- Email: [email protected]
Present state of pancreatic islet transplantation
ABSTRACTS
10
PRESENT STATE OF PANCREATIC ISLET TRANSPLANTATION
m m r m u 2 AM) .As3ExCs t1 -
bmx*, kcupational
PC C o l l h S t m t , , MeIbcLime,
Health ai?d Safety A u t b r i t y ,
'JIC 3ooo
Tm developm: of gavenment p h c y a? an issue like Ashes-a, where science, industrial relaticns, e c m i c s , avaiiable tec?nolcgy and ccmrw?ity cmcem all play B p r t , is a slcw and m p l e x process. The 1378 Asbestos Fegulatim esabiiskd a frmaork for deal% with cccupatimal qxxm to asbestos k a l a w l y m w f a c t u r ~ envimt. ;n develop% @ v e m t p h c y CT. asbfstos, a wlde E3Ilge of facbrs & to be m , i d e r e d : .:he asbestos i n d u t r y h 1991 is pr~kminantlj;a m v a l bindustry; .the e x p u r e standards for asbestos have Seen dmppirg ~mrlchjioein resprise to epldmiokgical in k t o i w 19.89 passec! a resolution b t m tk rwnufactm of asbestos and asbestos p r o d c t s Dy .'/:i;995; .indl*strial disputAticn over asbesm :has increased sigGificantlji - me dispute alcr'e i n 19.89 cos: akut $24 rrillim. to t.k ccmpany a d wxkers. .Minister for Labour in 1590 nquessted tbt tre Victorian QcupatimaJ ed.th and Safety Camissicc carry out at? inquiry into asbestos U S @ in c b r i a , and exxanine the feasibility of suts:itutes and alternatives.
Developnent of' new i-pglaLicm m asks+& rad m c e d witkin t k Vic'J3rian kci?@knal H d t h and W e t y Cmdssim 3 1%, kxt k a s e c i the geat cimplexities of t h i s issue, a dm-: w a s rot recawended p e Minister :mtii April 1%;. I n addi-im, tke Subrdinate Legxiation Act in Victoria q u i r e s an eccnmic asse-%xmtof all propsed n ~ w W a t i c m . Y c x m i c s dictate tbat the policy p i t i o n of the unicm for a total ban is mable +abe support&. Worlchjide tmGs ic legislation and c m i t y cmcems aim dictate tPa5 the p i t h of scme mployer p p s for very conservative regulatory ccntrol is equally Lqxmiole to tm&~r?e.
T. E. Mandel, Transplantation Unit, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3050 Transplantationof islets of Langerhans in type I diabetes mellitus, either by vascularized pancreas or free islet grafts, has the potential to cure this disease and, if performed sufficiently early after diagnosis, also prevent the development of diabetic complications. At present, however, most patients are transplanted only when their diabetic complications are already severe and generally necessitate a concurrentrenal allograft. Very few free islet grafts have been successful, and these only recently, but vascularized pancreas transplantation is becoming more widely accepted with lyear graft function rates >80% in some centres. The problems facing endocrine pancreas replacement are; 1) the need for non-specific continuing immunosuppression to prevent rejection; 2), a dearth of suitable allogeneic tissue, and 3), possible recurrence of autoimmune disease in the graft. The hope of islet replacement is that it will be able to be performed early in diabetes to prevent the development of complications and that methods will be found to minimize or even avoid immunosuppression to prevent graft rejection and disease recurrence. This has not been realized so far in patients but experiments in animals give hope that this will be possible clinically. If success is achieved the scarcity of human donor organs will become acute. We are studying the use of xenoeeneic (pig) islet grafts in a murine model of type I diabetes (in Non-Obese Diabetic Mice) where florid autoimmune destruction of endogenous islets occurs. The data so far suggest, 1) that xenogeneic islet grafts are more readily retained with less immunosuppression than allogeneic islets, and 2) that the xenografts may also be less susceptible to recurrent disease. The immune response generated against free (ie host-vascularized) xenografts may be more dependent on CD4+ve Tcells than the response against allografts that can be. rejected apparently with CD8+ve cells alone. This is in contrast to vascularized xenografts that are usually rejected hyperacutely by antibody-mediated damage to the donor vascular endothelium. Therefore, if xenografts can be shown to function and are less susceptible to recurrent disease and rejection, they may also solve the problem of donor shortage.
PATHOLOGY OF KIDNEY TRANSPLANTATION Expression and function of CAM-1 In the granulomatous Inflammation of temporal arterltls.
A.E. Seymour", Histopathology Department, Flinders Medical Centre, Bedford Park, South Australia 5042.
