Tuesday, December 06, 2005

Histamine H4 receptor antagonism as a rapidly emerging approach to autoimmune disease

Histamine is a biological amine that affects a variety of functions in the human body. It has been known to participate in the mechanisms of inflammatory reaction, gastric acid secretion, and neurotransmission. Four subtypes of histamine receptor, H1-4, have been identified. The histamine H4 receptor was most recently identified in the year 2000. H4 receptors are widely expressed by components of the immune system including the spleen, thymus, and leukocytes.

Johnson & Johnson were the first company to publish on a selective histamine H4 antagonist (Jablonowski et al, 2003) and JNJ 10191584 and JNJ 7777120 have been investigated as orally active antagonists. The first few studies into the function of H4 receptors suggested that their blockade would be of benefit to allergic diseases with an eosinophilic and/or mast cell component since histamine binding to this receptor subtype stimulated the chemotaxis of both cell types.

The two papers featured in the December 5th edition of DailyUpdates suggest that the efficacy of histamine H4 antagonists may extend to autoimmune disease. In particular the H4 subtype is now implicated in rheumatoid arthritis and inflammatory bowel disease. Both of these serious autoimmune disorders are evaluated in our recent report “Autoimmune Disorders & Transplant Rejection - Opportunities for the Drug Development Sector”. Both conditions are amongst the ten most prevalent autoimmune disorders affecting 300-600 people/100,000

Ulcerative colitis and Crohn’s disease, known collectively as inflammatory bowel disease (IBD) currently affects 0.5-1% of the Western world’s population. This translates to over one million people in America (525,000 Ulcerative Colitis, 490,000 Crohn's Disease) and four million people worldwide. Sufferers experience a range of gastrointestinal symptoms, including diarrhea, rectal bleeding and abdominal pain resulting in weight loss as well as other extraintestinal manifestation such as skin and eye disorders.

Rheumatoid arthritis is a chronic syndrome characterised by non-specific, usually symmetrical inflammation of the peripheral joints, potentially resulting in progressive destruction of articular and peri-articular structures, with or without generalised manifestations. This disease is one of the more difficult of the autoimmune diseases to control and can do considerable damage to the joints. The condition differs from osteoarthritis not only through the obligatory involvement of the immune system but also because disease onset occurs early on in life, generally between the ages of 20 and 50, although it can begin at any age.

Although recent advances, particularly the development of TNF blockers have improved the options available for the treatment of both IBD and rheumatoid arthritis significant unmet needs remain; in particular not all patients respond to TNF blockers and those that do rarely exhibit a complete response. Thus additional molecular targets are being sought for the development of new anti-inflammatory agents. The two papers featured on yesterday’s DailyUpdates present a good case for including H4 receptors as candidate targets.

The first of the featured papers reports that treatment with JNJ 10191584 dose-dependently reducted macroscopic damage, neutrophil infiltration and tumour necrosis factor-alpha levels. JNJ 7777120 produced similar effects. The second paper reports that human synoviocytes from rheumatoid arthritis patients express H4 receptors. Further studies investigated the efficacy of H4 receptor antagonist in models of this disease are therefore eagerly awaited.

Do you have any comments on the development of H4 receptor antagonists – perhaps you have preliminary data. Please feel free to submit your comments? This will hopefully drive forward this fascinating area of immunology while at the same time providing a platform for exciting data amongst our derug development audience?


Anonymous Anonymous said...

I believe that the single mediator approach will not be effective for complex diseases, such as autoimmune or allergic. Textbooks are plenty of examples of drugs that have failed during the drug development proccess.

9:04 AM  
Anonymous jpk said...

You just might be wrong. Asthma is a complex disease and LTRAs have been shown to be quite effective in some patients with this disease. It depends on what is primarily driving the problem.

1:57 PM  
Anonymous Anonymous said...

You are right, but their efficacy is limited...

10:22 AM  
Anonymous Anonymous said...

what about blockade of that single mediator called TNF-a.. that seem to have worked out quite well......

5:12 PM  
Anonymous Anonymous said...

Hi everyone! This forum looks very interesting. I am currently working in predictive toxicology and have seen a recent report (Takeshita et al, JPET 310:272, 2004) indicating that a dual H3/4 antagonist induced bone marrow neutrophil accumulation in zymosan- or histamine-challenged mouse. As granulocytopenia is a terrible side effect associated with several drugs (such as clozapine, NSAID’s, etc) I would like to know if someone has tested this potential side effect with a selective H4 antagonist.

3:26 PM  
Anonymous Anonymous said...

Is has been proposed that this agranulocytosis might be mediated by the H4 receptor but nothing is known yet when you look in literature. I have also tested several known drugs that cause agranulocytosis for affinity for the H4 receptor but all of them were inactive. Clozapine can be metabolised to an active metabolite that can covalently bind to white blood cells. Cells with covalently bound clozapine have been found in several tox studies.
No selective H4 antagonists have been tested for this side effect. It would be nice though and since there are already selective H4 antagonists this could be easily done.

7:53 PM  

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