Influence of cytokine and intercellular adhesion molecule‐1 gene polymorphisms on acute rejection in pediatric renal transplantation

Abstract

Immune response regulation by cytokines is a key to understanding AGR. The influence of the functional polymorphisms in genes coding for TNF-alpha (-308G > A), IL-10 (-819C > T, and -1082A > G), IFN-gamma [(CA)n], TGF-beta1 (+869T > C), and iCAM-1 (R241G and E469K), in addition to HLA and gender matching on the presentation of AGR in 51 pediatric renal recipients during a 36-month post-transplantation follow-up were analyzed. Also, donors and a control group were genotyped. All groups were within Hardy-Weinberg equilibrium for all polymorphisms except IL-10-819C > T and TNF-alpha (p < 0.005 and p < 0.01, respectively) in recipients. Transplants with gender mismatch showed a higher risk for AGR than those between individuals with gender match (OR, 4.227; p = 0.010). Recipients with a high-production compared with low-production TNF-alpha allele experienced earlier AGR (p = 0.030), and those with high-production alleles of both TNF-alpha and IFN-gamma showed a further increased risk (OR = 11.129, p = 0.024). These findings support the notion that a single genotype cannot by itself explain an event as complex as AGR. The sum or combination of different specific alleles of these genes could better account for the immune response to an allograft.

Tumor necrosis factor haplotype diversity in Mestizo and Native populations of Mexico

“…Polymorphisms at the TNF locus have been extensively studied worldwide, and a great genetic diversity has been found according to ethnicity and geographical region , which could have a differential epidemiological impact within each population. In Mexico, several studies have examined the influence of the polymorphism TNFA–308G>A in different clinical settings and geographic regions . However, the variability of this and other TNF polymorphisms among the Mexican population (both Mestizo and native) is unknown .…”

Increased immunogenicity is an integral part of the heat shock response following renal ischemia

“…This study clearly demonstrates that increased immunogenicity after ischemia-reperfusion stress is an integral part of renal HSR. Based on studies of MHC class II and ICAM-1 as key markers of renal immunogenicity (Khazen et al 2007;Mendoza-Carrera et al 2008;Shackleton 1998;Shoskes and Halloran 1991) and Hsp70 as the key marker and HSF-1 as the key regulator of the renal HSR (Shamovsky and Nudler 2008;Pirkkala et al 2001), our data show that HSF-1 plays a role in the concordant upregulation of tubular immunogenicity and HSR, representing a direct molecular link between ischemia-reperfusion injury and renal immunogenicity.…”

“…Restitution of blood flow with reperfusion sustains renal allograft injury by further generation of free oxygen radicals. Ischemia-reperfusion and the associated oxidative stress not only disrupt cellular homeostasis but also increase the expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and major histocompatibility complex (MHC) classes I and II in interstitial cells and importantly also in renal tubular cells, thereby increasing immunogenicity and risk for allograft rejection (Mendoza-Carrera et al 2008;Khazen et al 2007;Shackleton et al 1990;Shoskes et al 1990;Shackleton 1998). However, the direct molecular link between renal ischemia-reperfusion injury and tubular immunogenicity is still unknown.…”

Genetic polymorphisms in the immune response: A focus on kidney transplantation

“…The exception is TNFA rs1800629 (−308). Associations have been found between this SNP and numerous outcomes in donors and recipients: acute rejection, recipients [21,44,46,[58][59][60][61][62][63]; graft survival, recipients [27,64]; graft survival, donors [65]; associations in sub group analyses, recipients [66][67][68], associations in sub group analyses, donors [49]; associations with other phenotypes/multiple phenotypes [69][70][71][72]; donors: [73] (see Table 2). …”