Medawar prize acceptance speech.
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Awards and Prizes↗
Biomedical subjects
Pekka Häyry
Publications and source records attributed to Pekka Häyry.
An image analysis-based method for quantification of chronic allograft damage index parameters.
Chronic allograft damage index (CADI) is a semi-quantitative histopathological score that predicts renal graft outcome. We aimed to develop an objective image analysis-based method for quantification of CADI parameters. Thirty-five kidney transplant biopsies were visually analyzed according to the original CADI criteria, and divided into normal, mildly, moderately and severely altered groups. Digital images of the same samples were then analyzed with IPLab software. Areas of inflammation and fibrosis measured using image analysis increased simultaneously with corresponding visual scores, although the difference between non-inflamed and mildly inflamed groups was not statistically significant. Area of normal tubuli decreased in the images of samples with visually mild/moderate tubular atrophy and tended to be even smaller in the group with severe tubular atrophy. Image analysis-based glomerular sclerosis score increased concurrently with increasing visual score. Mesangial matrix increase score in image analysis was greater in the samples with visually mild/moderate mesangial matrix increase score compared to those with normal glomeruli, and it was highest in the group with severe mesangial matrix increase. An image analysis-based CADI scoring of renal allograft biopsies could provide more precise data for scientific studies, and help pathologists in renal allograft biopsy scoring.
Biopsy↗
Genetic profiling of aortic allografts: prothymosin alpha as potential target?
Transplant arteriosclerosis is the result of intima proliferation in large vessels upon organ transplantation. Obliteration of the vascular lumen will ultimately lead to ischemia and late graft failure. Gene array analysis was performed to identify factors involved in the pathogenesis of transplant arteriosclerosis. Aortic transplants from Dark Agouti to Wistar Furth rats were performed to identify potential target genes. Hierarchical clustering of genes specifically upregulated in allogeneic but not in syngeneic aortas revealed 19 genes. A gene that fulfilled these criteria is prothymosin alpha (PTMA), a regulator of estrogen receptor transcriptional activity. PTMA gene and protein expression levels were confirmed by PCR and immunohistochemistry. Estrogen receptor staining was increased in allogeneic aortas. Furthermore, cyclin D1 a downstream target of PTMA, was also up regulated in allogeneic aortas. In conclusion, PTMA was identified as potential candidate gene involved in transplant arteriosclerosis.
Animals↗
Effect of cytomegalovirus on cardiac allograft arteriosclerosis--indirect or direct?
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Animals↗
Selective estrogen receptor modulators prevent neointima formation after vascular injury.
Exploitation of estrogen's vasculoprotective properties in drug design is difficult due to its adverse effects on endometrium and breast. Selective estrogen receptor modulators (SERM) act as estrogen agonists in some tissues but are anti-estrogenic in others. We investigate here whether tamoxifen, raloxifene, and two novel SERMs, ospemifene and fispemifene, preserve estrogen's beneficial effects on the ovariectomized rat vascular wall, and correlate their effects with natural estrogen (17beta-E2) and a pure anti-estrogen ICI 182,780. All compounds dose-dependently (0.0025-25 mg/kg/day) inhibited neointimal thickening at 7 days after aorta denudation injury. At 28 days, tamoxifen and ospemifene (2.5 mg/kg/day) reduced intimal nuclei number and intimal area equal to 17beta-E2, while raloxifene and fispemifene had no effect. Replacing the drug at 14 days with vehicle did not induce any rebound effect at 28 days, and furthermore, resulted in a smaller neointima with raloxifene and fispemifene. 17beta-E2 and the SERMs also significantly enhanced reendothelialization. All compounds inhibited replication and all but fispemifene inhibited migration of vascular SMC and cells from cultured aortic explants in vitro. Finally, only 17beta-E2 increased the weight of the uterus above that of normal rats. Interestingly, ICI 182,780 also weakly inhibited neointima formation and SMC proliferation at 7 days, suggesting that non-estrogen receptor mediated effects may have also played a role. In conclusion, SERMs have beneficial estrogen agonist effects in the injured vascular wall through their regulation of vascular SMC function and reendothelialization. Early intervention is of particular importance in preventing the injury-response.
Animals↗
Correlation between gene expression and morphological alterations in baboon carotid after balloon dilatation injury.
