Chronic Allograft Research Articles

Acute and chronic hepatic allograft rejection: pathology and classification.

Hepatic allograft rejection has been divided into humoral (or hyperacute), acute (or cellular), and chronic (or ductopenic) forms. Humoral rejection is extremely uncommon in the liver and is not graded. Acute rejection will occur in approximately 50% of liver allografts, is more common in the first few weeks posttransplantation, and is defined by Snover's triad of portal hepatitis, endothelialitis (or endotheliitis), and lymphocytic cholangitis. This form of rejection is generally reversible, either spontaneously or with additional immunosuppressive therapy, and can be reliably graded using a system with categories of mild, moderate, and severe rejection, associated with 37%, 48%, and 75% unfavorable shortterm and 1%, 12%, and 14% unfavorable long-term outcomes, respectively. Chronic rejection is characterized histologically by progressive duct loss and a lipid-rich vasculopathy that can be difficult to diagnose in early phases. Chronic rejection typically occurs several months to a year posttransplantation, although exceptions exist.

Immunology of acute and chronic hepatic allograft rejection.

Immunology of acute and chronic hepatic allograft rejection.

In vivo migration of lymphocytes in chronically rejecting rat kidney allografts.

Histological analyses have identified lymphocytes and macrophages as the predominant leukocyte populations that infiltrate organs undergoing chronic rejection. In order to define the time frame of this infiltration, we investigated the in vivo migration pattern of lymphocytes in a well-established rat model of chronic kidney allograft rejection. F344 kidneys were orthotopically transplanted into bilaterally nephrectomized Lewis rats. Recipients were treated with cyclosporin A (1.5 mg/kg/per day) for the first 10 days. After anti-CD18 or vehicle pretreatment, peripheral blood lymphocytes obtained from naive Lewis rats and labeled with 3H-uridine were injected into transplanted rats 12 and 16 weeks after transplantation. Organs were harvested 4, 8, and 12 h thereafter. After 12 weeks, proteinuria developed, accompanied by all signs of chronic rejection including glomerular sclerosis. Labeled lymphocytes rapidly infiltrated grafted kidneys 4 h after injection. Even more lymphocytes had accumulated in the grafts 12 h after injection. After 16 weeks, few lymphocytes had emigrated into the graft at 4 h, while infiltration was most pronounced by 12 h. Pretreatment with anti-CD18 inhibited the influx of lymphocytes. There was no difference between the patterns of lymphocytes derived from naive and transplanted rats. Our results emphasize the importance of endothelial cells in chronically rejecting kidneys for the control of leukocyte influx. Beta2-integrins may play a central role in determining the transendothelial migration during this process.

Development of injury in a rat model of chronic renal allograft rejection: effect of dietary protein restriction

Non-allogeneic factors such as increased nephron "workload" may contribute to chronic renal allograft rejection. Reducing dietary protein from 20% to 8% was tested in a model of chronic rejection: Dark Agouti kidney to Albino Surgery recipient, "tolerised" by previous donor blood transfusions. Survival, weight gain, serum creatinine concentration and creatinine clearance were similar for both groups at all times. Urinary protein was significantly (P < 0.05) lower in the low-protein (LP) group 1 month after transplantation. After 3 and 6 months, both groups demonstrated mild chronic rejection. After 6 months, tubular atrophy was significantly (P < 0.05) less in the LP group and interstitial fibrosis was marginally reduced. Glomerular hypertrophy, glomerular sclerosis, tubular dilatation, leucocyte infiltration, adhesion molecule expression and TGF-beta1 mRNA expression were similarly increased in both groups. Thus, reducing dietary protein to 8% lowered urinary protein, but did not significantly affect the development of chronic rejection in renal allografts beyond affording a degree of protection from tubulointerstitial damage.

The detection of chronic heart graft rejection by 31P NMR spectroscopy.

