and MS (multiple sclerosis). The article "Translational Research in Inflammatory Bowel Disease" alludes to the dangers and risks associated with this drug. There are complications with the drug both in the intestine and blood brain barrier. There is an association of patients taking this drug and the disease PML. PML is a neurological condition involving and opportunistic virus. Currently the drug has been pulled off the European market, but is available to patients in the US with severe cases. The question again becomes does the benefit outweigh the cost? The FDA in the USA has made the decision that it does and leaves the drug available to patients.
This comment has been removed by the author.
ReplyDeleteSorry, forgot this!
ReplyDeletePharmacology of TNF blockade in rheumatoid arthritis and other
chronic inflammatory diseases
Peter C Taylor
Current Opinion in Pharmacology 2010, 10:308–315
Monoclonal antibody therapies to block or neutralize pleiotropic cytokines, such as the anti-TNF-α Infliximab, affect a multitude of biological pathways and have many consequences. Infliximab is a human-murine chimera, with a human IgG1 Fc primary structure. The murine CDR binds soluble TNF and its transmembrane precursor (tmTNF). The main pharmacological mechanism of infliximab is to bind soluble TNF, neutralize the cytokine, and disrupt the intended signaling pathways. This helps modulate the inflammatory response (advantage), but the response wanes as the concentration of mAb decreases and TNF increases (disadvantage). The anti-TNFs can also block the interaction between tmTNF and the responsive cell receptor, and induce “reverse signaling.” When the mAb binds to tmTNF, its role switches from that of a ligand to a receptor, and a signal is transduced into the cell. Although all the full effects are unknown, a major consequence of reverse signaling by tmTNF is the induction of endotoxin resistance in monocytes, leading to down regulation of TNF-α, IL-1β, IL-6, and IL-10. In activated T-cells, reverse signaling can arrest proliferation by halting the cell cycle at the G0/G1 stage, and may induce apoptosis. The effects of the reverse signaling may increase the response time between infliximab infusions (advantage), but more research is needed to determine its full significance. The human IgG1 Fc structure is also important to the pharmacological efficacy of anti-TNFs, giving the mAbs the potential for Fc mediated effects and interactions. The Fc can bind complement and Fc receptors leading to complement-medicated cytotoxicity and antibody dependent cytotoxicity, and may influence phagocytosis, cytokine release, degranulation and antibody formation (advantages). A major disadvantage to infliximab is the chimeric design, because anti-idiotype antibodies eventually develop. Patients who develop anti-infliximab antibodies are more likely to develop antibodies to fully humanized anti-TNFs as well (disadvantage). Degranulation associated with infliximab can also activate latent tuberculosis infections (disadvantage), but the risk can be easily avoided with a screening PPD.
ReplyDeleteAlyson, thank you for all the awesome information! This mechanism is important to understand because of how commonly infliximab is used for inflammatory diseases. Last week we read about it as a treatment for IDB. This week we are again hearing about it as a treatment for arthritis. In my undergrad, I've never heard of the "reverse signaling" that occurs when tmTNF is bound. How interesting! After looking it up, I have found out that TNF starts off as a transmembrane protein that is clipped out of the membrane by proteolytic cleavage via the enzyme TACE (TNF-alpha converting enzyme). I didn't know that! It makes a lot more sense now how the precursor to soluble TNF could be a ligand-turned-enzyme. I like the way you laid out the advantages and disadvantages to the drug. Its slightly concerning that there are such dramatic repercussions (apoptosis!) to a drug, but when considering an imbalance in immune cells that produce TNFalpha, but there are many other cells in the body that produce this cytokine: endothelial cells, cardio myocytes, adipose tissue, neuronal tissue (scary!), etc. Is there evidence of damage to these tissues or is study still underway?
ReplyDelete