The graft is vulnerable to all of the diseases that may affect the native kidney but exhibits several special patterns of damage. Fine needle aspiration h a s provided much useful information about the character of cellular infiltrates and the expression of various antigens but core biopsy remains the most useful diagnostic tissue procedure. Rejection (cellular, glomerular and vascular) is the major target for graft biopsies but other patterns may be encountered and special diagnostic problems include recurrent or de novo glomerulonephritisscarring without specific features and the normal or near normal biopsy. Early experience with Cyclosporin A given in high doses delineated specific vascular and tubular lesions but the toxic changes are more subtle in current dosage protocols. Thrombotic complications are more common in patients' receiving Cyclosporin A and need to be distinguished from the haemolytic uraemic syndrome. lmmunofluorescenceand electron microscopy are as important in the examination of graft as of natural kidney biopsies and may detect evidence of glomenrlonephols - recurrent or de novo - that is not apparent by light microscopy. Assessment of the glomerular cell population in evolving glomerulonephritis and glomerulopathy may provide insights into some of the mechanisms of damage and "proliferation" in native kidney disease.
Key Words: Kidney, Transplantation, Rejection, Cyclosporin A, Glomerulonephritis.
ddal 1.
Department of Anatomical Pathology, St. Vincent's Hospital, Fitzroy, The University of Melbourne. The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
*'
Human intercellular adhesion molecule-1 (ICAM-1) plays an important role in lymphocyte activation and in a wide range of leucocyte effector functions. In order to study the role of C A M - 1 in the adhesion of different types of leucocytes, the human ICAM-1 gene was transfected into mouse L cells and C A M - 1 transfectants were used in adhesion assays. Lymphocytes and monocytes showed high levels of ICAM-1 mediated adhesion. The ability of cytokines, particularly IFN-8, to induce CAM-1 gene expression on haemopoietic and non-haemopoietic cells was demonstrated using northem blot analysis and llow cytometry. As cytokines play a crucial part in the development of the granulomatous inflammatory process immunohistochemistry was used to study the invivn expression of CAM-1 in temporal arteritis. Temporal arteries with early features of arteritis, as well as a histologically unaffected skip area, showed a regional induction of ICAM-1 expression on smooth muscle cells of the media. In more florid cases of temporal arteritis, an additional induction of C A M - 1 expression was also seen on intimal myofibroblasts. Macrophages, epithelioid cells and multinucleated giant cells were also C A M - 1 positive. The pattern of expression of C A M - 1 in temporal arteritis suggests an important role in mediating the intercellular interactions which constitute the granulomatous response. Presented: Dr. Stefan Wawryk. Department of Anatomical Pathology, St. Vincent's Hospital.
10
PRESENT STATE OF PANCREATIC ISLET TRANSPLANTATION
m m r m u 2 AM) .As3ExCs t1 -
bmx*, kcupational
PC C o l l h S t m t , , MeIbcLime,
Health ai?d Safety A u t b r i t y ,
'JIC 3ooo
Tm developm: of gavenment p h c y a? an issue like Ashes-a, where science, industrial relaticns, e c m i c s , avaiiable tec?nolcgy and ccmrw?ity cmcem all play B p r t , is a slcw and m p l e x process. The 1378 Asbestos Fegulatim esabiiskd a frmaork for deal% with cccupatimal qxxm to asbestos k a l a w l y m w f a c t u r ~ envimt. ;n develop% @ v e m t p h c y CT. asbfstos, a wlde E3Ilge of facbrs & to be m , i d e r e d : .:he asbestos i n d u t r y h 1991 is pr~kminantlj;a m v a l bindustry; .the e x p u r e standards for asbestos have Seen dmppirg ~mrlchjioein resprise to epldmiokgical in k t o i w 19.89 passec! a resolution b t m tk rwnufactm of asbestos and asbestos p r o d c t s Dy .'/:i;995; .indl*strial disputAticn over asbesm :has increased sigGificantlji - me dispute alcr'e i n 19.89 cos: akut $24 rrillim. to t.k ccmpany a d wxkers. .Minister for Labour in 1590 nquessted tbt tre Victorian QcupatimaJ ed.th and Safety Camissicc carry out at? inquiry into asbestos U S @ in c b r i a , and exxanine the feasibility of suts:itutes and alternatives.
Developnent of' new i-pglaLicm m asks+& rad m c e d witkin t k Vic'J3rian kci?@knal H d t h and W e t y Cmdssim 3 1%, kxt k a s e c i the geat cimplexities of t h i s issue, a dm-: w a s rot recawended p e Minister :mtii April 1%;. I n addi-im, tke Subrdinate Legxiation Act in Victoria q u i r e s an eccnmic asse-%xmtof all propsed n ~ w W a t i c m . Y c x m i c s dictate tbat the policy p i t i o n of the unicm for a total ban is mable +abe support&. Worlchjide tmGs ic legislation and c m i t y cmcems aim dictate tPa5 the p i t h of scme mployer p p s for very conservative regulatory ccntrol is equally Lqxmiole to tm&~r?e.