The usefulness of phosphorus-31 nuclear magnetic resonance spectroscopy (31P NMRS) for detecting heart graft rejection after transplantation has been investigated by several researchers, and it has thus been demonstrated to be a valid technique for detecting acute myocardial rejection. In this study, we investigated the value of 31P NMRS to assess chronic cardiac allograft rejection. Lewis rat hearts were transplanted into the femoral region of F-344 rat recipients which were treated with cyclosporine, 5mg/kg body weight, by a daily intramuscular injection for 30 days beginning on the day of transplantation. The control isografts employed Lewis donors and recipients not given cyclosporine. The ratios of phosphocreatine (PCr) to inorganic phosphate (Pi), beta-adenosine triphosphate (beta-ATP) to Pi, and PCr to beta-ATP were monitored using surface coil 31P NMRS. 31P NMRS was performed 3, 30, and 60 days after transplantation, and the degree of the rejection and arteriosclerosis of the coronary arteries were then assessed histologically. The PCr:Pi and beta-ATP:Pi ratios for the allografts demonstrated a significant decrease on postoperative day (POD) 60 from that on POD 30 (PCr:Pi, P < 0.001; beta-ATP:Pi, P < 0.01). Although a significant difference existed between the isografts and allografts on POD 60 (PCr: Pi, P < 0.01; beta-ATP:P, P < 0.01), no significant difference was found in the PCr:beta-ATP ratio between the allografts and the isografts. On POD 60, the allografts showed significant graft rejection and arteriosclerotic changes in the coronary arteries. These findings therefore demonstrated the effectiveness of 31P NMRS for detecting chronic graft rejection in a rat model.

Evidence Against the Role of Th1 in the Development of Chronic Cardiac Allograft Rejection

Evidence Against the Role of Th1 in the Development of Chronic Cardiac Allograft Rejection

Adenosine decreases post-ischaemic cardiac TNF-alpha production: anti-inflammatory implications for preconditioning and transplantation.

Tumour necrosis factor-alpha (TNF-alpha) is an autocrine contributor to myocardial dysfunction and cardiomyocyte death in ischaemia-reperfusion injury (I/R), sepsis, chronic heart failure and cardiac allograft rejection. Cardiac resident macrophages, infiltrating leucocytes, and cardiomyocytes themselves produce TNF-alpha. Although adenosine reduces macrophage TNF-alpha production and protects myocardium against I/R, it remains unknown whether I/R induces an increase in cardiac TNF-alpha in a crystalloid-perfused model (in the absence of blood), and, whether adenosine decreases cardiac TNF-alpha and protects function after I/R. To study this, isolated rat hearts were crystalloid-perfused using the Langendorff method and subjected to I/R, with or without adenosine pretreatment. Post-ischaemic cardiac TNF-alpha (enzyme-linked immunosorbent assay and bioassay) and function were determined (Langendorff). I/R increased cardiac TNF-alpha and impaired myocardial function. Adenosine decreased cardiac TNF-alpha and improved post-ischaemic functional recovery. This study demonstrates that: first, I/R induces an increase in cardiac tissue TNF-alpha in a crystalloid-perfused model: second, adenosine decreases cardiac TNF-alpha and improves post-ischaemic myocardial function; third, decreased cardiac TNF-alpha may represent a mechanism by which adenosine protects myocardium; and fourth, adenosine-induced suppression of cardiac TNF-alpha may provide an anti-inflammatory link to preconditioning and have implications for cardiac allograft preservation.

1.P.125 Increased lipoproteins and fibrinogen in chronic renal allograft rejection

1.P.125 Increased lipoproteins and fibrinogen in chronic renal allograft rejection

Immunolocalization of acidic fibroblast growth factor and receptors in the tubulointerstitial compartment of chronically rejected human renal allografts.

Tubular damage and loss associated with interstitial inflammation and fibrosis may be the most important determinants in chronic renal allograft rejection. To elucidate potential pathophysiologic mechanisms associated with tubulointerstitial lesions, we examined the expression of a fibrogenic cytokine, acidic fibroblast growth factor (FGF-1) and its high-affinity receptors, in both relevant renal transplant controls (n=5) and tissue from patients (n=19) who underwent nephrectomy after graft loss, secondary to chronic rejection. In situ hybridization and immunohistochemical analyses demonstrated minimal expression of FGF-1 mRNA and protein in the tubulointerstitial compartment of the normal human kidney. In contrast, tubulointerstitial lesions in kidney allografts experiencing chronic rejection demonstrated the exaggerated appearance of both FGF-1 protein and mRNA in resident inflammatory and tubular epithelial cells. Patterns of staining were consistent throughout tubular compartments and did not appear to be localized to any particular region. The tubulointerstitium in kidneys with findings of chronic rejection also exhibited increased immunodetection of proliferating cell nuclear antigen in the tubular epithelium, inflammatory cell infiltrate, and neovascular structures. The enhanced appearance of FGF-1 and readily detectable fibroblast growth factor receptors suggests that this polypeptide mitogen may serve as an important mediator of growth and repair responses, associated with development of angiogenesis and tubulointerstitial lesions during chronic rejection of human renal allografts.

