BACKGROUND: With the increasing need for organ transplantation and the use of "marginal" organs, novel approaches are sought to increase the efficiency and survival of transplanted tissue. We tested the idea that treatment with the anti-inflammatory peptide, alpha-melanocyte-stimulating hormone (alpha-MSH), an endogenous hormone that does not cause marked immunosuppression but does reduce reperfusion injury, may protect allografts and prolong their survival. METHODS: Donor cardiac grafts (Brown Norway) were transplanted heterotopically into the abdomen of recipient (Lewis) rats. Treatments consisted of intraperitoneal injections of Nle DPhe -alpha-MSH (NDP-alpha-MSH) or saline from the time of transplantation until sacrifice or spontaneous rejection. Allografts were removed on day 1, day 4, or at the time of rejection and examined for histopathology and expression of molecules prominent in reperfusion injury, transplant rejection, and apoptosis. RESULTS: NDP-alpha-MSH treatment caused a significant increase in allograft survival and a marked decrease in leukocyte infiltration. Expression of molecules such as endothelin 1, chemokines, and adhesion molecules, which are involved in allograft rejection, was significantly inhibited in NDP-alpha-MSH-treated rats. CONCLUSIONS: The results indicate that protection of the allograft from early injury with alpha-MSH can postpone rejection. Addition of this early protection with the peptide to usual treatment with immunosuppressive agents may, therefore, improve success of organ transplants.
To examine the association of the interleukin 1 gene (IL1) cluster polymorphisms and their haplotypes with bilateral distal interphalangeal joint osteoarthritis (DIP OA).
Radiographs of both hands of 295 dentists and 248 teachers were examined and classified for the presence of OA using reference images. Bilateral DIP OA was defined by the presence of radiographic findings of grade 2 or more in at least 1 symmetrical pair of the DIP joints. We genotyped 10 single-nucleotide polymorphisms (SNP) in the IL1R1, IL1RL2, IL1A, IL1B, and IL1RN genes using polymerase chain reaction-based methods. Haplotypes were statistically reconstructed using the PHASE program. The association between the genotypes/diplotypes and bilateral DIP OA was examined with logistic regression analysis.
Two IL1B SNP (rs1143634 and rs1143633) were associated with bilateral DIP OA. The carriers of the IL1B rs1143634 minor allele had an increased OA risk [odds ratio (OR) 1.6; 95% confidence interval (CI) 1.08-2.26] compared to the noncarriers. The association was stronger in the dentists. The distribution of the IL1B rs1143633 genotype fit a recessive mode of inheritance (OR 3.03, 95% CI 1.35-6.83, p = 0.006). Two IL1B-IL1RN extended haplotype alleles (211-1 and 121-1) were associated with bilateral DIP OA. An interaction between the IL1B rs1143634 and the IL1R1-IL1RL2 and IL1B-IL1RN extended haplotypes and occupation (increased risk of OA among dentists only) was observed.
Our results provide further evidence for the role of IL1 gene cluster polymorphisms in the etiology of OA and suggest that some of these may predispose DIP joints to the effects of mechanical overload.
We performed a cross-sectional study involving workers from four European countries in which exposure to pesticides and immune parameters were evaluated over a short period of time. The total study population consisted of 238 workers occupationally exposed to pesticides and 198 nonoccupationally exposed workers. The study showed that pesticide exposure at levels encountered by workers under different conditions in Europe did not affect the ability of the immune system to respond to vaccination. We could, however, identify individuals within the group of pesticide exposed workers who were genetically characterized by the 2.2 IL-1alpha polymorphism and who showed a lower antibody response, pointing out the importance of the understanding of genetic variability and the interaction between genetic and environmental factors in the identification of high-risk individuals, which may eventually lead to preventive measures.
To examine the association between the IL1 gene cluster and susceptibility to ankylosing spondylitis (AS) in 3 independent case-control cohorts.
We analyzed 394 patients and 446 controls from Alberta, Newfoundland, and Toronto, Canada. Samples were genotyped using a panel of 38 single-nucleotide polymorphism (SNP) markers within the IL1 gene cluster. Data from 20 informative and nonredundant SNP markers were analyzed using several association test strategies. First, we used the program WHAP to identify single-marker associations. Second, we used WHAP to analyze "sliding windows" of 3 contiguous markers along the entire extent of the IL1 gene cluster in order to identify haplotypic associations. Third, we used the linkage disequilibrium mapping program DMLE to estimate the posterior probability distribution of a disease locus.