T. E. Mandel, Transplantation Unit, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3050 Transplantationof islets of Langerhans in type I diabetes mellitus, either by vascularized pancreas or free islet grafts, has the potential to cure this disease and, if performed sufficiently early after diagnosis, also prevent the development of diabetic complications. At present, however, most patients are transplanted only when their diabetic complications are already severe and generally necessitate a concurrentrenal allograft. Very few free islet grafts have been successful, and these only recently, but vascularized pancreas transplantation is becoming more widely accepted with lyear graft function rates >80% in some centres. The problems facing endocrine pancreas replacement are; 1) the need for non-specific continuing immunosuppression to prevent rejection; 2), a dearth of suitable allogeneic tissue, and 3), possible recurrence of autoimmune disease in the graft. The hope of islet replacement is that it will be able to be performed early in diabetes to prevent the development of complications and that methods will be found to minimize or even avoid immunosuppression to prevent graft rejection and disease recurrence. This has not been realized so far in patients but experiments in animals give hope that this will be possible clinically. If success is achieved the scarcity of human donor organs will become acute. We are studying the use of xenoeeneic (pig) islet grafts in a murine model of type I diabetes (in Non-Obese Diabetic Mice) where florid autoimmune destruction of endogenous islets occurs. The data so far suggest, 1) that xenogeneic islet grafts are more readily retained with less immunosuppression than allogeneic islets, and 2) that the xenografts may also be less susceptible to recurrent disease. The immune response generated against free (ie host-vascularized) xenografts may be more dependent on CD4+ve Tcells than the response against allografts that can be. rejected apparently with CD8+ve cells alone. This is in contrast to vascularized xenografts that are usually rejected hyperacutely by antibody-mediated damage to the donor vascular endothelium. Therefore, if xenografts can be shown to function and are less susceptible to recurrent disease and rejection, they may also solve the problem of donor shortage.
PATHOLOGY OF KIDNEY TRANSPLANTATION Expression and function of CAM-1 In the granulomatous Inflammation of temporal arterltls.
A.E. Seymour", Histopathology Department, Flinders Medical Centre, Bedford Park, South Australia 5042.
The graft is vulnerable to all of the diseases that may affect the native kidney but exhibits several special patterns of damage. Fine needle aspiration h a s provided much useful information about the character of cellular infiltrates and the expression of various antigens but core biopsy remains the most useful diagnostic tissue procedure. Rejection (cellular, glomerular and vascular) is the major target for graft biopsies but other patterns may be encountered and special diagnostic problems include recurrent or de novo glomerulonephritisscarring without specific features and the normal or near normal biopsy. Early experience with Cyclosporin A given in high doses delineated specific vascular and tubular lesions but the toxic changes are more subtle in current dosage protocols. Thrombotic complications are more common in patients' receiving Cyclosporin A and need to be distinguished from the haemolytic uraemic syndrome. lmmunofluorescenceand electron microscopy are as important in the examination of graft as of natural kidney biopsies and may detect evidence of glomenrlonephols - recurrent or de novo - that is not apparent by light microscopy. Assessment of the glomerular cell population in evolving glomerulonephritis and glomerulopathy may provide insights into some of the mechanisms of damage and "proliferation" in native kidney disease.
Key Words: Kidney, Transplantation, Rejection, Cyclosporin A, Glomerulonephritis.
ddal 1.
Department of Anatomical Pathology, St. Vincent's Hospital, Fitzroy, The University of Melbourne. The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
*'
Human intercellular adhesion molecule-1 (ICAM-1) plays an important role in lymphocyte activation and in a wide range of leucocyte effector functions. In order to study the role of C A M - 1 in the adhesion of different types of leucocytes, the human ICAM-1 gene was transfected into mouse L cells and C A M - 1 transfectants were used in adhesion assays. Lymphocytes and monocytes showed high levels of ICAM-1 mediated adhesion. The ability of cytokines, particularly IFN-8, to induce CAM-1 gene expression on haemopoietic and non-haemopoietic cells was demonstrated using northem blot analysis and llow cytometry. As cytokines play a crucial part in the development of the granulomatous inflammatory process immunohistochemistry was used to study the invivn expression of CAM-1 in temporal arteritis. Temporal arteries with early features of arteritis, as well as a histologically unaffected skip area, showed a regional induction of ICAM-1 expression on smooth muscle cells of the media. In more florid cases of temporal arteritis, an additional induction of C A M - 1 expression was also seen on intimal myofibroblasts. Macrophages, epithelioid cells and multinucleated giant cells were also C A M - 1 positive. The pattern of expression of C A M - 1 in temporal arteritis suggests an important role in mediating the intercellular interactions which constitute the granulomatous response. Presented: Dr. Stefan Wawryk. Department of Anatomical Pathology, St. Vincent's Hospital.