Die klinische Bedeutung des Nierenzellkarzinoms beim dialysepflichtigen Patienten im Vergleich zu Nieren- transplantatempfängern

The clinical relevance of de novo Renal Cell Cancer was compared in chronic hemodialysis patients and renal allograft recipients. Clinical course of these patients was followed for 15 years. 21 of 788 patients who underwent radical nephrectomy were suffering from renal insufficiency at the time of surgery. Evaluated data included clinical symptoms; tumor histology and clinical course. 19 patients received chronic hemodialysis treatment. 7 patients demonstrated stable function of the allograft. 92% of patients receiving hemodialysis treatment did not show metastasis and none died of renal cell carcinoma. On the contrary, 71% of patients who underwent renal transplantation showed advanced tumor disease or metastasis. 3 patients have died of RCC. Aggressive tumor growth of RCC requires close follow up in patients who received a renal allograft.

Is hepatitis C virus recurrence a risk factor for chronic liver allograft rejection?

Is hepatitis C virus recurrence a risk factor for chronic liver allograft rejection?

Low-density lipoprotein oxidation is increased in kidney transplant recipients.

Oxidative modification of low-density lipoproteins (LDL) plays an important role in the pathogenesis of atherosclerosis. In addition, there is evidence that chronic vascular allograft rejection may be mediated by oxidised LDL. Plasma lipoprotein concentrations and parameters of LDL oxidation were determined in 19 kidney transplant recipients and 19 healthy controls. Plasma triglycerides and total cholesterol was significantly higher in patients than in the controls. The mean LDL diameter was smaller in patients than in the controls (23.6 +/- 0.71 nm vs 27.78 +/- 1.16 nm, P < 0.002). Furthermore, the lag time of copper-induced in vitro LDL oxidation was shorter in patients than in the controls (101 +/- 23 min vs 148 +/- 81 min, P = 0.02). The titre and concentration of both IgG and IgM autoantibodies against malondialdehyde-modified LDL (MDA-LDL) were higher in the patients. We conclude that there is in vitro and in vivo evidence of increased LDL oxidation in renal transplant recipients. This might facilitate the progression of atherosclerosis and enhance the process of chronic vascular rejection.

Is hepatitis C virus recurrence a risk factor for chronic liver allograft rejection?

Several risk factors have been reported that may favour the development of chronic rejection. From October 1988 to December 1993, 97 liver transplants with survival of more than 3 months were included in the study. Fifty-two patients (54.1%) had chronic hepatitis C virus (HCV) infection before liver transplantation. Immunosuppression consisted of cyclosporine A and prednisone, whereas 14 patients received FK 506 and prednisone. Severe graft HCV reinfection was present in 32 patients (61.5%) after liver transplantation and chronic graft hepatitis C was found in 26 cases at the end of the study. Chronic rejection occurred in 8 of 97 allografts (8.25%); 5 presented chronic rejection and concomitant chronic graft hepatitis C. The incidence of chronic rejection in patients with HCV infection before liver transplantation (9.6%) did not differ when compared with the negative HCV patients (6.6%). However, when the 26 cases that developed graft dysfunction due to chronic hepatitis C after liver transplantation were considered, 5 presented chronic rejection, a significantly higher incidence than in the remaining patients (3 of 71) (Yates chi-square test: P < 0.05). In our experience, there appears to be a relationship between the development of chronic rejection and chronic hepatitis C in the graft after liver transplantation.

Intrathymic tolerance in the Lewis-to-F344 chronic cardiac allograft rejection model.

