Clin Investig (1992) 70:780-790
Guest Lecture, "Gese[lsehaft f~r Nephre[ogie", 23rd Congress
Glinical Investigator © Springer-Verlag 1992
Towards understanding the pathophysiology of chronic rejection P. Hfiyry, A. Mennander, S. Yilmaz, J. Ustinov, A. R/iisfinen, A. Miettinen, I. Lautenschlager, K. Lemstr6m, C.A. Bruggeman, and T. Paavonen Transplantation Laboratory, University of Helsinki
Summary. Chronic allograft rejection is the major reason why allografts are lost. While only 2%-3% of all allografts are lost during the first year to irreversible acute rejection, approximately 6%-7% are lost during each subsequent year to chronic rejection. The major manifestation of chronic rejection in all organs is persistent perivascular inflammation and allograft arteriosclerosis. Bearing this in mind, we have developed a model to investigate the pathophysiology of allograft arteriosclerosis using aortic transplantations between inbred rat strains. The results obtained thus far indicate that several different inflammatory cascades are operative within the vascular wall during allograft arteriosclerosis. The relative importance of these different cascades, and particularly the role of growth factors as final effectors, has not yet been defined. Attempts to suppress allograft arteriosclerosis under experimental conditions have already met with some success: under conditions where no immunosuppression is provided we have been able to delay the process by at least 3 months, though we have not been able to block it indefinitely. It may be expected, however, that once the inflammatory cascades leading to smooth muscle cell replication in the allograft media and their influx into the intima are better defined, more specific approaches to the inhibition of allograft arteriosclerosis will be developed.
Key words: Allograft arteriosclerosis - Chronic allograft rejection - Growth factors - Smooth muscle cell replication
Only 15 years ago most allografts were lost owing to acute rejection and/or complications linked with its treatment. Today, irreversible acute rejection is a rare phenomenon: both patient and graft survivAbbreviations." ATG=antilymphocyte globulin; CMV=cyto-
megalovirus; CyA=cyclosporine; LT=leukotriene; PCR= polymerase chain reaction; pfu = plaque-forming units; RCMV = rat cytomegalovirus; RIA = radioimmunoassay; TxB2 = thromboxane B2
al of renal, cardiac, and liver transplants are approaching 90% for the first year, and of the 200 transplants done annually in Helsinki, only two to six are lost to irreversible acute rejection. In contrast, the half-life of transplants, including renal transplants, has remained the same [21] or increased only slightly [17]. During the first 10 years after transplantation, approximately 6% of renal allografts are lost owing to chronic rejection every year (Opelz G, personal communication). Since there are approximately 1200 renal transplant recipients with functioning grafts in Finland, this indicates a loss of ca. 70 transplants to chronic rejection annually. The histopathology of chronic rejection differs remarkably from that of acute rejection. In renal allografts, the hallmarks of acute tubulointerstitial rejection are invasion of a transplant with mononuclear leukocytes carrying high levels of lymphoid activation, and invasion of tubuli, so-called tubulitis. The type of rejection is easily reversible. Another pattern, overlapping with the previous one, is so-called acute vascular rejection, i.e., invasion of the graft vascular wall with inflammatory leukocytes. This pattern is more difficult to treat, and most lost transplants belong to this category. The end-point of acute rejection is irreversible damage to the microvascular endothelium, thrombosis, and necrosis of the graft. In chronic rejection, the most prominent feature in a renal allograft is persistent perivascular inflammation, often with relatively low level lymphoid cell activation, arterial intimal thickening, proliferative and sclerotic changes in the glomeruli, interstitial fibrosis, and tubular atrophy. These remarkable differences in histopathology indicate that the basic underlying mechanisms in acute and chronic rejection are essentially different. Demetris et al. [8] have compared the manifestations of chronic rejection in different organs. Their results and those of other investigators [7, 16, 19] are summarized in Table 1. Excluding the organ-specific changes referred to above, the common manifestations in all these transplants are per-
781 Table 1. Manifestations of chronic rejection in different organs
Heart a
Kidney b
Inflammation Inflammation Arteriosclerosis Arteriosclerosis Fibrosis
Liverc Inflammation Arteriosclerosis
BM thickening Vanishing bile ducts and Glomerular sclerosis portal arteries Tubular atrophy Fibrosis Fibrosis
BM, Basement membrane a Rose and Uys [19] b Croker and Salomon [7] c Oguma et al. [16]
ized. It affects all intramural arteries to the level of arterioles. Demetris et al. [8] have described the fine microscopic features of allograft arteriosclerosis in heart, kidney, and liver transplants. With minor variations, the most common features are, in addition to the perivascular inflammation, thinning of the vascular media, focal breaks in the internal elastic lamina, and concentric, generalized intimal thickening, where smooth muscle cells in the intima are intermingled with some inflammatory T cells and macrophages, often characterized as foam cells (Fig. 1).
