Lack of effect of intravenous administration on time to respond to azathioprine for steroid-treated Crohn's disease

Sandborn, William J.; Tremaine, William J.; Wolf, Douglas C.; Targan, Stephan R.; Sninsky, Charles A.; Sutherland, Lloyd R.; Hanauer, Stephen B.; McDonald, John W.D.; Feagan, Brian G.; Fedorak, Richard N.; Isaacs, Kim L.; Pike, M.Gennette; Mays, Dennis C.; Lipsky, James J.; Gordon, Susan; Kleoudis, C.; Murdock, Robert H.

doi:10.1016/s0016-5085(99)70445-2

Cited by 228 publications

(140 citation statements)

References 33 publications

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“…Therefore, azathioprine therapy would require time to inhibit Rac activity indirectly via suppression of Vav guanosine exchange activity on Rac GTPases. Consistently, azathioprine exhibits a well-known delayed onset of therapeutic efficacy in autoimmune and chronic inflammatory diseases in humans (6,7).…”

Section: Discussionmentioning

confidence: 99%

Azathioprine Suppresses Ezrin-Radixin-Moesin-Dependent T Cell-APC Conjugation through Inhibition of Vav Guanosine Exchange Activity on Rac Proteins

Poppe

Tiede

Fritz³

et al. 2006

The Journal of Immunology

185

159

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We have shown recently that the azathioprine metabolite 6-Thio-GTP causes immunosuppression by blockade of GTPase activation in T lymphocytes. In the present study, we describe a new molecular mechanism by which 6-Thio-GTP blocks GTPase activation. Although 6-Thio-GTP could bind to various small GTPases, it specifically blocked activation of Rac1 and Rac2 but not of closely related Rho family members such as Cdc42 and RhoA in primary T cells upon stimulation with αCD28 or fibronectin. Binding of 6-Thio-GTP to Rac1 did not suppress Rac effector coupling directly but blocked Vav1 exchange activity upon 6-Thio-GTP hydrolysis, suggesting that 6-Thio-GTP loading leads to accumulation of 6-Thio-GDP-loaded, inactive Rac proteins over time by inhibiting Vav activity. In the absence of apoptosis, blockade of Vav-mediated Rac1 activation led to a blockade of ezrin-radixin-moesin dephosphorylation in primary T cells and suppression of T cell-APC conjugation. Azathioprine-generated 6-Thio-GTP thus prevents the development of an effective immune response via blockade of Vav activity on Rac proteins. These findings provide novel insights into the immunosuppressive effects of azathioprine and suggest that antagonists of the Vav-Rac signaling pathway may be useful for suppression of T cell-dependent pathogenic immune responses.

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Section: Discussionmentioning

confidence: 99%

Azathioprine Suppresses Ezrin-Radixin-Moesin-Dependent T Cell-APC Conjugation through Inhibition of Vav Guanosine Exchange Activity on Rac Proteins

Poppe

Tiede

Fritz³

et al. 2006

The Journal of Immunology

185

159

View full text Add to dashboard Cite

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“…Indeed, some studies have been done to decrease the response time, such as by giving an intravenous loading dose of AZA; however, there are other studies showing that this step has no advantage (22,23).…”

Section: Resultsmentioning

confidence: 99%

How long should we treat patients with azathioprine/ 6-mercaptopurine before deciding that it is refractory to immunomodulatory treatment?

Kabaçam

Törüner²

2012

Turk J Gastroenterol

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“…Because of the delayed onset of action of thiopurines analogues, even with intravenous administration [14] , this drugs have been most frequently used, with concomitant use of steroids or more recently with infliximab [15] , in patients with active disease in the context of corticosteroid-dependent CD. A Cochrane database meta-analysis [6] found eight randomized, Table 2 Montreal classification of Crohn's disease [13] www.wjgnet.com…”

Section: Aza To Induce CD Remissionmentioning

confidence: 99%

Are we giving azathioprine too late? The case for early immunomodulation in inflammatory bowel disease

Etchevers

Aceituno²,

Sans³

2008

WJG

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Inflammatory bowel disease (IBD) includes two entities, Crohn's disease and ulcerative colitis. Both are chronic conditions with frequent complications and surgical procedures and a great impact on patient's quality of life. The thiopurine antimetabolites azathioprine and 6-mercaptopurine are widely used in IBD patients. Current indications include maintenance therapy, steroid-dependant disease, fistula closure, prevention of infliximab immunogenicity and prevention of Crohn's disease recurrence. Surprisingly, the wide use of immunosuppressants in the last decades has not decreased the need of surgery, probably because these treatments are introduced at too late stages in disease course. An earlier use of immunossupressants is now advocated by some authors. The rational includes: (1) failure to modify IBD natural history of present therapeutic approach, (2) demonstration that azathioprine can induce mucosal healing, a relevant prognostic factor for Crohn's disease and ulcerative colitis, and (3) demonstration that early immunossupression has a very positive impact on pediatric, recently diagnosed Crohn's disease patients. We are now awaiting the results of new studies, to clarify the contribution of azathioprine, as compared to infliximab (SONIC Study), and to demonstrate the usefulness of azathioprine in recently diagnosed adult Crohn's disease patients (AZTEC study).

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Lack of effect of intravenous administration on time to respond to azathioprine for steroid-treated Crohn's disease

Abstract: A loading dose does not decrease the time to response in patients with steroid-treated Crohn's disease beginning azathioprine therapy. Steady state of erythrocyte 6-thioguanine nucleotide and complete response occurred earlier than previously reported.

Cited by 228 publications

References 33 publications

Azathioprine Suppresses Ezrin-Radixin-Moesin-Dependent T Cell-APC Conjugation through Inhibition of Vav Guanosine Exchange Activity on Rac Proteins

Azathioprine Suppresses Ezrin-Radixin-Moesin-Dependent T Cell-APC Conjugation through Inhibition of Vav Guanosine Exchange Activity on Rac Proteins

How long should we treat patients with azathioprine/ 6-mercaptopurine before deciding that it is refractory to immunomodulatory treatment?

Are we giving azathioprine too late? The case for early immunomodulation in inflammatory bowel disease

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