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Autoimmune diseases - Innate immune suppressors - Details of this area of development

Eczema, Digestion, Pain, Skin Conditions | December 1, 2015 | Author: The Super Pharmacist

general, eczema, Digestion

Autoimmune diseases - Innate immune suppressors - Details of this area of development

To understand the potential role of innate immune suppressors as therapeutics, one must understand the innate immune system. The innate immune system is the first barrier of protection against infection with microorganisms. It can be thought of as a rapid response system, of sorts. The innate immune system is present at birth, in contrast to the acquired immune that develops in response to antigens or vaccines encountered in life.1 It selects targets that it has evolved to recognise, rather than being primed to recognize as it would with adaptive immunity.1 The innate immune system is comprised of several components:

  • Autoimmune diseases - Innate immune suppressors - Details of this area of developmentThe skin and tight junctions between skin cells that prevent microbial invasion
  • Enzymes in epithelial cells that break down proteins of invading microorganisms
  • Phagocytic cells that "eat" microorganisms
  • Special pattern recognition receptors (PPRs) (e.g. Toll-like receptors) that recognize certain microorganisms
  • A host of antimicrobial peptides
  • Proteins that circulate in the blood such as C-reactive protein and complement
  • Cells that release inflammatory cytokines such as macrophages, mast cells, and natural killer cells

The innate immune system rapidly detects and response to certain microorganisms and generates an inflammatory response including swelling, redness, heat, and discomfort. The innate immune system also coordinates with the adaptive immune system.2

Why suppress the innate immune system?

The innate immune system is incredibly important to survival and is actually an ancient system present in all sorts of animals, insects, and even plants3; however, an overactive innate immune system, especially excessive inflammation, can cause problems. Indeed, most rheumatologic diseases are caused by prolonged and excessive inflammation (by both the innate and adaptive immune systems).4 Diseases such as lupus, rheumatoid arthritis, gout, inflammatory bowel disease, atherosclerosis, and many others are made worse by excessive inflammation of the innate immune system.5 Thus, in some cases it seems reasonable to suppress the innate immune system to control disease.

The prototypical innate immune system suppressor

Corticosteroids such as prednisone suppress the acquired and innate immune systems in various ways. They affect gene transcription and block secretion of inflammatory cytokines.6 corticosteroids also interfere with several cells of the innate immune system such as monocytes and macrophages, mast cells, neutrophils, and eosinophils.7,8 Unfortunately, corticosteroids may cause a number of side effects, some of which can be serious or irreversible.9 The risk of these side effects increases with the amount of time one takes corticosteroids.

Newer innate immune suppressors

Researchers have delved more deeply Autoimmune diseases - Innate immune suppressors - Details of this area of developmentinto the specific processes involved in the innate immune system. The goal is to develop therapies that will allow the innate immune system to detect and fight infectious microorganisms but prevent it from causing destructive inflammation. One of the most promising targets for this drug development research are Toll-like receptors. Toll-like receptors are found on various innate immune system cells such as mast cells and natural killer cells.10 When these receptors encounter certain microorganisms (more accurately, certain molecules on or in microorganisms such as nucleic acids lipoproteins), they stimulate various pro-inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1, interleukin-6, and interleukin-12.11,12 Partially blocking Toll-like receptors or blocking specific subtypes of Toll-like receptors is believed to be able to suppress the subsequent inflammation. Indeed, other targets such as NOD (nucleotide-binding oligomerization domain)-protein and MyD88 (myeloid differentiation primary-response protein 88) may be therapeutically valuable.13

How close are we to an innate immune suppressor in the clinic?

Currently available drugs are being screened for their ability to affect the innate immune system. For example, imiquimod is a drug used by dermatologists to treat genital warts and actinic keratosis. The drug also binds to Toll-like receptor 7, though it is not clear if it actually blocks inflammation. The drug does seem to be able to help relax airways, making it a possible treatment for asthma.14 Other drugs in development have proprietary names such as VTX-2337, 852A, and ANA773.15 Perhaps the most developed drug targeting this system is eritoran tetrasodium, a drug that has shown modest promise in clinical trials in the treatment of severe sepsis.16 The molecule appears to partially interfere with the innate immune system’s response to bacterial infection. Indeed, the drug dose-dependently reduces death associated with severe sepsis.17 HEPLISAV-B is a combination Toll-like receptor-9 agonist and a Hepatitis B surface antigen.15 The drug is currently in Phase III clinical trials. PF-3512676 (ProMune) is also a Toll-like receptor-9 agonist and in Phase II trials. While the drug may eventually be shown to treat various illnesses from asthma to infections, Pfizer is testing the drug as a combination drug (along with chemotherapy) to treat non-small cell lung cancer.18

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