Working hypothesis sistent perivascular inflammation and arteriosclerotic changes. These findings suggest that the basic underlying cause of chronic rejection in all transplants is allograft arteriosclerosis. When investigating the pathophysiology of chronic rejection, one should concentrate on the question of how persistent perivascular immune inflammation regulates smooth muscle cell replication in the media and the migration of these cells into the intima.
Allograft arteriosclerosis In contrast to ordinary atherosclerosis, which is usually focal and excentric, the common form of allograft arteriosclerosis is concentric and general-
A possible sequence of events leading to smooth muscle cell replication in the vascular walls in transplants undergoing chronic rejection is shown in Fig. 2. As such changes are not observed in syngeneic experimental transplants, it is assumed that the driving force behind allograft arteriosclerosis is histoincompatibility. In acute rejection, continuous recirculation of immunocompetent T lymphocytes carrying receptors to donor MHC antigens interact with the antigen-presenting cells (APC) and are induced to display receptors to interleukin 2 (IL2) and produce IL2. As a consequence, blast transformation and proliferation are induced in these lymphocytes. At least two types of T cells, T helper and T cytotoxic
Fig. 1A-C. Histopathology of rat kidney allograft rejection. A General v i e w o f glomerular (arrow) and vascular changes (double arrow); note also increased interstitial inflammation and fibrosis. B Enhanced glomerular sclerosis: increased mesangial matrix and thickening of the capillary basement membrane. C Severe intimal thickening in a medium-sized artery
782
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Guest Lecture, "Gese[lsehaft f~r Nephre[ogie", 23rd Congress
Glinical Investigator © Springer-Verlag 1992
Towards understanding the pathophysiology of chronic rejection P. Hfiyry, A. Mennander, S. Yilmaz, J. Ustinov, A. R/iisfinen, A. Miettinen, I. Lautenschlager, K. Lemstr6m, C.A. Bruggeman, and T. Paavonen Transplantation Laboratory, University of Helsinki
Summary. Chronic allograft rejection is the major reason why allografts are lost. While only 2%-3% of all allografts are lost during the first year to irreversible acute rejection, approximately 6%-7% are lost during each subsequent year to chronic rejection. The major manifestation of chronic rejection in all organs is persistent perivascular inflammation and allograft arteriosclerosis. Bearing this in mind, we have developed a model to investigate the pathophysiology of allograft arteriosclerosis using aortic transplantations between inbred rat strains. The results obtained thus far indicate that several different inflammatory cascades are operative within the vascular wall during allograft arteriosclerosis. The relative importance of these different cascades, and particularly the role of growth factors as final effectors, has not yet been defined. Attempts to suppress allograft arteriosclerosis under experimental conditions have already met with some success: under conditions where no immunosuppression is provided we have been able to delay the process by at least 3 months, though we have not been able to block it indefinitely. It may be expected, however, that once the inflammatory cascades leading to smooth muscle cell replication in the allograft media and their influx into the intima are better defined, more specific approaches to the inhibition of allograft arteriosclerosis will be developed.
