Article

IL-2 and TNF-alpha promoter polymorphisms in patients with acute kidney graft rejection.

Department of Pharmacokinetics and Therapeutic Drug Monitoring, Pomeranian Medical University, 70-111 Szczecin, Powst Wlkp 72, Poland.
Transplantation Proceedings (impact factor: 1). 07/2005; 37(5):2041-3. DOI:10.1016/j.transproceed.2005.03.091 pp.2041-3
Source: PubMed

ABSTRACT Proinflammatory cytokines have been implicated in the pathogenesis of acute kidney allograft rejection. The aim of the study was to examine the association between interleukin (IL)-2 -330 and tumor necrosis factor (TNF)-alpha -308 promoter polymorphisms and acute kidney allograft rejection.
The study included 72 patients with long-term stable graft function, and 57 diagnosed with acute kidney allograft rejection.
Patients with acute kidney allograft rejection showed a prevalence of subjects with TNF-alpha T2 allele (P < .05). The risk of acute kidney allograft rejection diagnosis was 2.5-fold greater among carriers of the T2 allele than those homozygous for T1T1 (OR 2.53, 95% CI 1.19 to 5.37, P < .05) There was no statistically significant difference in the distribution of IL-2 genotypes between patients with stable graft function and acute kidney allograft rejection.
The results suggest that TNF-alpha-308 promoter polymorphism is a risk factor for acute kidney allograft rejection.

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    Article: Genetic aspects of outcome in kidney transplantation: cytokine and thrombosis associated candidate genes and gene expression biomarkers
    Noora Alakulppi
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    ABSTRACT: Kidney transplantation (Tx) is the treatment of choice for end stage renal disease. Immunosuppressive medications are given to prevent an immunological rejection of the transplant. However, immunosuppressive drugs increase e.g. the risk of infection, cancer or nephrotoxicity. A major genetic contributors to immunological acceptance of the graft are human leukocyte antigen (HLA) genes. Also other non-HLA gene polymorphisms may predict the future risk of complications before Tx, possibly enabling individualised immunotherapy. Graft function after Tx is monitored using non-specific clinical symptoms and laboratory markers. The definitive diagnosis of graft rejection however relies on a biopsy of the graft. In the acute rejection (AR) diagnostics there is a need for an alternative to biopsy that would be an easily repeatable and simple method for regular use. Frequent surveillance of acute or subclinical rejection (SCR) may improve long-term function. In this thesis, associations between cytokine and thrombosis associated candidate genes and the outcome of kidney Tx were studied. Cytotoxic and co-stimulatory T lymphocyte molecule gene expression biomarkers for the diagnosis of the AR and the SCR were also investigated. We found that polymorphisms in the cytokine genes tumor necrosis factor and interleukin 10 (IL10) of the recipients were associated with AR. In addition, certain IL10 gene polymorphisms of the donors were associated with the incidence of cytomegalovirus infection and occurrence of later infection in a subpopulation of recipients. Further, polymorphisms in genes related to the risk of thrombosis and those of certain cytokines were not associated with the occurrence of thrombosis, infarction, AR or graft survival. In the study of biomarkers for AR, whole blood samples were prospectively collected from adult kidney Tx patients. With real-time quantitative PCR (RT-QPCR) gene expression quantities of CD154 and ICOS differentiated the patients with AR from those without, but not from the patients with other causes of graft dysfunction. Biomarkers for SCR were studied in paediatric kidney Tx patients. We used RT-QPCR to quantify the gene expression of immunological candidate genes in a low-density array format. In addition, we used RT-QPCR to validate the results of the microarray analysis. No gene marker differentiated patients with SCR from those without SCR. This research demonstrates the lack of robust markers among polymorphisms or biomarkers in investigated genes that could be included in routine analysis in a clinical laboratory. In genetic studies, kidney Tx can be regarded as a complex trait, i.e. several environmental and genetic factors may determine its outcome. A number of currently unknown genetic factors probably influence the results of Tx. Terminaalisen munuaissairauden paras hoitomuoto on munuaissiirto. Immuunivastetta heikentävää lääkitystä (immunosuppressiivit) annetaan estämään siirteen immunologinen hyljintä. Toisaalta immunosuppressiivit ovat haitallisia munuaisille ja lisäävät infektioiden ja syövän vaaraa. Tärkeimmät siirteen immunologiseen hyväksyntään vaikuttavat geenit ovat ihmisen valkosoluantigeeneja koodaavat geenit (HLA). Muut HLA:n ulkopuolisten geenien eri muodot voivat ennustaa ennen siirtoa hoidon sivuvaikutuksia ehkä mahdollistaen yksilöllisen immunosuppressiivisen lääkityksen. Siirron jälkeen siirteen toimintaa seurataan yleisluontoisten sairauden oireiden ja laboratoriokokeiden avulla. Siirteen hyljintä määritetään ottamalla neulakoepala siirteestä. Äkillisen hyljinnän määritykseen tarvitaan koepalan oton sijaan helposti toistettava ja yksinkertainen menetelmä säännölliseen seurantaan, mikä voi parantaa siirteen pitkäaikaistoimintaa. Väitöskirjassa tutkittiin sytokiinigeeneistä ja laskimotukokseen liittyvistä geeneistä eri geenimuotoja ja näiden vaikutusta munuaissiirteen ennusteeseen. Hyljinnän määrityksen avuksi tutkittiin myös soluille myrkyllisiä ja soluja ärsyttäviä T-imusolumolekyyligeenien ilmentymisbiomerkkejä. Sytokiinigeenien TNF ja IL10 tietyt muodot siirteen saajissa vaikuttivat hyljintäriskiin pienessä aineistossa. Lisäksi IL10 geenin tietyt muodot siirteen luovuttajissa vaikuttivat sytomegaloviruksen lisääntymiseen tietyissä siirteen saajissa. Toisaalta emme löytäneet laskimotukokselle, infarktille, hyljintään sairastuvuudelle tai siirteen elinikää lyhentäville altistavia sytokiini- tai tukosgeenimuotoja. Hyljinnän biomerkkejä tutkittaessa reaaliaikaisella kvantitatiivisella polymeraasiketjureaktiolla CD154- ja ICOS-geenien ilmentyminen oli erilaista hyljintäpotilaiden ja normaalien potilaiden välillä muttei muiden hyljinnänkaltaisia oireita ilmentäneiden potilaiden ja hyljintäpotilaiden välillä. Tutkittaessa kliinisesti oireettomien mutta koepalan perusteella hyljintätautimäärityksen saaneita lapsipotilaita hyljintäpotilaita ei pystytty erottamaan normaalipotilaista tutkimalla ehdokasgeenien ilmentymistä tai koko genomin ilmentymistä. Munuaissiirtoa voidaan pitää kompleksitautina, jossa useat ympäristö- ja geneettiset tekijät vaikuttavat siirron jälkeiseen aikaan. Suuri joukko tällä hetkellä tuntemattomia geneettisiä tekijöitä vaikuttavat mahdollisesti siirron onnistumiseen.
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Keywords

72 patients
 
acute kidney allograft rejection
 
acute kidney allograft rejection diagnosis
 
homozygous
 
IL-2 genotypes
 
patients
 
statistically significant difference
 
T2 allele
 
TNF)-alpha -308 promoter polymorphisms
 
TNF-alpha T2 allele
 
TNF-alpha-308 promoter polymorphism
 
tumor necrosis factor