Treatment for fibroproliferative restenosis after angioplasty and endovascular surgery is an unmet medical need. Rational therapy and drug design still lack the very basic knowledge about the underlying biological processes leading to pathological changes in the vessel wall. We have developed a primate model for vascular response to denudation-overstretch injury of baboon carotid artery. With this model, we have investigated the time course of vascular expression of 41,000 human cDNA clones and correlated these changes with carotid histology and function. Analysis revealed 20,788 differentially regulated cDNA clones. After high stringency data selection, the most prominently regulated 1629 cDNA clones representing 1510 genes of known function were clustered. Genes corresponding to functional and anatomical alterations in the injured carotid wall were further aligned into functional groups according to Gene Ontology classification. The observed expression patterns faithfully reflected the functional and anatomical alterations observed in the vascular wall in response to injury. The analysis presents a tentative model for genomic response to balloon catheter injury and a road map to identify time-related genomic alterations in human vascular specimens.
Animals↗
Estrogen regulates insulin-like growth factor 1, platelet-derived growth factor A and B, and their receptors in the vascular wall.
BACKGROUND: Peptide growth factors induce vascular smooth muscle cell (SMC) proliferation and migration after vascular injury, leading to arterial stenosis. Estrogen provides vasculoprotective effects by regulating endothelial and vascular SMC function. METHODS: We performed aortic denudations in male Wistar rats. One group received 17beta-estradiol, 0.25 mg/kg per day subcutaneously, and the other group vehicle. Growth factor and receptor mRNA in the aorta wall was quantitated at 15 minutes, 3 days, and 7 days after denudation. Western blotting and immunohistochemistry were used to quantify and localize the protein. RESULTS: Aortic injury caused SMC proliferation in the intima and media, indicated by an increase in the number of intimal nuclei and area. Quantitative reverse-transcriptase polymerase chain reaction and Western blotting showed concomitant up-regulation of insulin-like growth factor (IGF)-1, platelet-derived growth factor (PDGF)-B, and PDGF-receptor (R)alpha. 17beta-estradiol significantly inhibited SMC proliferation and intimal thickening. Similarly, estrogen administration completely suppressed IGF-1 mRNA (P=0.004) and protein but had no effect on IGF-1R. Estrogen had virtually no effect on PDGF-A mRNA or protein levels; however, on day 7, it inhibited PDGF-Ralpha mRNA by 74% (P=0.005) and protein by 67%. On day 7, it also inhibited PDGF-B mRNA expression by 36% (P=0.04) but had little effect on protein. PDGF-Rbeta expression was unaffected by estrogen. Estradiol treatment reduced immunoreactivity of IGF-1, PDGF-A, PDGF-Ralpha, and PDGF-B in vascular lesions, whereas no changes were seen with respect to IGF-1R and PDGF-Rbeta. CONCLUSIONS: Our findings demonstrate that estrogen regulates IGF-1, PDGF-A, PDGF-B, and PDGF-Ralpha, which may be related to the vasculoprotective effect of estrogen, but has no effect on IGF-1R or PDGF-Rbeta.
Animals↗
Sirolimus-based therapy following early cyclosporine withdrawal provides significantly improved renal histology and function at 3 years.
Graft function and histology are predictive of renal transplant survival. The Rapamune Maintenance Regimen study demonstrated that early cyclosporine (CsA) withdrawal from a sirolimus (SRL)-CsA-steroid (ST) regimen improved renal function and blood pressure. We report the protocol-mandated biopsy findings from that study. Renal transplant patients (n = 430) receiving SRL-CsA-ST were randomized at 3 months after transplantation to remain on SRL-CsA-ST, or to have CsA withdrawn (SRL-ST group). Protocol-mandated biopsies were performed at engraftment and at 12 and 36 months. Two pathologists blindly evaluated 484 biopsies to obtain the Chronic Allograft Damage Index (CADI) scores. At 36 months among patients with serial biopsies (n = 63), the mean CADI score was significantly lower with SRL-ST(4.70 vs. 3.20, p = 0.003), as was the mean tubular atrophy score (0.77 vs. 0.32, p < 0.001). All six components of the CADI score were numerically lower in SRL-ST group; moreover, inflammation and the tubular atrophy scores decreased significantly in the SRL-ST group between 12 and 36 months. The calculated glomerular filtration rate at 36 months was significantly better in the CsA-withdrawal group (54.8 vs. 68.2 mL/min, p = 0.009). In conclusion, withdrawing CsA from the SRL-CsA-ST regimen resulted in improved renal histology and function.
