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Lectures
Abstracts . 227
Lectures
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183
EFFECTS OF RECOMBINANT NEUROPOIETIC CYTOKINES ON DORSAL ROOT GANGLION NEURONS AND BAF/3 CELLS 1. WEISl (a.G.), A. KRUTTGENl (a.G.), M. THIERl (a.G.), R. SIMONI (a.G.),1. MULLBERG2 (a.G.), P. C. HEINRICH2 (a.G.), 1. M. SCHRO DERl, S. ROSE-JOHN2 (a.G.) Institute fur lNeuropathologie und 2Biochemie, RWTH Aachen, Germany Aims: Interleukin-6 (IL-6), interleukin-ll (IL-II), ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), and oncostatin M (OSM) are members ofthe neuropoietic cytokine faniily. These molecules are tro phic factors for subsets of neurons. They also influeuce growth and diffe rentiation of various types of neoplasms. We investigated the range ofbio logical effects and structure-function relationships of these factors. Methods: N-(N-14, N-23, N-32) and C-(C-3, C-18, C-21, C-24) terminal deletion mutants and a double point mutant (LysI54Glu, Trp I 57Pro ) of human CNTF were generated using PCR and expressed in E. coli. Survival and growth promoting effects of these muteins and of recombinant human wild type (wt) CNTF, human IL-6, human lL-II, mouse LlF, and human OSM were determined nsing cultures of newbom rat dorsal root ganglion (DRG) and BAF/3 cells. The BAF/3 cells were rendered CNTF-sensitive by transfection with CNTF receptur subunit cDNAs. Results: Mouse LIF and human OSM had survival promoting effects on rat DRG cells similar to the well known activity of CNTF. 1L-6 and IL-I I were inactive in this assay. The N-23, N-32, C-21, C-24 and Glu154, Pro 157 mnteins had rednced (compared to wtCNTF) or abolished bioactivities in both cell culture systems used. The distribution of sequences essential for biological function in CNTF was similar to the recently de scribed pattem in 1L-6. The survival promoting activities of the N-14 and C-18 CNTF muteins on DRG cells was significantly increased compared to wtCNTF. The Gin I 54, Prol57 mutein, on the other hand, had an antago nistic effect on wtCNTF activity on BAF13 cells. Conclusions: The present results corroborate the structural similarities and overlapping bioactivities of the five neuropoietic cytokines studied. They also demonstrate that modification of CNTF structure can lead to muteins with antagonistic or improved agonistic properties.
THE EXPLANTED LIVER OF THE RECIPIENT IN LIVER TRANSPLAN TATION - SPECTRUM OF LIVER DIESEASES FROM FULMINANT LIVER FAILURE TO TERMINAL CHRONIC LIVER DISEASE w.J HOFMANN
182
184
MALFORMATIVE GLIONEURONAL LESIONS AND DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMORS IN CHRONIC PHARMACORESISTANT EPILEPSIES
PATHOLOGY OF THE TRANSPLANTED LIVER B.PORTMANN King's College Hospital School of Medicine, London, UK
H.K. WOLF, J. WELLMER (a.G.), MARIANNE B. MULLER (a.G.), O.D. WIESTLER (a.G.), A. HUFNAGEL (a. G.), T. PIETSCH (a.G.) Institut fUr Neuropathologie und Klinik fUr Epileptologie, Universitiit Bonn, BRD
Over the past 30 years, liver transplantation has evolved from an experimental therapy to a routine procedure and most pathology textbooks have now a section dedicated to the pathology of liver allograft. There remain problems of biopsy interpretation due to the numerous posttransplant factors which can operate singly or in association to often produce a pleomorphic histological picture. Many features, such as the outcome of donor fatty liver, reperfusion damage, some ischaemic lesions and massive haemorrhagic necrosis are unique to the transplanted liver. Similarly the patterns of rejections, in particular the rarity and delayed occurrence of hyperacute rejection and the selective involvement of the small interlobular bile ducts and vascular endothelia in both acute and chronic graft rejection are quite distinctive. Acute cellular rejection with its triad of portal inflammation, venular endotheliitis and cholangitis is no longer a diagnostic problem. Chronic rejection which variably combines foam cell arteriopathy, ductopenia with perivenular hepatocyte drop-out and fibrosis remains a