Ten-Year Results of Renal Transplantation With Azathioprine and Prednisolone as Only Immunosuppression

Mcgeown, MaryG.; Donaldson, R. A.; Kennedy, J. A.; Douglas, John; Hill, ClaireM.; Loughridge, W. G. G.; Middleton, Derek

doi:10.1016/s0140-6736(88)91792-8

Cited by 26 publications

(7 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[12][13][14] Azathioprine is the pro-drug that is converted in vivo initially into 6-MP and subsequently into thioguanosine nucleotides that, at high doses, may interfere with nucleotide metabolism in proliferating cells. 25 The dose at which azathioprine is applied chronically in transplantation protocols and inflammatory bowel disease does not invoke systemic cytostatic effects and is even compatible with normal pregnancy.…”

Section: Discussionmentioning

confidence: 99%

“…11 6-MP is currently used for the treatment of leukemia, whereas azathioprine, the pro-drug of 6-MP, is prescribed at relatively low doses as a chronic immunosuppressive drug in inflammatory bowel disease as well as after organ transplantation. [12][13][14] A well-defined mouse model of neointima formation consists of placement of a nonconstrictive perivascular cuff around the femoral artery. 15 Previously we showed that the nonconstrictive perivascular cuff may be constructed from a polymeric formulation suitable for controlled drug delivery.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Activation of Nuclear Receptor Nur77 by 6-Mercaptopurine Protects Against Neointima Formation

Pires¹,

Pols²,

Vries³

et al. 2007

Circulation

View full text Add to dashboard Cite

Background-Restenosis is a common complication after percutaneous coronary interventions and is characterized by excessive proliferation of vascular smooth muscle cells (SMCs). We have shown that the nuclear receptor Nur77 protects against SMC-rich lesion formation, and it has been demonstrated that 6-mercaptopurine (6-MP) enhances Nur77 activity. We hypothesized that 6-MP inhibits neointima formation through activation of Nur77. Methods and Results-It is demonstrated that 6-MP increases Nur77 activity in cultured SMCs, which results in reduced [ 3 H]thymidine incorporation, whereas Nur77 small interfering RNA knockdown partially restores DNA synthesis. Furthermore, we studied the effect of 6-MP in a murine model of cuff-induced neointima formation. Nur77 mRNA is upregulated in cuffed arteries, with optimal expression after 6 hours and elevated expression up to 7 days after vascular injury. Local perivascular delivery of 6-MP with a drug-eluting cuff significantly inhibits neointima formation in wild-type mice. Locally applied 6-MP does not affect inflammatory responses or apoptosis but inhibits expression of proliferating cell nuclear antigen and enhances protein levels of the cell-cycle inhibitor p27 Kip1 in the vessel wall. An even stronger inhibition of neointima formation in response to local 6-MP delivery was observed in transgenic mice that overexpressed Nur77. In contrast, 6-MP does not alter lesion formation in transgenic mice that overexpress a dominant-negative variant of Nur77 in arterial SMCs, which provides evidence for the involvement of Nur77-like factors. Conclusions-Enhancement of the activity of Nur77 by 6-MP protects against excessive SMC proliferation and SMC-rich neointima formation. We propose that activation of the nuclear receptor Nur77 is a rational approach to treating in-stent restenosis. (Circulation. 2007;115:493-500.)

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Activation of Nuclear Receptor Nur77 by 6-Mercaptopurine Protects Against Neointima Formation

Pires¹,

Pols²,

Vries³

et al. 2007

Circulation

View full text Add to dashboard Cite

show abstract

“…Both azathioprine and 6-MP are immunosuppressive agents with potent antiinflammatory functions that have been used in childhood leukemia, organ transplantation, and the treatment of autoimmune and chronic inflammatory diseases (2)(3)(4)(5). In particular, azathioprine has been used therapeutically in kidney transplantation (4) and inflammatory bowel diseases (IBD), such as Crohn's disease and ulcerative colitis (2, 6 -8), and is considered the gold standard of immunosuppressive therapy for IBD (9,10).…”

mentioning

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

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.

show abstract

“…This rather extraordinary profile makes Campath-1H an interesting molecule for further clinical development despite the fact that in its present situation it is not a tolerogenic agent. Patients never treated with MoAb's and maintained on a lowdose azathioprine and steroids [18], recipients that received total lymphoid irradiation [19] or more recently, tacrolimus monotherapy [20], are in fact not much different from the patients who became 'near'-tolerant in the alemtuzumab trials. It is also noteworthy that similar results of 'near' specific tolerance have been found by using the old polyclonal rabbit ATG in combination with either an intermittent, very low dosing strategy of tacrolimus monotherapy or with sirolimus monotherapy [21,22].…”

Section: The Lymphocyte Depleting Anti-cd52 Moab Campath-1h (Alemtuzumentioning

confidence: 99%

Monoclonal antibodies in renal transplantation: old and new

Vanrenterghem

2004

Nephrology Dialysis Transplantation

View full text Add to dashboard Cite

Ten-Year Results of Renal Transplantation With Azathioprine and Prednisolone as Only Immunosuppression

Cited by 26 publications

References 9 publications

Activation of Nuclear Receptor Nur77 by 6-Mercaptopurine Protects Against Neointima Formation

Activation of Nuclear Receptor Nur77 by 6-Mercaptopurine Protects Against Neointima Formation

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

Monoclonal antibodies in renal transplantation: old and new

Contact Info

Product

Resources

About