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Azathioprine therapy selectively ablates human V?2? T cells in Crohn's disease.

ABSTRACT: Tumor-derived and bacterial phosphoantigens are recognized by unconventional lymphocytes that express a V?9V?2 T cell receptor (V?2 T cells) and mediate host protection against microbial infections and malignancies. V?2 T cells are absent in rodents but readily populate the human intestine, where their function is largely unknown. Here, we assessed V?2 T cell phenotype and function by flow cytometry in blood and intestinal tissue from Crohn's disease patients (CD patients) and healthy controls. Blood from CD patients included an increased percentage of gut-tropic integrin ?7-expressing V?2 T cells, while "Th1-committed" CD27-expressing V?2 T cells were selectively depleted. A corresponding population of CD27+ V?2 T cells was present in mucosal biopsies from CD patients and produced elevated levels of TNF? compared with controls. In colonic mucosa from CD patients, V?2 T cell production of TNF? was reduced by pharmacological blockade of retinoic acid receptor-? (RAR?) signaling, indicating that dietary vitamin metabolites can influence V?2 T cell function in inflamed intestine. V?2 T cells were ablated in blood and tissue from CD patients receiving azathioprine (AZA) therapy, and posttreatment V?2 T cell recovery correlated with time since drug withdrawal and inversely correlated with patient age. These results indicate that human V?2 T cells exert proinflammatory effects in CD that are modified by dietary vitamin metabolites and ablated by AZA therapy, which may help resolve intestinal inflammation but could increase malignancy risk by impairing systemic tumor surveillance.

SUBMITTER: McCarthy NE

PROVIDER: S-EPMC4563752 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Azathioprine therapy selectively ablates human Vδ2⁺ T cells in Crohn's disease.

McCarthy Neil E NE Hedin Charlotte R CR Sanders Theodore J TJ Amon Protima P Hoti Inva I Ayada Ibrahim I Baji Vidya V Giles Edward M EM Wildemann Martha M Bashir Zora Z Whelan Kevin K Sanderson Ian I Lindsay James O JO Stagg Andrew J AJ

The Journal of clinical investigation 20150713 8

Tumor-derived and bacterial phosphoantigens are recognized by unconventional lymphocytes that express a Vγ9Vδ2 T cell receptor (Vδ2 T cells) and mediate host protection against microbial infections and malignancies. Vδ2 T cells are absent in rodents but readily populate the human intestine, where their function is largely unknown. Here, we assessed Vδ2 T cell phenotype and function by flow cytometry in blood and intestinal tissue from Crohn's disease patients (CD patients) and healthy controls. ...[more]

PMID: 26168223

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Project description:The combination therapy of thalidomide and azathioprine (AZA) offers an alternative in clinical practice for Crohn's disease (CD) patients experiencing a loss of response to AZA monotherapy. However, little is known about the efficacy and safety of this combination therapy for patients with CD. This was a retrospective study of 122 consecutive CD patients who lost response to AZA therapy and had switched to a combination therapy of thalidomide and AZA. The primary outcomes were clinical response and clinical remission rates at week 24. Patients who had an initial response to combination therapy were continued on the treatment for remission maintenance. The secondary outcomes were the proportion of clinical relapse throughout maintenance. The Kaplan-Meier method was used to calculate cumulative rates, and Cox regression analysis was used for multivariate analysis. During induction, 80.3% (98/122) patients achieved clinical response within a median duration of 6.5 weeks, (interquartile range, 4.3-8.1 weeks). The rate of clinical remission at 24 weeks was 70.5%. During follow-up, 22.4% (22/98) of the patients that were maintained on combination therapy experienced clinical relapse. The proportions of patients in remission status at 12, 24, and 36 months were 85.1, 78.3, and 70.1%, respectively. Multivariate analysis revealed C-reactive protein >10 mg/L at disease relapse on AZA monotherapy [adjusted hazard ratio (HR), 4.72; 95% CI, 1.19-18.75, P = 0.027] and 6-thioguanine nucleotides level ≥235 pmol/8 × 108 erythrocytes at AZA monotherapy (adjusted HR, 5.32; 95% CI, 1.40-20.14, P = 0.014) were associated with disease relapse on combination therapy. The endoscopic remission rate was 63.6%. Mucosal healing was achieved in 23.6% of the patients. Both Crohn's Disease Endoscopic Index of Severity (13.4 ± 4.92 vs. 6.12 ± 5.24, P < 0.001) and Rutgeerts scores (3.23 ± 0.73 vs. 1.77 ± 1.59, P = 0.003) were significantly decreased with the use of combination therapy. Adverse events occurred in 62 (50.8%) patients, but only 13 (10.7%) necessitated therapy discontinuation. Thalidomide combined with AZA was effective in inducing clinical remission and sustaining long-term steroid-free remission in CD patients who lost response to AZA monotherapy.

Project description:AimTo determine the risk factors of nonadherence to azathioprine (AZA) maintenance therapy for Crohn's disease (CD) and to evaluate the influence of patients' educational program on adherence to AZA maintenance therapy.MethodsPatients receiving AZA as maintenance therapy for CD were enrolled. Demographic data, clinical data, and usage information were collected. Univariate and multivariate analyses were performed to identify the risk factors of nonadherence. Then, patients' educational program was conducted. One year after the program, the improvements in adherence and relapse rates were compared between educational and noneducational groups.ResultsA total of 378 CD patients receiving AZA as maintenance therapy were enrolled from September 2008 to September 2018. Nonadherence occurred in 43.9% (166/378) of patients. Univariate analysis revealed that young age, education, alcoholism, anxiety, depression, concern belief, and lack of necessity belief and AZA knowledge were risk factors of nonadherence (P < 0.05). Multivariate logistic regression showed that anxiety (OR 6.244, 95% CI 2.563-15.213), depression (OR 3.801, 95% CI 1.281-11.278), and concern belief (OR 19.531, 95% CI 3.393-120.732) were independent risk factors of nonadherence. Necessity belief (OR 0.961, 95% CI 0.925-0.999) and AZA knowledge (OR 0.823, 95% CI 0.758-0.903) were protective factors of adherence. One year after the AZA educational program, the necessity belief, AZA knowledge, and adherence of the educational group significantly improved (P < 0.05). Concern belief was significantly lower in the educational group than that in the noneducational group (P < 0.05). Moreover, the noneducational group suffered significantly higher endoscopic relapse rates than that the educational group (15.9% vs. 30.1%, P = 0.035).ConclusionsNonadherence occurred frequently in CD patients receiving AZA maintenance therapy. Educational programs could improve patients' adherence mainly by promoting their beliefs and knowledge of AZA and could reduce relapse rates during treatment.

Dataset Information

Azathioprine therapy selectively ablates human V?2? T cells in Crohn's disease.

Publications

Azathioprine therapy selectively ablates human Vδ2⁺ T cells in Crohn's disease.

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