Adult↗
Leflunomide analogue FK778 is vasculoprotective independent of its immunosuppressive effect: potential applications for restenosis and chronic rejection.
BACKGROUND: Leflunomide (LFM) inhibits experimentally both acute and chronic allograft rejection. The inhibition of dihydroorotate dehydrogenase (DHODH) in pyrimidine synthesis is suggested to be the major immunosuppressive mechanism. The mechanism of its vasculoprotective effect is not known, although it may be linked to inhibition of receptor tyrosine kinases (RTK). Here, we have investigated whether sufficient vasculoprotective effect could be obtained upon administration of FK778, a LFM analogue with shorter half-life, and compared the dose response with that of a known platelet-derived growth factor RTK inhibitor, imatinib, after endothelial injury in vivo. METHODS AND RESULTS: Wistar rats were used for aorta denudations. The rats remained untreated or received either FK778 or imatinib (STI571) at decreasing oral doses from 10 mg/kg per day. Half of the animals in both treatment groups also received uridine to reverse DHODH activity. Morphometric analysis was done after 14 day follow-up. In the untreated group, moderate neointima formation was detected. FK778 almost completely inhibited intimal formation, with or without uridine addition (P<0.05). Imatinib also inhibited neointima formation (P<0.05), whereas exogenous uridine reversed its effect. CONCLUSIONS: Our results demonstrate that FK778 inhibits neointima formation by way of a mechanism that is independent of DHODH inhibitory activity on vascular smooth muscle cell. Interestingly, the effect of imatinib was inhibited by uridine, suggesting that part of its action on vascular stenosis could be mediated through inhibition of pyrimidine synthesis.
Alkynes↗
Cytomegalovirus and transplant arteriopathy: evidence for a link is mounting, but the jury is still out.
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Coronary Artery Disease↗
Protocol core needle biopsy and histologic Chronic Allograft Damage Index (CADI) as surrogate end point for long-term graft survival in multicenter studies.
This study is an investigation of whether a protocol biopsy may be used as surrogate to late graft survival in multicenter renal transplantation trials. During two mycophenolate mofetil trials, 621 representative protocol biopsies were obtained at baseline, 1 yr, and 3 yr. The samples were coded and evaluated blindly by two pathologists, and Chronic Allograft Damage Index (CADI) score was constructed. At 1 yr, only 20% of patients had elevated (>l.5 mg/100 ml) serum creatinine, whereas 60% of the biopsies demonstrated an elevated (>2.0) CADI score. The mean CADI score at baseline, 1.3 +/- 1.1, increased to 3.3 +/- 1.8 at 1 yr and to 4.1 +/- 2.2 at 3 yr. The patients at 1 yr were divided into three groups, those with CADI <2, between 2 and 3.9, and >4.0, the first two groups having normal (1.4 +/- 0.3 and 1.5 +/- 0.6 mg/dl) and the third group pathologic (1.9 +/- 0.8 mg/dl) serum creatinine. At 3 yr, there were no lost grafts in the low CADI group, six lost grafts (4.6%) in the in the elevated CADI group, and 17 lost grafts (16.7%) in the high CADI group (P < 0.001). One-year histologic CADI score predicts graft survival even when the graft function is still normal. This observation makes it possible to use CADI as a surrogate end point in prevention trials and to identify the patients at risk for intervention trials.
Biopsy, Needle↗
Chronic rejection: prospects for therapeutic intervention in fibroproliferative vascular disease.
Vascular disease, manifesting as either transplant arteriopathy or native atherosclerosis, is currently the main obstacle to successful transplant outcome. In addition, vascular restenosis following balloon angioplasty or stenting continues to limit the long-term efficacy of these procedures. Neointimal hyperplasia is refractory to conventional immunosuppression although newer agents, such as rapamycin, have shown considerable promise in controlling it. By allowing large-scale study of gene expression during vascular remodelling, the emerging field of genomics is poised to revolutionise the drug discovery process. Here we summarise our initial experience using genomic methods to identify new targets for therapeutic intervention in vascular disease.