Key words: Allograft arteriosclerosis - Chronic allograft rejection - Growth factors - Smooth muscle cell replication
Only 15 years ago most allografts were lost owing to acute rejection and/or complications linked with its treatment. Today, irreversible acute rejection is a rare phenomenon: both patient and graft survivAbbreviations." ATG=antilymphocyte globulin; CMV=cyto-
megalovirus; CyA=cyclosporine; LT=leukotriene; PCR= polymerase chain reaction; pfu = plaque-forming units; RCMV = rat cytomegalovirus; RIA = radioimmunoassay; TxB2 = thromboxane B2
al of renal, cardiac, and liver transplants are approaching 90% for the first year, and of the 200 transplants done annually in Helsinki, only two to six are lost to irreversible acute rejection. In contrast, the half-life of transplants, including renal transplants, has remained the same [21] or increased only slightly [17]. During the first 10 years after transplantation, approximately 6% of renal allografts are lost owing to chronic rejection every year (Opelz G, personal communication). Since there are approximately 1200 renal transplant recipients with functioning grafts in Finland, this indicates a loss of ca. 70 transplants to chronic rejection annually. The histopathology of chronic rejection differs remarkably from that of acute rejection. In renal allografts, the hallmarks of acute tubulointerstitial rejection are invasion of a transplant with mononuclear leukocytes carrying high levels of lymphoid activation, and invasion of tubuli, so-called tubulitis. The type of rejection is easily reversible. Another pattern, overlapping with the previous one, is so-called acute vascular rejection, i.e., invasion of the graft vascular wall with inflammatory leukocytes. This pattern is more difficult to treat, and most lost transplants belong to this category. The end-point of acute rejection is irreversible damage to the microvascular endothelium, thrombosis, and necrosis of the graft. In chronic rejection, the most prominent feature in a renal allograft is persistent perivascular inflammation, often with relatively low level lymphoid cell activation, arterial intimal thickening, proliferative and sclerotic changes in the glomeruli, interstitial fibrosis, and tubular atrophy. These remarkable differences in histopathology indicate that the basic underlying mechanisms in acute and chronic rejection are essentially different. Demetris et al. [8] have compared the manifestations of chronic rejection in different organs. Their results and those of other investigators [7, 16, 19] are summarized in Table 1. Excluding the organ-specific changes referred to above, the common manifestations in all these transplants are per-
781 Table 1. Manifestations of chronic rejection in different organs
Heart a
Kidney b
Inflammation Inflammation Arteriosclerosis Arteriosclerosis Fibrosis
Liverc Inflammation Arteriosclerosis
BM thickening Vanishing bile ducts and Glomerular sclerosis portal arteries Tubular atrophy Fibrosis Fibrosis
BM, Basement membrane a Rose and Uys [19] b Croker and Salomon [7] c Oguma et al. [16]
ized. It affects all intramural arteries to the level of arterioles. Demetris et al. [8] have described the fine microscopic features of allograft arteriosclerosis in heart, kidney, and liver transplants. With minor variations, the most common features are, in addition to the perivascular inflammation, thinning of the vascular media, focal breaks in the internal elastic lamina, and concentric, generalized intimal thickening, where smooth muscle cells in the intima are intermingled with some inflammatory T cells and macrophages, often characterized as foam cells (Fig. 1).
Working hypothesis sistent perivascular inflammation and arteriosclerotic changes. These findings suggest that the basic underlying cause of chronic rejection in all transplants is allograft arteriosclerosis. When investigating the pathophysiology of chronic rejection, one should concentrate on the question of how persistent perivascular immune inflammation regulates smooth muscle cell replication in the media and the migration of these cells into the intima.
Allograft arteriosclerosis In contrast to ordinary atherosclerosis, which is usually focal and excentric, the common form of allograft arteriosclerosis is concentric and general-
A possible sequence of events leading to smooth muscle cell replication in the vascular walls in transplants undergoing chronic rejection is shown in Fig. 2. As such changes are not observed in syngeneic experimental transplants, it is assumed that the driving force behind allograft arteriosclerosis is histoincompatibility. In acute rejection, continuous recirculation of immunocompetent T lymphocytes carrying receptors to donor MHC antigens interact with the antigen-presenting cells (APC) and are induced to display receptors to interleukin 2 (IL2) and produce IL2. As a consequence, blast transformation and proliferation are induced in these lymphocytes. At least two types of T cells, T helper and T cytotoxic
Fig. 1A-C. Histopathology of rat kidney allograft rejection. A General v i e w o f glomerular (arrow) and vascular changes (double arrow); note also increased interstitial inflammation and fibrosis. B Enhanced glomerular sclerosis: increased mesangial matrix and thickening of the capillary basement membrane. C Severe intimal thickening in a medium-sized artery
782
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