Successful induction of donor-specific unresponsiveness by intrathymic inoculation of alloantigen in several experimental acute rejection models has led us to hypothesize that similar immune manipulations can prevent chronic rejection and development of graft arteriosclerosis in the Lewis-to-F344 rat chronic cardiac allograft rejection model. Recipient F344 rats were treated with donor (Lewis) splenocytes by intrathymic injection (i.t.) alone (10 x 10(6) cells/lobe); with donor splenocytes i.t. plus a one-time dose of ALS (1 mg) by intraperitoneal injection (i.p.); or with ALS i.p. (1 mg) alone 2 and 6 weeks prior to heterotopic Lewis heart transplantation. Control F344 recipients received saline i.t. Allografts were monitored by daily palpation, and long-term surviving grafts were harvested on day 90 for histopathologic analysis. Control allografts had 28.6% long-term survival (> 90 days) with mean graft survival of 46.7 +/- 12.2 days. At day 90 the surviving control allografts were enlarged and fibrotic with barely palpable heartbeat (mean heartbeat grade 0.29 +/- 0.18), and histologically showed diffuse moderate mononuclear cell infiltrates and advanced graft arteriosclerosis (mean vessel score 3.57 +/- 0.10 and 89 +/- 1% vessels diseased). Recipient treatment with intrathymic donor splenocytes alone significantly prolonged graft survival (89% long-term survival; mean 83.8 +/- 6.2 days, P < 0.04), but did not significantly inhibit the development of graft arteriosclerosis (score 2.98 +/- 0.53 and 79 +/- 8% diseased, P = NS). By contrast, treatment with i.t. donor splenocytes plus ALS 2 weeks prior to transplantation prolonged graft survival (100% long-term; mean 90.0 +/- 0.0 days, P < 0.04), and markedly inhibited graft arteriosclerosis (score 0.80 +/- 0.14, P < 0.05; 27 +/- 4% diseased, P < 0.05). ALS alone given two weeks prior to transplantation also prolonged graft survival (100% long-term; mean 90.0 +/- 0.0 days, P < 0.04), and inhibited graft arteriosclerosis (score 0.89 +/- 0.31, P < 0.05; 25 +/- 7% diseased, P < 0.05). However, when ALS was given 6 weeks prior to heart transplantation the beneficial effect of ALS alone was abolished, suggesting that lymphocyte depletion may have been responsible for the observed effects when ALS was administered at 2 weeks. Interestingly, intrathymic donor splenocytes plus ALS 6 weeks prior to transplantation, on the other hand, showed significant prolongation of allograft survival (100% long-term, mean 90.0 +/- 0.0 days, P < 0.04), and inhibited graft arteriosclerosis (score 0.41 +/- 0.02, P < 0.05; 16 +/- 2% diseased, P < 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)

Functional Impairment Of Enteric Smooth Muscle And Nerves Caused By Chronic Intestinal Allograft Rejection Regresses After Fk506 Rescue

Functional Impairment Of Enteric Smooth Muscle And Nerves Caused By Chronic Intestinal Allograft Rejection Regresses After Fk506 Rescue

Physiological and structural responses to chronic experimental renal allograft injury

Chronic rejection necessitates a return to dialysis or retransplantation for a significant number of patients with renal allografts. Although alloresponses between donor organ and recipient importantly determine this process, the detailed immunologic processes and organ physiology of chronic rejection are unclear; in consequence its mechanism and therapy are uncertain. A model of chronic rejection in the rat was used to examine several facets of this process. Fisher-to-Lewis (F-L), allogeneic, and Lewis-to-Lewis (L-L), syngeneic, renal transplants were performed in nephrectomized recipients. All rats were treated with cyclosporin A (5 mg.kg-1.day-1) for 10 days from the time of grafting. At 6 wk, allogeneically grafted animals had a higher protein excretion rate (F-L, 47 +/- 30 mg/day; L-L, 17 +/- 6 mg/day; P < 0.05) and an increase in glomerular capillary pressure (F-L, 69 +/- 5 mmHg; L-L, 58 +/- 8 mmHg; P < 0.05) and fractional cortical interstitial volume (F-L, 29.8 +/- 4.3%; L-L, 19.5 +/- 4.0%; P < 0.01). This model of chronic rejection is characterized by glomerular capillary hypertension, proteinuria, and cortical interstitial expansion. Because these findings are also present in other models of chronic renal injury, mechanisms in addition to alloresponses may operate in chronic rejection.

Arterial endothelialitis in chronic renal allograft rejection: a histopathological and immunocytochemical study

Transplantation is the preferred method of renal replacement therapy in end-stage renal failure. Short- and medium-term graft survival is good but, in the longer term, grafts are lost due to vascular obliteration, i.e. chronic vascular rejection. The pathogenesis of these changes is unclear. We carried out a histopathological and immunocytochemical study of 31 vessels from 20 graft nephrectomies. Four patterns of arterial pathology were identified: (1) subendothelial inflammation ('endothelialitis') with little intimal thickening; (2) 'Endothelialitis' with thickening; (3) Intimal thickening without 'endothelialitis'; and (4) Intimal thickening with calcification and cholesterol clefts ('natural atherosclerosis'). We suggest that the lesions of chronic vascular rejection evolve, at varying rates, from an early 'endothelialitis' to a later stage with pronounced intimal thickening but no subendothelial inflammation. These changes probably reflect a delayed type hypersensitivity response involving activated macrophages and T lymphocytes and smooth muscle cell proliferation.

