Immunosuppressive Effects Of Azathioprine Research Articles

The Effect of Azathioprine on Anastomotic Healing: An Experimental Study in Rats

The cytotoxic and immunosuppressive effects of azathioprine, which mitigate the disease activity in inflammatory bowel disease, may compromise the healing of intestinal anastomoses leading to an increased risk of anastomotic leakage. The effect of azathioprine treatment on intestinal healing was tested. In an experimental study, rats were randomly given one oral dose of azathioprine (5 mg or 20 mg/kg body weight per day) or placebo. After 28 days of treatment, a left colonic anastomosis was performed. After three days of healing, the breaking strengths of the anastomoses were tested, along with measurements of azathioprine major metabolite concentrations: 6-thioguanine and 6-methyl-mercaptopurine. There were no significant differences in the anastomotic breaking strength between the three groups. Daily treatment for four weeks with high or low azathioprine doses has no inhibitory effect on colonic healing in rats.

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

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 alphaCD28 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.

Azathioprine-induced in vitro inhibition of prostaglandin E2 production by rabbit retina

Although much work exists concerning the clinical and immunosuppressive effects of azathioprine, little is known of the mechanism of action of this drug. The present study reports that azathioprine at the concentrations of 0.1 and 0.05 μg/ml causes a significant suppression of in vitro prostaglandin E2 production by rabbit retinas. However, at concentrations below (0.01 μg/ml) or above (1,10 μ/ml) azathioprine was not inhibitory effect. These results suggest a dose-dependent inhibitory effect of azathioprine on prostaglandin E2 production.

The effects of immunosuppressive drugs on human immunocompetence.

Immunosuppressive drugs are agents capable of suppressing the development of at least one type of immune response in vivo at doses with minimal side-effects. After an introduction in which different types of immune responses are briefly discussed, some characteristics regarding the mechanism of action of prednisolone, azathioprine, cyclophosphamide and anti-lymphocyte serum (ALS) will be reviewed. Corticosteroids display mainly an anti-inflammatory effect. The immunosuppressive effect of azathioprine is questionable, cyclophosphamide influences the immune system itself and ALS suppresses fairly specific cellular immunity.

841 INTENSIVE PLASMA EXCHANGE (PE) IN REFRACTORY ACUTE AUTOIMMUNE HEMOLYTIC ANEMIA (AIHA)

Idiopathic AIHA in childhood is usually an acute self-limited disease, responding well to steroids and transfusion. In severe refractory cases, immunosuppressive agents may be of help, but the slow onset of effect (usually weeks) limits their usefulness. Presented with a 17 year-old boy with severe acute AIHA unresponsive to prednisone (10 mg/kg/d), exchange transfusion & splenectomy, we performed PE using the IBM model 2997 Blood Cell Separator. Before PE he required 20 u PRBC over 14 days to keep his Hb > 4 g/dl. Post-PE his Hb remained stable for 5 days. Azathioprine was begun, but when his Hb fell 2 days later a 2nd PE was performed. Again there was abrupt stabilization of Hb levels followed by return to normal over the next 3 weeks, without further transfusion. Total volumes of blood processed in the 2 PE were 8500 & 8250 ml, representing 4240 & 4140 ml plasma (incl. extracellular fluid). Transient coagulation defects were observed, but were corrected by fresh frozen plasma infused post-PE; no bleeding problems developed. Our observations in this case suggest that antibody removal by PE enabled prompt control of severe hemolysis, ‘buying time’ until the immunosuppressive effect of azathioprine took place. Further trial of this combined therapy seems warranted in cases of acute disease refractory to large doses of steroids, and perhaps in younger children with chronic drug-dependent disease prior to consideration of splenectomy.

Effect of azathioprine on the affinity of antibodies against acetylcholine receptor: Analysis with purified antibodies

Rabbit anti-acetylcholine receptor (AChR) † † AChR, acetylcholine receptor; Az, azathioprine CFA, complete Freund's adjuvant; CNBr, cyanogen bromide; NRS, normal rabbit serum; SDS, sodium dodecyl sulfate; EAMG, experimental autoimmune myasthenia gravis. antibodies were purified on an AChR-toxin-Sepharose immunoadsorbent. The immunoadsorbent was prepared by attaching first toxin covalently to Sepharose and then reacting the toxin-Sepharose with AChR. Purified anti-AChR antibodies were utilized for studying the association between the immunosuppressive effect of azathioprine (Az) on AChR-induced experimental autoimmune myasthenia gravis and on the affinity of the antibodies. Mathematical analysis of the data obtained from binding experiments of 125I-AChR to the purified antibodies suggest that treatment with Az decreases the amount of anti-AChR antibodies possessing high affinity values.

Comparison of therapeutic and immunosuppressive effects of azathioprine, prednisolone and combined therapy in NZP-NZW mice.

AbstractSince NZB/NZW mice develop an immune nephritis similar to that of systemic lupus erythematosus in man, a study was designed in these mice to compare the clinical and immunologic effects of three immunosuppressive drug regimens. For 72 weeks, groups of 20 mice received daily oral therapy with a) no drugs, b) azathioprine, c) prednisolone or d) combined azathioprine‐prednisolone. The combined regimen was superior to either drug used alone in preventing deaths from renal disease. Prednisolone alone also prolonged life significantly, but not as effectively as combination therapy. Azathioprine alone was not effective. All drugs suppressed the antibody response to an exogenous antigen (Vi polysaccharide) equally well. None of the drug regimens prevented the appearance of proteinuria, antinuclear antibodies, Coombs' antibody, or γ‐globulin deposits in glomeruli. However, the ability of a therapeutic regimen to suppress antibodies to native DNA correlated well with its ability to suppress renal disease. No malignancies were found among 73 animals autopsied, but significant hepatic damage occurred in the groups receiving prednisolone. Thus, combined therapy was superior to either drug used alone, and the immunosuppressive effect of greatest clinical importance seemed to be the ability to prevent formation of anti‐DNA antibodies.