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E A Kallio

Publications and source records attributed to E A Kallio.

11 recordsLinked to original sources
PubMed2001

Prevention of cytomegalovirus infection-enhanced experimental obliterative bronchiolitis by antiviral prophylaxis or immunosuppression in rat tracheal allografts.

In this study, the prevention of rat cytomegalovirus (RCMV) infection-enhanced experimental obliterative bronchiolitis in rat tracheal allografts was investigated. RCMV infection markedly enhanced cell proliferation and histological changes of obliterative bronchiolitis, a form of chronic rejection after lung transplantation. These alterations were linked to increased interleukin (IL)-2 and tumor necrosis factor-alpha (TNF-alpha) immunoreactivity, and reduction of IL-10 expression. In recipient rats with acute RCMV infection, prophylaxis with either ganciclovir (DHPG) or hyperimmune serum (HIS) totally prevented RCMV infection-enhanced tracheal occlusion. DHPG treatment initiated during acute RCMV infection also reduced lesion development but markedly less than DHPG prophylaxis. Treatment of acute RCMV infection with HIS alone or in combination with DHPG had no significant effect on tracheal occlusion. Inhibition of the transcription of cytokines by high doses of cyclosporine A significantly reduced RCMV infection-enhanced tracheal obliteration. In rats with chronic RCMV infection, obliterative alterations were prevented by DHPG prophylaxis initiated at the time of transplantation. Prophylaxis either with DHPG or HIS did not affect the amount of infectious RCMV recovered from host salivary glands, nor were there differences seen in RCMV major immediate early DNA expression in tracheal allografts between different antiviral drug regimens. Immunohistochemical analysis of allografts revealed that inhibition of tracheal occlusion by antiviral prophylaxis was associated with a reduction in the number of ED1(+) macrophages and cells staining for Th1 cytokines and TNF-alpha, while immune modulation by cyclosporine A up-regulated IL-10 production. In conclusion, the results of the present study suggest that the CMV infection-enhanced chronic rejection develops independently of viral load but requires both immune activation and simultaneous CMV gene expression beyond immediate early genes.

Acute Disease↗
PubMed2001

Early induction of platelet-derived growth factor ligands and receptors in acute rat renal allograft rejection.

BACKGROUND: Acute rejection is the single most important risk factor for the development of subsequent chronic rejection. Platelet-derived growth factor (PDGF) is a major mitogen that mediates mesenchymal cell proliferation in chronic rejection. Therefore, we investigated whether PDGF ligands and receptors are induced during acute renal allograft rejection in rat. METHODS: Kidney transplantations were performed from Dark Agouti (DA) to Wistar-Furth (WF) rats, and syngenic controls were performed from DA to DA rats. Allografts were immunosuppressed with cyclosporine (CsA) 1.5 mg/kg/d subcutaneously or left untreated. Grafts were harvested at 1, 3, 5, and 7 days for histology and immunohistochemistry. RESULTS: In syngenic grafts, no histological signs of acute rejection were seen and the expression of PDGF ligands and receptors remained almost nonexistent. In nontreated allografts, intense rejection resulted in graft necrosis in 7 days. Acute rejection was associated with the induction of all PDGF ligands and receptors (P<0.05 compared to syngenic controls). The expression of PDGF ligands and receptors was located mainly to graft-infiltrating macrophages but also to capillary endothelium and arteriolar smooth muscle cells. CsA significantly ameliorated acute rejection but failed to inhibit the induction of PDGF and its receptors in CsA-treated allografts. CONCLUSIONS: Our results demonstrate that PDGF ligands and receptors are induced during acute rejection. PDGF may be induced directly as a reparative response to graft injury in acute rejection or indirectly by various inflammatory mediators released by graft-infiltrating inflammatory cells. This study indicates that PDGF ligands and receptors are already induced in acute rejection, which suggests a link between acute rejection and the subsequent development of chronic rejection.

Acute Disease↗
PubMed2000

Blockade of complement inhibits obliterative bronchiolitis in rat tracheal allografts.