major diagnostic challenge as well as an unsolved pathogenic problem. "Functional" cholestasis with hepatocyte ballooning is thought to reflect an organelle damage, whereas cholangiolar cholestasis, typically associated with sepsis is a common finding in liver graft biopsy specimens. Cholangiodestruction of the larger bile ducts, biliary strictures and bile sludging may result from preservation damage, immune andlor ischaemic cholangitis and closely resemble the changes observed in primary or acquired sclerosing cholangitis occurring in a non-transplant setting. Later in the posttransplant course, changes due to de novo or recurrent hepatitis, especially CMV, HCV, HBV and EBV infection, have to be distinguished from those due to (a) late cellular rejection, the two being not mutually exclusive; (b) protracted biliary complications; (d) drug, in particular azathioprine toxicity; (e) possible disease recurrence, such as autoimmune chronic hepatitis, primary biliary cirrhosis and sclerosing cholangitis; (f) B-cell Iymphoproliferative disorder. Special techniques, such as immunostaining for CMV and HBV antigens, PCR for HCV -RNA have somewhat improved the diagnostic rate, but the interpretation of biopsy changes in conjunction with radiological, laboratory and clinical data is of crucial importance to improve the diagnostic skill of the pathologist.
Aims: Malformative glioneuronal lesions and dysembryoplastic neuroepithelial tumors (DNT), an entity which has been proposed to be malformative rather than neoplastic, are common in patients with chronic focal epilepsies. The goal of the study was to determine the scope of the histopathological changes and to better understand the biological nature and pathogenesis of these lesions. Methods: We examined malformative lesions and DNT in surgical specimens from 43 epilepsy patients with respect to their location, size, cellular composition, and expression of the Ki-67 antigen, and the developmentally regulated embryonal form of the neural cell adhesion molecule (E-NCAM). Results: There were 24 hamartias composed of randomly oriented neurons and astrocytes. Most of these lesions also contained clustered oligodendrocyte-like cells which were strongly immunoreactive for E NCAM. These hamartias were typically minute, multifocal, and were arranged in a pattem suggestive of a migration disorder. There were 8 cases with aggregates of large disfigured neurons, oversized atypical astrocytes and ballooned multinucleated giant cells reminiscent of tuberous sclerosis. Finally, there were 11 DNT. The oligodendroglia like cells in DNT were negative for E-NCAM. However, strong E NCAM expression was present in many dysplastic neurons of tuberous sclerosis-like lesions, hamartias and DNT and in reactive astrocytes. Significant immunoreactivity for the Ki-67 antigen was not observed. No similar lesions were observed in 500 consecutive autopsies from patients without epilepsy. Conclusions: Malformative glioneuronallesions appear to be highly epileptogenic and most likely result from disordered cell migration and differentiation.
Pathologisches Institut der Universitiit Heidelberg Liver transplantation is now a routine therapeutic procedure for liver diseases without alternative therapeutic possibilities. Fulminant liver failure, end stage chronic liver diseases and metabolic disorders are main indications for liver transplantation (see Table). Indications for Liver Transplantation HD 7/87 - 11194 (n = 187) Cirrhoses
total
110
with Malign.
22
without Malign.
88
Malignancies
54
Fulminant liver failure
25
Metabolic disorders
13
Vascular diseases (Budd Chiari)
7
Others (E alveolaris) Explanted livers thus represent a spectrum of liver diseases from fulminat liver failure, malignancies and metabolic disorders to end stage chronic liver diseases. Explanted livers permit a morphologic examination and evaluations within the different groups of diseases which are not possible with bioptic or aut optic material. The experience with the diagnosis and evaluation of explanted livers during a time period of 7 years is reported.