Chronic Disease↗
A peptide mimic of selectin ligands abolishes in vivo inflammation but has no effect on the rat heart allograft survival1.
Acute heart allograft rejection is characterized by leukocyte infiltration and myocyte damage, key elements in the histological grading of rejection. The induction of selectins and their ligands on the graft postcapillary venular endothelium increases leukocyte tethering to, rolling on, and extravasation through the endothelium into graft parenchyma. We have characterized peptide mimicking selectin ligands by screening phage peptide libraries using anti-Lewis A antibodies and E-selectin as target molecules. The effect of this selectin- binding peptide, IELLQAR, on the prevention of inflammation and tissue damage and on the prolongation of graft survival in inbred DA (RT1a) rat heart allografts transplanted to WF (RT1v) recipients was tested. Bovine serum albumin (0.1%, solvent), VTSIAQA (control peptide), or IELLQAR were either continuously infused into the peritoneum via osmotic mini pumps or injected twice daily IV. Treatment with bovine serum albumin and VTSIAQA did not alter the number of graft infiltrating leukocytes or the histological grade of acute rejection, all scored as grade 4. On the contrary, the selectin binding peptide, IELLQAR, dose-dependently reduced inflammation and at the highest dose (6.0 mg/kg per day) eliminated the majority of graft infiltrating leukocytes, reduced the histological grade from 4 to 1B, but had no effect on graft survival. These data indicate that the intensity of inflammation related to the allograft rejection does not correlate to the graft survival.
Animals↗
Glycosylation might provide endothelial zip codes for organ-specific leukocyte traffic into inflammatory sites.
Inflammatory diseases are characterized by the leukocyte infiltration into tissues. L-selectin on lymphocytes and its endothelial glycosylated ligands are instrumental in the initiation of lymphocyte extravasation. Immunohistochemical stainings with monoclonal antibodies against functionally active glycan-decorated L-selectin ligands, ie, sialyl-Lewis x (sLex, 2F3, and HECA-452) or sulfated extended core 1 lactosamine (MECA-79), were performed on more than 400 specimen representatives for thyroiditis, myocarditis, psoriasis, vasculitis, ulcerative colitis, and their corresponding noninflamed tissues. The endothelial expression of sLex or sulfo sLex glycans in postcapillary venules was either absent or low in control tissues. The de novo induction of endothelial expression of sLex or sulfo sLex glycans was detected in all inflamed tissues. Furthermore, each organ carried its own modification of sLex or sulfo sLex glycans, ie, zip code. Our results suggest that these zip code glycans may provide means for organ selective leukocyte traffic that could be used in selective leukocyte traffic inhibition.
Cell Movement↗
De novo induction of endothelial L-selectin ligands during kidney allograft rejection.
Acute kidney allograft rejection is characterized by a lymphocyte infiltration. L-selectin on lymphocytes and its endothelial glycosylated ligands are instrumental in the initiation of lymphocyte extravasation to sites of inflammation. From more than 500 core biopsy specimens taken from kidneys after transplantation, 250 biopsies were graded to have signs of acute rejection. Of these, 52 biopsies with various grades of histologic signs of acute rejection were selected for the study. Controls were 15 biopsies taken within 30 min after revascularization and 10 specimens from well-functioning allografts showing no clinical or histologic evidence of rejection. Immunochemical stainings with monoclonal antibodies against functionally active decorated L-selectin ligands. i.e., sialyl-Lewis x (sLex, 2F3 and HECA-452) or sulfated lactosamine (MECA-79) were performed. Although no endothelial 2F3 and MECA-79 epitopes were detected in nonrejecting control specimens, the expression was induced at the onset and during acute allograft rejections. The level of expression (in semi-quantitative score) of 2F3 reactivity correlated with the severity of rejection (P<0.0001, grade I versus grade IIB), and the level of expression decreased as the rejection resolved. Kidney biopsies taken shortly after revascularization and thus undergoing reperfusion injury showed endothelial staining with another anti sLex antibody, HECA-452. This staining disappeared from well-functioning grafts and reappeared at the onset of an acute allograft rejection. These results suggest that expression of functionally active, properly glycosylated L-selectin ligands might have a role in reperfusion injury and in the initiation of acute rejections after human kidney allograft transplantation.
Amino Sugars↗