The role of complement activation in the development of obliterative bronchiolitis, a manifestation of chronic lung allograft rejection, was investigated in the heterotopic rat tracheal allograft model. An increase in intragraft complement components C3 and C5b-9 (membrane attack complex) as well as IgM and IgG deposits were demonstrated during the progressive loss of respiratory epithelium and airway occlusion in nontreated allografts compared with syngeneic grafts. A 7-d treatment with recombinant human soluble complement receptor type 1 (sCR1; 20 mg/kg/d, intraperitoneal), an inhibitor of both the classic and alternative complement pathways, significantly decreased epithelial necrosis and intragraft neutrophil infiltration, and reduced obliterative changes by 40%. Immunohistochemical analysis of the grafts showed that sCR1 treatment significantly decreased early C5b-9 and IgG deposits, neutrophil chemoattractant IL-8 immunoreactivity, and ICAM-1 expression. Treatment with sCR1 was associated with increased staining for Th2 cytokines, in particular IL-10, with concomitant downregulation of IL-2 and TNF-alpha immunoreactivity. In contrast, sCR1 treatment did not affect the number of graft-infiltrating CD4(+) and CD8(+) T cells, CD45(+) B cells, ED1(+) and ED3(+) macrophages, or immune activation with expression of IL-2Ralpha or MHC class II. In conclusion, this is the first study to demonstrate that blockade of complement activation attenuates the development of OB and suggests that in addition to T cell-driven responses, humoral and antigen-independent immune responses also operate in the disease process. A blockade of complement activation renders the chemokine milieu unattractive to neutrophils and also modulates the alloimmune response toward Th2 cytokines, which may have an antiproliferative role in fibroproliferative disorders.

Animals↗
PubMed1999

Cytomegalovirus infection and cardiac allograft vasculopathy.

There is a wealth of clinical and experimental evidence indicating the interaction of cytomegalovirus (CMV) infection and rejection in cardiac and other solid organ allografts. A plausible explanation for this association comes from data showing that therapy with biologicals, sepsis, and rejection, all lead to the release of TNF-alpha which, upon binding to its receptor, activates NF-kB. TNF-alpha is also able to stimulate the activity of the CMV-IE enhancer/promoter region. CMV infection of several cell lines leads to NF-kB activation. NF-kB binding sites are present in regulatory regions of various cellular and viral genes, including the IE enhancer region of CMV. In a reciprocal situation, CMV infection, most likely via gamma-interferon, leads to upregulation of MHC antigens in the transplant and, thereby, to increased transplant immunogenicity. Thus, a vicious circle is induced. We have investigated in detail the pathobiology of CMV and allograft vasculopathy (chronic rejection) in experimental animals, using aortic and cardiac allografts as well as a trachea model. The results may be summarized as follows: Infection of the recipient with rat CMV results in an early inflammatory response in the aortic and cardiac allograft vascular adventitia and intima (endothelialitis) and in the airway wall of tracheal allografts. This early inflammatory response leads to enhanced intimal thickness in aortic and cardiac allografts and enhanced luminal occlusion of tracheal allografts. Timewise, this coincides with early activation of intragraft inflammatory leukocytes and increased mRNA of various growth factors and cytokines. When the recipients receive gancyclovir, the enhanced intimal response in aortic and cardiac allografts and luminal occlusion in tracheal allografts is entirely abolished. Gancyclovir treatment dramatically reduces the inflammatory response in the allograft, and thereby growth factor synthesis in response to injury. However, gancyclovir does not prevent the expression of IE antigen of CMV, suggested to inactivate tumor suppressor protein p53 predisposing smooth muscle cells to increased growth. Taken together, the effect of CMV infection on cardiac allograft dysfunction is bidirectional and biphasic. The bidirectional nature emerges from the observations that acute CMV infection may accelerate acute rejection, and, on the other hand, acute alloimmune response-associated cytokine response may activate latent CMV infection. The biphasic effect of CMV on allograft dysfunction refers to its early and late detrimental effects, i.e. during the time of acute and chronic rejection. These two effects of CMV on allograft dysfunction emphasize the need for precise diagnosis of CMV infection in transplant recipients and pre-emptive or prophylactic anti-viral therapy. The benefits of this strategy may not be evident during the early post-transplant period, but 5-10 years after transplantation they manifest as better graft survival.