Lectures
181
183
EFFECTS OF RECOMBINANT NEUROPOIETIC CYTOKINES ON DORSAL ROOT GANGLION NEURONS AND BAF/3 CELLS 1. WEISl (a.G.), A. KRUTTGENl (a.G.), M. THIERl (a.G.), R. SIMONI (a.G.),1. MULLBERG2 (a.G.), P. C. HEINRICH2 (a.G.), 1. M. SCHRO DERl, S. ROSE-JOHN2 (a.G.) Institute fur lNeuropathologie und 2Biochemie, RWTH Aachen, Germany Aims: Interleukin-6 (IL-6), interleukin-ll (IL-II), ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), and oncostatin M (OSM) are members ofthe neuropoietic cytokine faniily. These molecules are tro phic factors for subsets of neurons. They also influeuce growth and diffe rentiation of various types of neoplasms. We investigated the range ofbio logical effects and structure-function relationships of these factors. Methods: N-(N-14, N-23, N-32) and C-(C-3, C-18, C-21, C-24) terminal deletion mutants and a double point mutant (LysI54Glu, Trp I 57Pro ) of human CNTF were generated using PCR and expressed in E. coli. Survival and growth promoting effects of these muteins and of recombinant human wild type (wt) CNTF, human IL-6, human lL-II, mouse LlF, and human OSM were determined nsing cultures of newbom rat dorsal root ganglion (DRG) and BAF/3 cells. The BAF/3 cells were rendered CNTF-sensitive by transfection with CNTF receptur subunit cDNAs. Results: Mouse LIF and human OSM had survival promoting effects on rat DRG cells similar to the well known activity of CNTF. 1L-6 and IL-I I were inactive in this assay. The N-23, N-32, C-21, C-24 and Glu154, Pro 157 mnteins had rednced (compared to wtCNTF) or abolished bioactivities in both cell culture systems used. The distribution of sequences essential for biological function in CNTF was similar to the recently de scribed pattem in 1L-6. The survival promoting activities of the N-14 and C-18 CNTF muteins on DRG cells was significantly increased compared to wtCNTF. The Gin I 54, Prol57 mutein, on the other hand, had an antago nistic effect on wtCNTF activity on BAF13 cells. Conclusions: The present results corroborate the structural similarities and overlapping bioactivities of the five neuropoietic cytokines studied. They also demonstrate that modification of CNTF structure can lead to muteins with antagonistic or improved agonistic properties.
THE EXPLANTED LIVER OF THE RECIPIENT IN LIVER TRANSPLAN TATION - SPECTRUM OF LIVER DIESEASES FROM FULMINANT LIVER FAILURE TO TERMINAL CHRONIC LIVER DISEASE w.J HOFMANN
182
184
MALFORMATIVE GLIONEURONAL LESIONS AND DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMORS IN CHRONIC PHARMACORESISTANT EPILEPSIES
PATHOLOGY OF THE TRANSPLANTED LIVER B.PORTMANN King's College Hospital School of Medicine, London, UK
H.K. WOLF, J. WELLMER (a.G.), MARIANNE B. MULLER (a.G.), O.D. WIESTLER (a.G.), A. HUFNAGEL (a. G.), T. PIETSCH (a.G.) Institut fUr Neuropathologie und Klinik fUr Epileptologie, Universitiit Bonn, BRD
Over the past 30 years, liver transplantation has evolved from an experimental therapy to a routine procedure and most pathology textbooks have now a section dedicated to the pathology of liver allograft. There remain problems of biopsy interpretation due to the numerous posttransplant factors which can operate singly or in association to often produce a pleomorphic histological picture. Many features, such as the outcome of donor fatty liver, reperfusion damage, some ischaemic lesions and massive haemorrhagic necrosis are unique to the transplanted liver. Similarly the patterns of rejections, in particular the rarity and delayed occurrence of hyperacute rejection and the selective involvement of the small interlobular bile ducts and vascular endothelia in both acute and chronic graft rejection are quite distinctive. Acute cellular rejection with its triad of portal inflammation, venular endotheliitis and cholangitis is no longer a diagnostic problem. Chronic rejection which variably combines foam cell arteriopathy, ductopenia with perivenular hepatocyte drop-out and fibrosis remains a major diagnostic challenge as well as an unsolved pathogenic