A total of 14 SNP markers showed significant single-locus disease associations, the most significant being rs3783526 (IL1A) (P = 0.0009 in the Alberta cohort, P = 0.04 in the Newfoundland cohort) and rs1143627 (IL1B) (P = 0.0005 in the Alberta cohort, P = 0.02 in the Newfoundland cohort). Analysis of 3-marker sliding windows revealed significant and consistent associations with all of the haplotypes in the IL1A and IL1B loci in the Alberta cohort and with IL1B in the Newfoundland cohort, especially haplotypes rs1143634/rs1143630/rs3917356 and rs1143630/rs3917356/rs3917354 (P = 0.006-0.0001). With DMLE, a strong peak in the probability distribution was estimated near IL1A in both the Alberta and the Newfoundland populations.
These results indicate that the IL1 locus, or a locus close to IL1, is associated with susceptibility to AS.
BACKGROUND: Implant failure and biologic complications such as periimplantitis are not completely avoidable. Are there any genetic and microbiologic parameters that could be used to identify patients at risk for implant failure, preferably prior to treatment? This would result in improvement of the diagnostics, treatment decision, and risk assessment. PURPOSE: The aims of this retrospective study were to describe (1) the absolute failure rate of Brånemark System implants (Nobel Biocare AB, Göteborg, Sweden) consecutively installed over a 10-year period in partially edentulous patients treated for periodontal disease prior to implant treatment and under regular professional maintenance, (2) the rate of interleukin-1 (IL-1) polymorphism in those patients who experienced at least one implant failure during the first year of function, and (3) the prevalence of periodontal pathogens in dental and periimplant sites with and without signs of inflammation. MATERIAL AND METHODS: Of 766 patients, 81 encountered at least one implant failure; 22 patients were clinically examined and were tested genetically for IL-1 genotypes. The presence of Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, and Prevotella nigrescens was analyzed. RESULTS: The absolute implant survival rate for the whole population was 95.32%; 10.57% of the patients encountered an implant loss. Implant loss in the examined group (n = 22) was 32 of 106 (30.1%); 10 (45%) of the 22 patients were smokers, and 6 (27%) of the 22 patients were IL-1 genotype positive. Patients positive for IL-1 genotype were not more prone to implant loss; however, a significant synergistic effect with smoking was demonstrated. Between patients who were IL-1 genotype positive and those who were IL-1 genotype negative, the differences in regard to bleeding on probing or periodontal pathogens did not reach statistical significance. CONCLUSION: The overall implant failure rate in a population treated and maintained for periodontal disease is similar to that of healthy subjects. A synergistic effect found between smoking and a positive IL-1 genotype resulted in a significantly higher implant loss. This indicates that further research with a larger patient group should focus on multifactorial analysis for adequate risk assessment.
Interleukin-1beta mRNA, interleukin-1beta receptor mRNA, and erythropoietin receptor mRNA are expressed in the brain of (CBAxC57Bl)F1 mice. Immunization with sheep erythrocytes stimulated the expression of these cytokines in the cerebral hemispheres. Injection of recombinant erythropoietin reduced expression of interleukin-1beta, interleukin-1beta receptor, and erythropoietin receptor genes in the brain of experimental animals and considerably increased their motor activity in the open field test.
Several studies have demonstrated a linkage or association of the atopic phenotype with T-cell cytokine genes involved in the regulation of the TH1/TH2 balance (eg, IL4, IL13, and their common receptor, IL4RA). We have recently shown that polymorphism of the pro-inflammatory cytokine IL1A gene is strongly associated with atopy.
We now examined whether the polymorphisms of IL1A (G/T at +4845) and IL4RA (T/C at +22446) would show an epistatic effect on the risk of atopy.
Skin prick tests and gene polymorphism analyses were performed in a population-based sample of asthmatic and nonasthmatic subjects.
Our results showed that in the nonasthmatic group the previously described elevated risk of atopy in noncarriers of allele T of IL1A (ie, having the genotype GG) was restricted to individuals who were also noncarriers of allele C of IL4RA (genotype TT). This finding applies to the general population of Finland, where 3.3% of adults are asthmatic.
These data suggest that the IL1A and IL4RA genes show an epistatic effect on the risk of atopy.