The role of ultraviolet B-irradiated leukocyte transfusions and cyclosporine in intestinal transplantation.

To explore the efficacy of ultraviolet B-irradiated donor-specific leukocyte transfusions (UV-DSLT) with short-term cyclosporine to control intestinal allograft rejection, 75 adult Lewis (RT1l) rats underwent total small-intestinal transplantation from Brown-Norway (RT1n) donors. Recipients were randomly divided into ten treatment and control groups utilizing various combinations of donor-specific and third-party (Wistar-Furth, RT1u) leukocyte transfusions (TPLT), with or without transfusion UVB irradiation, and either alone or in combination with short-term cyclosporine administration (5 mg/kg intramuscularly on days -7, 0, 1, and 2 relative to transplantation). Leukocytes (10(8) cells) separated from a spleen cell suspension were infused on day -7. Certain transfused leukocytes were treated with 12,000 joules/m2 of UVB irradiation. Groups were monitored for mean survival time (MST) and cause of death. UV-DSLT alone (MST = 19.8 +/- 4.6) or in combination with cyclosporine (UV-DSLT+CsA, MST = 53.1 +/- 22.5) significantly (P less than 0.003-0.0002, Mantel-Cox) prolonged recipient survival when compared with appropriate controls (i.e., no treatment, MST = 11.2 +/- 3.4; CsA, MST = 17.2 +/- 9.0; UV-TPLT, MST = 12.4 +/- 4.0; and UV-TPLT+CsA, MST = 25.1 +/- 9.7) No significant increase in graft-versus-host disease occurred in any group, with 85% (64/75) of the recipients dying of acute rejection. Conversely, the UV-DSLT+CsA group had a significant increase (9/11; chi-square, P less than 0.0001) in chronic rejection. Because UV-DSLT+CsA improved survival as compared with third-party controls, a limited donor-specific unresponsiveness may have been induced. Furthermore, this treatment produces a consistent, chronic rejection rodent intestinal allograft model.

Plasma Renin Activity in Renal Transplant Patients With Hypertension

Chronic renal allograft rejection (CR) is the major cause of graft loss after 1 year following transplantation. Hypertension (HTN) and proteinuria (Up) are the hallmarks of this immunologic allograft response. Over 1 year, 23 patients posttransplantation and with HTN (diastolic greater than 95 mm Hg) were examined. Serial serum creatinine (Scr), Up, urine creatinine (Ucr), and resting and enalapril challenged (EC) plasma renin activity (PRA) were all determined. Renal artery stenosis was excluded by noninvasive imaging. Of the 23 patients, eight eventually lost their renal allografts, while 15 maintained satisfactory renal function (Scr less than 2.5). Results of this study show that: 1) worsening renal function (RF) increases EC reactivity; 2) the presence of proteinuria is not itself related to increase in EC activity; 3) renin before and after EC was higher (P = .06) in the allograft loss group. In this study, patients with high PRA represent the highest EC responses. Therefore, they display not macrovascular lesions, but microvascular intrarenal disease; this defect is most likely secondary to chronic immunologic insult.

Immunological aspects of clinical liver transplantation

With the improved survival achieved in the 1980s it has become apparent that graft rejection is a major problem following liver transplantation [1]. Hyperacute rejection is uncommon, although syndromes of fulminant graft failure due to immunological mechanisms have been described. Acute cellular rejection occurs in approximately 70% of patients and usually responds to high-dose steroids. Between 10 and 15% develop chronic rejection, characterised by a progressive destruction of intrahepatic bile ducts which is irreversible [2]. The principal targets of both acute and chronic liver allograft rejection are intrahepatic bile ducts and endothelium [2]. The increased ability of these cell types to express MHC antigens and adhesion molecules may be responsible for their involvement [2, 3] and may be enhanced by the release of proinflammatory cytokines associated with viral infection, particularly CMV [3]. Although the importance of HLA matching remains unknown patients transplanted with ABO incompatible livers have a higher incidence of graft rejection [4]. Lymphocytes probably instigate rejection but liver damage may result from the recruitment of several effector mechanisms involving the activation of neutrophils, macrophages and B cells as well as cytotoxic T cells [5]. Clinical studies are required to determine the optimum immunosuppressive management of liver transplants and in particular to assess the role of new immunosuppressive agents such as monoclonal antibodies and FK506.