problem. "Functional" cholestasis with hepatocyte ballooning is thought to reflect an organelle damage, whereas cholangiolar cholestasis, typically associated with sepsis is a common finding in liver graft biopsy specimens. Cholangiodestruction of the larger bile ducts, biliary strictures and bile sludging may result from preservation damage, immune andlor ischaemic cholangitis and closely resemble the changes observed in primary or acquired sclerosing cholangitis occurring in a non-transplant setting. Later in the posttransplant course, changes due to de novo or recurrent hepatitis, especially CMV, HCV, HBV and EBV infection, have to be distinguished from those due to (a) late cellular rejection, the two being not mutually exclusive; (b) protracted biliary complications; (d) drug, in particular azathioprine toxicity; (e) possible disease recurrence, such as autoimmune chronic hepatitis, primary biliary cirrhosis and sclerosing cholangitis; (f) B-cell Iymphoproliferative disorder. Special techniques, such as immunostaining for CMV and HBV antigens, PCR for HCV -RNA have somewhat improved the diagnostic rate, but the interpretation of biopsy changes in conjunction with radiological, laboratory and clinical data is of crucial importance to improve the diagnostic skill of the pathologist.
Aims: Malformative glioneuronal lesions and dysembryoplastic neuroepithelial tumors (DNT), an entity which has been proposed to be malformative rather than neoplastic, are common in patients with chronic focal epilepsies. The goal of the study was to determine the scope of the histopathological changes and to better understand the biological nature and pathogenesis of these lesions. Methods: We examined malformative lesions and DNT in surgical specimens from 43 epilepsy patients with respect to their location, size, cellular composition, and expression of the Ki-67 antigen, and the developmentally regulated embryonal form of the neural cell adhesion molecule (E-NCAM). Results: There were 24 hamartias composed of randomly oriented neurons and astrocytes. Most of these lesions also contained clustered oligodendrocyte-like cells which were strongly immunoreactive for E NCAM. These hamartias were typically minute, multifocal, and were arranged in a pattem suggestive of a migration disorder. There were 8 cases with aggregates of large disfigured neurons, oversized atypical astrocytes and ballooned multinucleated giant cells reminiscent of tuberous sclerosis. Finally, there were 11 DNT. The oligodendroglia like cells in DNT were negative for E-NCAM. However, strong E NCAM expression was present in many dysplastic neurons of tuberous sclerosis-like lesions, hamartias and DNT and in reactive astrocytes. Significant immunoreactivity for the Ki-67 antigen was not observed. No similar lesions were observed in 500 consecutive autopsies from patients without epilepsy. Conclusions: Malformative glioneuronallesions appear to be highly epileptogenic and most likely result from disordered cell migration and differentiation.
Pathologisches Institut der Universitiit Heidelberg Liver transplantation is now a routine therapeutic procedure for liver diseases without alternative therapeutic possibilities. Fulminant liver failure, end stage chronic liver diseases and metabolic disorders are main indications for liver transplantation (see Table). Indications for Liver Transplantation HD 7/87 - 11194 (n = 187) Cirrhoses
total
110
with Malign.
22
without Malign.
88
Malignancies
54
Fulminant liver failure
25
Metabolic disorders
13
Vascular diseases (Budd Chiari)
7
Others (E alveolaris) Explanted livers thus represent a spectrum of liver diseases from fulminat liver failure, malignancies and metabolic disorders to end stage chronic liver diseases. Explanted livers permit a morphologic examination and evaluations within the different groups of diseases which are not possible with bioptic or aut optic material. The experience with the diagnosis and evaluation of explanted livers during a time period of 7 years is reported.