Animals↗
PubMed1999

Role of platelet-derived growth factor in obliterative bronchiolitis (chronic rejection) in the rat.

The role of platelet-derived growth factor (PDGF) in the development of obliterative bronchiolitis (OB) as a manifestation of chronic rejection was investigated in the heterotopic rat tracheal allograft model. An increase in intragraft PDGF-Ralpha and -Rbeta mRNA expression, and in PDGF-AA and -Ralpha immunoreactivity, was demonstrated during the progressive loss of respiratory epithelium and airway occlusion in nontreated allografts compared with syngeneic grafts. Treatment with CGP 53716, a protein-tyrosine kinase inhibitor selective for PDGF receptor, alone and in combination with suboptimal doses of cyclosporin A, significantly reduced myofibroproliferation and the degree of OB by more than 50%. CGP 53716 did not affect airway wall inflammatory cell proliferation, the number of graft-infiltrating CD4(+) or CD8(+) T cells, ED3(+) macrophages, or the level of immune activation determined as IL-2R and MHC class II expression. This study suggests a regulatory role for PDGF, especially for PDGF-AA and -Ralpha, in the development of obliterative bronchiolitis in this model, and demonstrates that inhibition of PDGF receptor protein-tyrosine kinase activation prevents these obliterative changes. Thus, receptor protein-tyrosine kinase inhibitors may provide a novel therapeutic strategy for the prevention of chronic rejection.

Animals↗
PubMed1997

Role of nitric oxide in experimental obliterative bronchiolitis (chronic rejection) in the rat.

The role of nitric oxide in obliterative bronchiolitis development, i.e., chronic rejection, was investigated in the heterotopic rat tracheal allograft model. An increase in the intragraft inducible nitric oxide synthase (iNOS) mRNA and mononuclear inflammatory cell iNOS immunoreactivity was demonstrated during progressive loss of respiratory epithelium and airway occlusion in nontreated allografts compared to syngeneic grafts. In nontreated allografts, however, intragraft nitric oxide production was decreased, most likely because of loss of iNOS epithelial expression. Treatment with aminoguanidine, a preferential inhibitor of inducible nitric oxide synthase, was associated with enhanced proliferation of alpha-smooth muscle actin immunoreactive cells and the intensity of obliterative bronchiolitis early after transplantation. Aminoguanidine treatment did not affect iNOS mRNA synthesis or intragraft nitric oxide production, but decreased iNOS immunoreactivity in smooth muscle cells. Treatment with L-arginine, a precursor of nitric oxide, significantly reduced obliterative changes. L-arginine supplementation enhanced intragraft iNOS mRNA synthesis and iNOS immunoreactivity in capillary endothelial and smooth muscle cells as well as intragraft nitric oxide production. Immunohistochemical analysis of allografts showed that neither iNOS inhibition nor supplementation of the nitric oxide pathway affected the number of graft-infiltrating CD4+ and CD8+ T cells, ED1+ and ED3+ macrophages, immune activation with expression of IL-2R or MHC class II, or production of macrophage or Th1 cytokines. In contrast, L-arginine treatment was associated with increased staining for Th2 cytokines IL-4 and IL-10. In conclusion, this study demonstrates that nitric oxide has a protective role in obliterative bronchiolitis development in this model, and suggests that nitric oxide either directly or indirectly inhibits smooth muscle cell proliferation and modulates immune response towards Th2 cytokines.

Animals↗
PubMed1997

A dose-dependent inhibitory effect of cyclosporine A on obliterative bronchiolitis of rat tracheal allografts.

Inbred DA and WF rats were used as donors and recipients of heterotopic tracheal allografts. To investigate cellular and molecular mechanisms as well as inhibitory effects of differently acting immunosuppressive drugs on the development of obliterative bronchiolitis (OB), the recipient rats received either cyclosporine A (CsA; 1, 2, or 5 mg/kg/d), 15-deoxyspergualin (DSG; 1 or 2 mg/kg/d), or mycophenolate mofetil (MMF; 20 or 40 mg/kg/d), or were left without immunosuppression. The grafts were removed at various time points for histology and immunohistochemistry. In tracheal allografts removed from nonimmunosuppressed animals, respiratory epithelium was replaced by cuboidal or squamous cell epithelium, with markedly enhanced expression of epithelial major histocompatibility class (MHC) Class II antigens at 3 d after transplantation. This was associated with a pronounced inflammatory episode and proliferation of T cells and macrophages, with the prominence of lymphoid activation markers, MHC Class II antigens and interleukin-2R (IL-2R). Later, total epithelial necrosis developed and intense proliferation of granulation tissue occluded the airway lumen producing a condition resembling OB in humans. In syngeneic tracheal grafts, no such changes could be observed. CsA decreased the development of OB in a dose-dependent fashion, in association with downregulation of epithelial MHC Class II antigen expression, IL-2R expression, and the infiltration of T cells. The new immunosuppressive drugs DSG (suppression of the monocyte/macrophage action and lymphocyte proliferation) and MMF (blocking of the de novo pathway of purine synthesis), in the dose range tested, showed no significant effect on the development of OB. These results suggest that an acute alloimmune response to airway targets, perhaps to epithelium, is the primary cause of OB, since CsA, with a nearly exclusive effect on the transcription of immune cytokines, entirely inhibited the generation of OB, and that preventive intervention for OB must occur early in the T-cell activation pathway.

Animals↗
PubMed1997

Cytomegalovirus infection enhances experimental obliterative bronchiolitis in rat tracheal allografts.

Inbred DA (AG-B4, RT1a) and WF (AG-B2, RT1v) rat immunosuppressed with cyclosporine A (CsA) 2 mg/kg/day subcutaneously were used as donors and recipients of heterotopic rat tracheal allografts. Acute infection was established by inoculating the recipients with 10(5) plaque-forming units of rat cytomegalovirus (RCMV) intraperitoneal on the day of transplantation. Chronic RCMV infection was similarly established 8 wk before transplantation in donors alone, recipients alone, and in both donor and recipients. The control rats were left noninfected. For in vivo cell proliferation, the rats received bromedeoxyuridine intravenously 3 h before being killed. RCMV infection significantly enhanced the generation of experimental obliterative bronchiolitis (OB). First, acute RCMV infection was linked to markedly enhanced MHC class II expression on the respiratory epithelium and prominent airway wall inflammation of W3/25+ T cells (CD4+) and ED1+/ED2+ macrophages. Second, acute infection induced a fivefold increase in luminal occlusion of the trachea, due to proliferating inflammatory and alpha-smooth muscle actin+ myofibroblast-like cells. Acute RCMV infection was particularly associated with markedly increased expression of platelet-derived growth factor (PDGF) AA-isoform in various structures of the graft 10 d after transplantation. At 30 d, RCMV significantly increased PDGF alpha- and beta-receptor expression in alpha-smooth muscle actin+ cells and TNF-alpha expression in capillary endothelial cells of the fibroproliferative lesion. In chronic recipient RCMV infection, the histopathological changes were quite similar to acute infection. Chronic donor infection did not amplify the development of experimental OB. As analyzed by immunohistochemistry from the grafts and by plaque assays from salivary gland biopsies of the recipients, trace RCMV antigen expression, while no infectious RCMV could be recovered in the chronic donor infection group. In other infected groups, RCMV antigen expression was mild to moderate and salivary glands contained plenty of infectious RCMV. To conclude, our results indicate that RCMV infection enhances epithelial MHC class II expression and myofibroproliferation in heterotopic rat tracheal allografts and suggest that these changes may be induced by increased PDGF-AA and PDGF alpha-receptor expression, respectively.

Acute Disease↗